Pulmonary Embolism Case Study Diagnosis and Treatment

Pulmonary Embolism Case Study: Diagnosis and Treatment

by John Landry, BS, RRT | Updated: Feb 2, 2024

A pulmonary embolism is a blockage in the pulmonary artery caused by a blood clot in the lungs. This is a life-threatening condition and results in symptoms that respiratory therapists and medical professionals must be able to identify.

This case study will explore the events leading up to a patient being diagnosed with a pulmonary embolism, as well as the treatment and management of this condition.

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Pulmonary Embolism Clinical Scenario

You are called to the emergency room to treat a 25-year-old, 67 kg female patient. She is experiencing new onset chest pain and shortness of breath. She describes her chest pain as a stabbing sensation that radiates down to her left arm and gets worse during periods of exertion. She also feels lightheaded and highly anxious. In addition, the patient has a history of allergic asthma. Her only home medications are Microgestin Fe 1/20 (i.e., birth control) and albuterol PRN. She has no history of smoking or vaping.

Patient Assessment

  • The patient’s pupils are round and reactive.
  • She is mildly diaphoretic.
  • She is showing signs of nasal flaring without pursed-lip breathing.
  • Her trachea is located in the midline.
  • She has no jugular venous distention.
  • She has been coughing up small amounts of blood-tinged sputum.
  • She has bilateral, decreased chest rise.
  • Auscultation reveals crackles and a third heart sound.
  • Palpation reveals normal tactile fremitus.
  • Her percussion findings are normal at the apexes and decreased at the bases.
  • She has a normal anterior-posterior chest diameter.
  • Her chest is not tender to the touch.
  • Her abdomen is soft and not distended.

Extremities:

  • She shows no sign of digital clubbing.
  • Her capillary refill time is 4 seconds.
  • Her fingertips are slightly cyanotic and cool to the touch.
  • She shows no signs of pedal edema.
  • She has a moderately sized bruise on her right leg that is tender and warm to the touch.

Vital Signs:

  • Respiratory rate: 30 breaths/min
  • Heart rate: 120 beats/min
  • Blood pressure: 100/75 mmHg
  • Chest x-ray: Consolidation in both lung bases

Diagnosis and Treatment

Based on the patient’s assessment , history, and vital signs, what condition does the patient have, and why?

The patient is presenting with a pulmonary embolism (PE).

Key Components:

  • The use of oral contraceptives is important for the diagnosis because one common side effect is hyper-coagulation.
  • A bruise that is accompanied by tenderness and warmth in her leg is a sign of deep vein thrombosis (i.e., blood clot). This is important because blood clots can travel from the legs to the lungs, resulting in a pulmonary embolism.
  • Other important signs include hypoxemia (i.e., low SpO2), increased capillary refill, cyanosis, and coolness to the touch. This could be caused by decreased perfusion and/or atelectasis .
  • Diaphoresis and anxiety
  • The patient has decreased percussion and crackles in the lung bases, which indicates atelectasis. Atelectasis can occur in patients who experience pulmonary infarction due to a pulmonary embolism.
  • A third heart sound is sometimes heard in patients with a pulmonary embolism.
  • Another important finding is the patient’s chest x-ray, which only shows atelectasis. A pulmonary embolism will not show up on a chest x-ray, but sometimes a wedge-shaped inflate will appear if pulmonary infarction has occurred as a result.
Bonus Point: You should have been able to recognize that, while the patient had a history of allergic asthma, their current presentation did not align with that of an asthma exacerbation. Remember that additional information may be given to you in scenario-based testing. When this happens, take note of the information in case it becomes important later on, but don’t let it distract you from the task at hand.

What tests can confirm the presence of a pulmonary embolism?

  • Computed tomography pulmonary angiogram (CTPA): This is the preferred test for confirming a pulmonary embolism. The presence of a blood clot will show as a darkened area.
  • V/Q scan: This is the second most preferred radiological test for a suspected pulmonary embolism. It will show a disturbance in gas distribution in the patient’s lungs when a thrombus is present.
  • Pulmonary angiogram: This is the least preferred test because it is the most invasive. It involves the insertion of a catheter while dye is injected into the pulmonary artery, which will reveal the presence of an embolism.

You may also wish to recommend specific blood tests, such as D-dimer and platelet count. These will give you clues about the patient’s clotting status. D-dimer is most often used to look for the presence of a blood clot, as it will be increased if a clot is present.

It is important to remember that other factors can cause a patient’s d-dimer and clotting factors to increase; therefore, you should not rely on this test solely to confirm that a pulmonary embolism is present.

Additional Treatment

Let’s assume that you initiated the patient on oxygen therapy via nasal cannula at 2 L/min to try and correct their hypoxemia. After 20 minutes, you decided to incrementally increase the flow to 5 L/min, but there was no improvement in their oxygenation status.

Why is the patient’s SpO2 and PaO2 unresponsive to receiving supplemental oxygen?

This occurs because blood clots reduce or entirely prevent blood from flowing past a clot. Therefore, any alveoli distal to the clot will receive little to no perfusion. This decrease in perfusion prevents carbon dioxide and oxygen from effectively being exchanged at the alveolar-capillary membrane, even when the patient is ventilating normally.

This prevention of effective gas exchange due to low perfusion is part of what causes patients with a pulmonary embolism to be unresponsive to supplemental oxygen. The development of atelectasis due to pulmonary infarction secondary to a pulmonary embolism can further reduce the patient’s responsiveness to oxygen.

What other treatment methods would you recommend?

  • Anticoagulants: The administration of a fast-acting anticoagulant, like heparin, and a slow-acting anticoagulant, like Warfarin should be recommended. This can help stop the existing clot from growing and to prevent new clots from forming. Patients who are prescribed Warfarin will need to have their other medications, dietary supplements, and nutrition plan reviewed. That is because medications, supplements, or food can impact the blood’s ability to clot while potentially negatively impacting the drug.
  • Thrombolytic agents: The administration of thrombolytic drugs, such as altepase, streptokinase, or urokinase, can help break down the embolism. Patients who are prescribed a thrombolytic should be monitored for an increased risk of bleeding. This is especially true when prescribed heparin alongside a thrombolytic agent.
  • Analgesics: These drugs can be administered for any pain the patient may be experiencing.
  • Preventative actions: Ensuring the patient stays active, moves their limbs, is well-hydrated, and wears compression socks can help prevent another clot from forming.
  • Pneumatic compression cuffs: These should be placed on the patient’s legs while they’re bedridden to decrease the risk of more blood clots forming.
  • Surgical interventions: A pulmonary embolectomy can be performed to remove an existing clot that is not dissolved by medications. The placement of an inferior vena cava filter can also be used to prevent future clots from reaching the patient’s lungs. These filters are usually reserved for patients who are at high risk for developing further embolisms despite receiving pharmaceutical interventions.

Final Thoughts

A pulmonary embolism is a serious medical condition that can be difficult to diagnose. Respiratory therapists must be aware of the risk factors and symptoms to properly assess and treat their patients. A few key things to remember about patients with a pulmonary embolism include:

  • They often present with radiating chest pain.
  • They need radiological testing that is more extensive than a simple chest x-ray.
  • They are often unresponsive to supplemental oxygen.

Treatment for a pulmonary embolism should be aimed at dissolving existing clots while preventing future clots from forming. Thanks for reading, and, as always, breathe easy, my friend.

John Landry, BS, RRT

Written by:

John Landry is a registered respiratory therapist from Memphis, TN, and has a bachelor's degree in kinesiology. He enjoys using evidence-based research to help others breathe easier and live a healthier life.

  • Egan’s Fundamentals of Respiratory Care. 12th ed., Mosby, 2020.
  • Wilkins’ Clinical Assessment in Respiratory Care. 8th ed., Mosby, 2017.
  • Clinical Manifestations and Assessment of Respiratory Disease. 8th ed., Mosby, 2019.
  • Tarbox, Abigail K., and Mamta Swaroop. “Pulmonary Embolism.” National Library of Medicine, Int J Crit Illn Inj Sci, Jan. 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3665123 .
  • Turetz, Meredith, et al. “Epidemiology, Pathophysiology, and Natural History of Pulmonary Embolism.” National Library of Medicine, Semin Intervent Radiol, Jan. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5986574 .
  • Morrone, Doralisa, and Vincenzo Morrone. “Acute Pulmonary Embolism: Focus on the Clinical Picture.” National Library of Medicine, Korean Circ J., May 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5940642 .
  • Lavorini, Federico, et al. “Diagnosis and Treatment of Pulmonary Embolism: A Multidisciplinary Approach.” National Library of Medicine, Multidiscip Respir Med, 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3878229 .

Recommended Reading

Pulmonary embolism: overview and practice questions, copd: overview and practice questions, pulmonary edema: overview and practice questions, pleural effusion: overview and practice questions, myocardial infarction: overview and practice questions, the 50+ diseases to learn for the clinical sims exam (cse).

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Pulmonary Embolism: Clinical Case

The following are key points to remember about this clinical case on pulmonary embolism (PE):

  • Although approximately 20% of patients who are treated for PE die within 90 days, true short-term mortality attributed to PE is estimated to be <5%. Approximately 50% of the patients who receive a diagnosis of PE have functional and exercise limitations 1 year later (known as post–PE syndrome), and the health-related quality of life for patients with a history of PE is diminished as compared with that of matched controls.
  • Newer approaches such as YEARS algorithm and age adjustment for D-dimer thresholds for ruling out PE are recommended.
  • Diagnostic chest imaging is reserved for patients in whom PE cannot be ruled out based on clinical decision making.
  • After initial diagnosis, clinical risk stratification into high, intermediate high risk, intermediate low risk, and low risk is recommended next. The nomenclature of “massive” and “submassive” in describing PE is confusing, given that clot size does not dictate therapy.
  • High risk: Intravenous systemic thrombolysis is the most readily available reperfusion option in high-risk PE patients. Alternative reperfusion approaches include surgical thrombectomy and catheter-directed thrombolysis (with or without thrombectomy). Additional supportive measures include the administration of inotropes and the use of extracorporeal life support.
  • Intermediate high risk: When available, catheter-directed thrombus removal remains an option for such. At this time, there is insufficient evidence to support catheter-directed thrombolysis over anticoagulation alone in these patients. Systemic thrombolysis is not typically recommended for these patients.
  • Intermediate low risk: Anticoagulation with low molecular weight heparin and close monitoring for 24-48 hours for clinical worsening is recommended.
  • Low risk: Outpatient management with direct oral anticoagulants is the preferred strategy.
  • All patients with acute PE should receive anticoagulant therapy for ≥3 months. The decision to continue treatment indefinitely depends on whether the associated reduction in the risk of recurrent venous thromboembolism outweighs the increased risk of bleeding and should take into account patient preferences.
  • Patients should be followed longitudinally after an acute PE to assess for dyspnea or functional limitation, which may indicate the development of post–PE syndrome or chronic thromboembolic pulmonary hypertension.

Clinical Topics: Anticoagulation Management, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Interventions and Imaging, Interventions and Vascular Medicine

Keywords: Anticoagulants, Diagnostic Imaging, Dyspnea, Extracorporeal Membrane Oxygenation, Heparin, Low-Molecular-Weight, Outpatients, Pulmonary Embolism, Quality of Life, Reperfusion, Risk Assessment, Secondary Prevention, Thrombectomy, Thrombolytic Therapy, Thrombosis, Vascular Diseases, Venous Thromboembolism

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  • Deep vein thrombosis with pulmonary thromboembolism in a case of severe COVID-19 pneumonia
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  • Sujata Devi 1 ,
  • Sudipta Mohakud 2 ,
  • Nilanjan Kar 1 and
  • Divya Muthuvel 2
  • 1 General Medicine , All India Institute of Medical Sciences Bhubaneswar , Bhubaneswar , India
  • 2 Radiodiagnosis , All India Institute of Medical Sciences Bhubaneswar , Bhubaneswar , India
  • Correspondence to Dr Sudipta Mohakud; radiol_sudipta{at}aiimsbhubaneswar.edu.in

A 53-year-old man with diabetes came to the emergency department with fever and dry cough for 5 days, swelling of the left leg for 2 days, shortness of breath and chest pain for 1 hour. He had raised temperature, tachycardia, tachypnoea, reduced oxygen saturation and swollen tender left leg on examination. The frontal chest radiograph showed bilateral ground-glass opacities; he tested positive for COVID-19 with elevated D-dimer. The colour Doppler examination of the left leg revealed acute deep vein thrombosis (DVT) of the common femoral and the popliteal veins. The chest CT showed bilateral diffuse ground-glass opacities predominantly involving peripheral zones and the lower lobes. The CTPA revealed left pulmonary thromboembolism (PTE), treated with low-molecular-weight heparin. COVID-19 predominantly affects the respiratory system. DVT and PTE are common in COVID-19 but lethal. They should be diagnosed early by clinical and radiological examinations and treated promptly with anticoagulants.

  • venous thromboembolism
  • radiology (diagnostics)

This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://doi.org/10.1136/bcr-2020-240932

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The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), was declared a pandemic by the WHO on March 11, 2020. 1 2 Although it primarily affects the respiratory system, there are abundant reports on thrombotic complications. In patients with COVID-19, diagnosis of deep vein thrombosis (DVT) and pulmonary embolism may be challenging because of overlapping of symptoms. 3 We report a case of COVID-19 associated with pulmonary embolism and DVT in a 53-year-old man.

Case presentation

A 53-year-old man who was a known case of type 2 diabetes mellitus, presented to the emergency department with a history of fever and dry cough for 5 days, swelling of the left leg for 2 days, and shortness of breath and chest pain for 1 hour. On examination, his pulse rate was 138 beats/min, with blood pressure of 138/70 mm Hg, respiratory rate of 30 breaths/min, and oxygen saturation was 64% on room air with a temperature of 98.6℉. His left leg was swollen, and tenderness was present over the calf region ( figure 1 ). A difference of 5 cm was observed between the left and right calf diameters. On auscultation, bilateral basal crepitation was found. The abdominal, neurological and cardiovascular systems were within normal limits.

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Left lower limb of a COVID-19-positive patient with deep vein thrombosis appears swollen and inflamed.

Investigations

Laboratory tests showed haemoglobin of 1.41 g/L, total leucocyte count of 10×10 9 cells/L (with neutrophils of 81% and lymphocyte of 13%), total platelet count of 234× 10 9 cells/L, random blood sugar level of 481 mg/dL, elevated D-dimer of 35.2 µg/L, lactate dehydrogenase of 724 U/L, with normal liver and kidney functions test. The nasal swab for COVID-19 real-time PCR test was positive. A Chest X-ray revealed GGOs on bilateral lung fields attributed to COVID-19 disease ( figure 2 ).

Frontal chest radiograph of a COVID-19-positive patient showing bilateral peripheral ground-glass opacities predominantly affecting the lower lobes.

Colour Doppler study of the left lower limb showed distended, non-compressible common femoral, superficial femoral and popliteal veins, which did not show colour filling or spectral waveform. No flow was seen even in the augmentation test by distal compression. These grey-scale and colour Doppler features were suggestive of acute deep venous thrombosis. CT pulmonary angiography (CTPA) was done to rule out pulmonary thromboembolism (PTE) as the patient has DVT with sudden-onset breathlessness, raised D-dimer and positive PCR test for COVID-19, which itself is now thought to incite inflammation and thrombosis. The CTPA showed a non-enhancing hypodense filling defect in the left main pulmonary artery extending into left lingular and superior basal segmental arteries suggestive of acute PTE ( figure 3A,B ). The CT sections of the lower limb in the venous phase also revealed the DVT as a hypodense filling defect in the expanded common femoral, superficial femoral and popliteal veins ( figure 4A,B ). Diffuse GGO and interlobular septal thickening were noted, predominantly involving peripheral zones of bilateral lungs, more so in the lower lobes consistent with COVID-19 Reporting and Data System (CORADS) 6 ( figure 5 ). The scoring on CT was 12/25, almost affecting 48% of the lung parenchyma.

Axial (A) and coronal (B) pulmonary angiography images of a COVID-19-positive patient who developed deep vein thrombosis in the lower limb and presented with sudden onset breathlessness showing a hypodense filling defect (arrows) in the left inferior pulmonary artery suggestive of acute pulmonary thromboembolism.

Axial CT images of the venous phase of the lower limbs of a COVID-19-positive patient showing hypodense filling defect in the common femoral (A) and the popliteal (B) veins of the left lower limb indicating deep vein thrombosis. These veins appear distended.

Coronal lung window image of a COVID-19-positive patient showing patchy areas of peripherally distributed ground-glass opacities in bilateral lungs, more so in the lower lobes consistent with COVID-19 Reporting and Data System (CORADS) 6.

The patient was started on high flow oxygen at 12 L/min through a face mask. Oxygen saturation was maintained at 95%, and the respiratory rate decreased to 22 breaths/min. The patient started on injection of low-molecular-weight heparin 60 mg subcutaneous two times per day for DVT with pulmonary embolism. The patient started on injection of methylprednisolone 50 mg intravenous daily, injection of remdesvir 200 mg intravenous on the first day followed by 100 mg intravenous infusion for the next 4 days, injection of doxycycline 100 mg two times per day, ivermectin tablet 18 mg daily on an empty stomach for 3 days, along with zinc and vitamin C. Gradually, oxygen requirement decreased, and swelling of the leg decreased. The patient was discharged in good condition after 2 weeks of admission to this hospital with warfarin 5 mg/day.

Outcome and follow-up

The limb pain had subsided with reduced swelling at follow-up after 1 month. The patient complained of mild swelling on prolonged standing and was advised to use compression stockings and limb elevation. Follow-up colour Doppler imaging showed recanalisation of the thrombosed vessels with wall thickening.

Coronaviruses are a group of enveloped RNA viruses responsible for upper respiratory tract diseases, out of which SARS-CoV-2 is known to cause severe and fatal disease in humans. 1 4 Patients affected by COVID-19 mostly present with fever, dry cough, malaise and shortness of breath. 5 Patients with COVID-19 have a very high risk of developing DVT. 3 5 The common symptoms and signs of DVT are swelling, redness and tenderness of the lower limbs. In our patient, all the typical symptoms and signs of COVID-19 and DVT are present.

DVT and PTE in patients with COVID-19 occur mainly due to increased inflammatory response due to the release of proinflammatory cytokines combined with hypoxia, immobilisation and disseminated vascular coagulation. 5 Hypoxia acts as a prothrombotic condition by increasing blood viscosity and triggering a transcription factor-mediated thrombotic pathway. 6 This can also be due to the disruption of vascular endothelium caused by the viral infection itself. 7 The other risk factors for DVT development are severely ill patients in the intensive care unit, mechanical ventilation, infection, cancer, obesity, comorbidities, male sex and old age. 8 Elevation of D-dimer levels and fibrin degradation products seen in patients with COVID-19 are due to the breakdown of fibrin clots. 3 9

In the case of COVID-19 pneumonia, which is a prothrombotic condition, the presence of a swollen, painful limb should raise the suspicion of DVT. A progressive increase in breathlessness with falling oxygen saturation, especially with associated DVT and raised D-dimer level, should raise the suspicion of PTE. 4 Duplex ultrasound of the venous system of the affected limb confirms the diagnosis of DVT. CTPA can clearly demonstrate the pulmonary arterial thrombus even in the subsegmental arteries. 5

The use of prophylactic anticoagulation in hospitalised patients with COVID-19 decreases venous thromboembolism (VTE) and also decreases mortality. 3 A retrospective study by Lodigiani et al 4 reported a 21% incidence of VTE within 24 hours of admission, whereas Klok et al 5 reported a 31% VTE even after thromboprophylaxis. A study by Middeldorp et al 3 reported that incidence of VTE among hospitalised patients with COVID-19 undergoing thromboprophylaxis was 16%, 33% and 42% at days 7, 14 and 21, respectively. However, ambulation should be the mainstay of thromboprophylaxis in patients who do not require admission. 10 Unfractionated heparin and low-molecular-weight heparin can be used both prophylactically and therapeutically. 11 12

Patients with COVID-19 with documented VTE require a minimum of 3 months of anticoagulation. 13

SARS-CoV-2 is known to cause a more severe form of pneumonia in human beings causing severe morbidity and mortality. COVID-19 association with DVT and pulmonary embolism is common yet very critical and lethal and should be detected early by proper clinical examination, using colour Doppler venous ultrasound and CT pulmonary angiogram. The use of anticoagulants judiciously will prevent further complications.

Learning points

An increased inflammatory response occurs in COVID-19, leading to venous thrombosis.

2.The risk factors for deep vein thrombosis (DVT) in patients with COVID-19 are hypoxia, severely ill patients in the intensive care unit, mechanical ventilation, infection, cancer, obesity, comorbidities, male sex and old age.

In patients with COVID-19, diagnosis of DVT and pulmonary embolism may be challenging because of overlapping of symptoms.

DVT with pulmonary thromboembolism is a well-documented but critical association of COVID- 19 and can be detected early by proper clinical examination using duplex ultrasound of extremity venous system and CT pulmonary angiogram.

Low-molecular-weight heparin can be used both prophylactically and therapeutically for DVT.

  • Wang W , et al
  • World Health Organization
  • Middeldorp S ,
  • Coppens M ,
  • van Haaps TF , et al
  • Lodigiani C ,
  • Iapichino G ,
  • Carenzo L , et al
  • Kruip MJHA ,
  • van der Meer NJM , et al
  • Li D , et al
  • Atallah B ,
  • Mallah SI ,
  • AlMahmeed W
  • Savarimuthu S ,
  • Leung MST , et al
  • Giannis D ,
  • Ziogas IA ,
  • Quintili AL ,
  • Karamchandani K , et al
  • Thachil J ,
  • Gando S , et al
  • Belen-Apak FB ,
  • Sarialioglu F
  • Moores LK ,
  • Tritschler T ,
  • Brosnahan S , et al

Contributors SD: primary consultant of the patient, clinical history, follow-up, drafting of the manuscript and manuscript review; SM: radiological diagnosis, drafting of the manuscript and manuscript review; NK: clinical data collection and drafting of the manuscript; DM: collection of radiological data and manuscript editing.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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  • Case report
  • Open access
  • Published: 15 September 2009

Pulmonary embolism presenting as syncope: a case report

  • Ahmet Demircan 1 ,
  • Gulbin Aygencel 2 ,
  • Ayfer Keles 1 ,
  • Ozgur Ozsoylar 3 &
  • Fikret Bildik 1  

Journal of Medical Case Reports volume  3 , Article number:  7440 ( 2009 ) Cite this article

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Introduction

Despite the high incidence of pulmonary embolism its diagnosis continues to be difficult, primarily because of the vagaries of symptoms and signs in presentation. Conversely, syncope is a relatively easy clinical symptom to detect, but has varied etiologies that lead to a documented cause in only 58% of syncopal events. Syncope as the presenting symptom of pulmonary embolism has proven to be a difficult clinical correlation to make.

Case presentation

We present the case of a 26-year-old Caucasian man with pulmonary embolism induced-syncope and review the pathophysiology and diagnostic considerations.

Conclusions

Pulmonary embolism should be considered in the differential diagnosis of every syncopal event that presents at an emergency department.

Recognized venous thromboembolism (pulmonary embolism and deep venous thrombosis) is responsible for more than 250,000 hospitalizations and approximately 50,000 deaths per year in the United States. Because it is difficult to diagnose, the true incidence of pulmonary embolism is unknown, but it is estimated that approximately 650,000 cases occur annually [ 1 ].

Despite this high incidence, the diagnosis of pulmonary embolism continues to be difficult primarily because of the notorious vagaries of symptoms and signs in its presentation. Conversely, syncope is a relatively easy clinical symptom to detect, but has varied etiologies that lead to a documented cause in only 58% of syncopal events [ 2 ].

Syncope as the presenting symptom of pulmonary embolism has proven to be a difficult clinical correlation to make. We present the case of a patient with pulmonary embolism-induced syncope and review the pathophysiology and diagnostic considerations.

A 26-year-old Caucasian man with no history of disease was admitted to Gazi University Emergency Department after he had a syncopal episode in his home. The patient was in his usual good state of health until he suddenly collapsed while standing and lost consciousness for approximately five minutes. He recovered spontaneously but was extremely weak and dyspneic. He was also diaphoretic and tachypneic, but denied any associated chest pain or palpitations. No tonic-clonic activity was witnessed, and he experienced no incontinence.

The patient was a computer programmer and he had been working 18 hours a day without rest periods for a month. On admission, physical examination revealed a diaphoretic and dyspneic patient without focal neurologic findings. His heart rate was regular but tachycardic at 128 beats/minute, his blood pressure was 126/72 mmHg without orthostatic changes, and his respiratory rate was 32 breaths/minute. The room air oxygen saturation was 90%, and arterial blood gas analysis in room air revealed hypoxemia (PO 2 = 58 mmHg) with an elevated alveolo-arterial oxygen gradient (A-a O 2 gradient). Examination of his head and neck was normal. The results of chest wall examination revealed reduced breath sounds bilaterally at the lung bases. The findings of heart and abdominal examinations were unremarkable, but on examination of his legs, deep venous thrombosis (DVT) was noted in his left leg, with a positive Homans' sign in the left leg and the left calf measured 3 cm more than the right one.

Levels of serum electrolytes, glucose, blood urea and creatinine, and complete blood counts were normal. Results of a computed tomographic scan of his head were negative for bleeding, aneurysm or an embolic event. Chest X-ray was clear. An electrocardiogram showed a regular rhythm consistent with sinus tachycardia; there were Q and T waves in lead III and an S wave in lead I. A ventilation-perfusion scan demonstrated an unmatched segmental perfusion defect, indicating a high probability of the presence of a pulmonary thromboembolism (PTE) (Figures 1 and 2 ). A transthoracic echocardiogram revealed normal left ventricle function without a patent foramen ovale, an atrial septal defect or a ventricular septal defect, but with mild pulmonary hypertension (42 mmHg). A Doppler scan of the legs revealed an acute DVT in the patient's left leg, in the popliteal vein. Thrombolytic treatment was not given - the patient received standard anticoagulation treatment with unfractionated heparin and an oral anticoagulant. Before treatment, a blood sample was taken to examine the thrombophilia panel. After a 12-day course of hospital treatment, he was discharged on oral warfarin therapy. The patient's long-term follow-up was performed by the Department of Pulmonary Disease, and we learned that the patient was well for four months after that episode without any evidence of recurrent syncope or pulmonary embolism.

figure 1

Decreased perfusion is seen to the right lung (particularly evident in the right lower lobe on the RPO image) in our case (perfusion scan was performed with Tc-99m MAA) .

figure 2

There is no significant ventilation defect in our case (ventilation scan was performed with Xe-133 gas) .

Pulmonary embolism is a frequent cause of death in the United States. Nevertheless, it remains difficult to diagnose. Pulmonary emboli differ considerably in size and number, and the underlying disorders, including malignancy, trauma, and protein C or S deficiency, are numerous [ 1 ]. The classic triad of pleuritic chest pain, dyspnea, and hemoptysis is rare, and clinically apparent DVT is present in only 11% of confirmed cases of pulmonary embolism in patients without underlying cardiopulmonary disease [ 3 ].

However, the clinical picture of pulmonary embolism is variable and most patients suffering from acute pulmonary embolism present with one of three different clinical syndromes. These clinical syndromes are pulmonary infarction, acute unexplained dyspnea, and acute cor pulmonale. The pulmonary infarct syndrome usually occurs with a submassive embolism that completely occludes a distal branch of the pulmonary circulation. Patients with this condition have pleuritic chest pain, hemoptysis, rales, and abnormal findings on chest X-ray. The acute, unexplained dyspnea pattern may also be the result of submassive pulmonary embolism without pulmonary infarction. Results of a chest X-ray and electrocardiogram are usually normal, but pulse oxygen saturation is often depressed. The third pattern, acute cor pulmonale syndrome, is caused by the complete obstruction of 60 to 75% of pulmonary circulation. Patients with this pattern experience shock, syncope, or sudden death [ 4 , 5 ].

Syncope, in contrast to pulmonary embolism, is relatively easy to detect, but can be a difficult symptom from which to determine the etiology. In as many as 50% of patients with syncope, no specific cause is found despite extensive evaluation. Syncope has been classified as cardiovascular (reflex and cardiac syncope), noncardiovascular (including neurologic and metabolic disorders) and unexplained [ 2 , 6 ]. It occurs in approximately 10% of patients with acute pulmonary embolism and is commonly ascribed to a massive, hemodynamically unstable acute pulmonary embolism. Although the prognostic value of syncope has not been specifically addressed, it has generally been considered a poor indicator in diagnosing pulmonary embolism [ 7 ].

Syncope in the setting of pulmonary embolism can be the result of three possible mechanisms. First, greater than 50% occlusion of the pulmonary vascular tree causes right ventricular failure and impaired left ventricular filling, leading to a reduction in cardiac output, arterial hypotension, reduced cerebral blood flow, and ultimately syncope. The second mechanism of syncope associated with pulmonary embolism is the appearance of arrhythmias associated with right ventricular overload. In the third mechanism, the embolism can trigger a vasovagal reflex that leads to neurogenic syncope. However, the contribution of hypoxemia secondary to ventilation or perfusion abnormalities must also be considered and may play an important role in the development of syncope. Moreover, acute pulmonary hypertension may also lead to right-to-left flow across a patent foramen ovale, and thus exacerbate hypoxemia [ 8 , 9 ].

The clinician should seek the following clues to the diagnosis of pulmonary embolism in patients who have had a syncopal episode: (a) hypotension and tachycardia or transient bradyarrhythmia; (b) acute cor pulmonale according to electrocardiogram criteria or physical examination; and (c) other signs and symptoms indicative of pulmonary embolism. The presence of any of these findings without other obvious causes of syncope should lead to further work-up, including arterial blood gas analysis, ventilation-perfusion scanning, lower extremity duplex sonogram, echocardiography, multislice computed tomography and angiography, if necessary. Although oxygen saturation levels are inadequate for screening purposes, respiratory alkalosis with hypoxia and increased A-a O 2 gradient are typically seen. However, results of blood gas analysis are normal in 10% of cases [ 4 , 10 ].

In our case, the patient presented to the emergency department with complaints of dyspnea, tachypnea and tachycardia, following a syncopal episode. He had experienced immobilization for one month, hypoxemia in room air, and DVT according to the ultrasonographic results. PTE was initially considered and all of the diagnostic procedures were carried out to prove this presumptive diagnosis. Because DVT and PTE developed in this young patient with no history of any underlying diseases or disorders, he was referred for thrombophilia panel testing (including protein C or S deficiency and Factor V mutation) before treatment; however, as his long-term follow-up was performed by the Department of Pulmonary Diseases, we do not have any further detailed results from these examinations. This case is interesting because the patient did not experience a massive embolism but did develop syncope.

Pulmonary embolism presenting with syncope is difficult to diagnose. Physicians and other health care professionals must be vigilant with patients who have syncope, because this symptom may be a 'forgotten sign' of life-threatening pulmonary embolism.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

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Department of Emergency Medicine, Gazi University Faculty of Medicine, Ankara, Turkey

Ahmet Demircan, Ayfer Keles & Fikret Bildik

Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey

Gulbin Aygencel

Department of Anesthesiology and Reanimation, Gazi University Faculty of Medicine, Ankara, Turkey

Ozgur Ozsoylar

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AD, AK and FB analyzed and interpreted the patient data regarding the syncope and the pulmonary embolism. GA and OO performed the acute treatment of the patient, and were major contributors in writing the manuscript. All authors read and approved the final manuscript.

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Demircan, A., Aygencel, G., Keles, A. et al. Pulmonary embolism presenting as syncope: a case report. J Med Case Reports 3 , 7440 (2009). https://doi.org/10.4076/1752-1947-3-7440

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Pulmonary embolism: update on management and controversies

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  • Peer review
  • Lisa Duffett , associate scientist , assistant professor 1 2 ,
  • Lana A Castellucci , scientist , assistant professor 1 2 ,
  • Melissa A Forgie , vice dean of undergraduate medical education and professor of medicine 2
  • 1 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  • 2 Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
  • Correspondence to: L A Castellucci lcastellucci{at}toh.ca

Pulmonary embolism is a common and potentially fatal cardiovascular disorder that must be promptly diagnosed and treated. The diagnosis, risk assessment, and management of pulmonary embolism have evolved with a better understanding of efficient use of diagnostic and therapeutic options. The use of either clinical probability adjusted or age adjusted D-dimer interpretation has led to a reduction in diagnostic imaging to exclude pulmonary embolism. Direct oral anticoagulation therapies are safe, effective, and convenient treatments for most patients with acute venous thromboembolism, with a lower risk of bleeding than vitamin K antagonists. These oral therapeutic options have opened up opportunities for safe outpatient management of pulmonary embolism in selected patients. Recent clinical trials exploring the use of systemic thrombolysis in intermediate to high risk pulmonary embolism suggest that this therapy should be reserved for patients with evidence of hemodynamic compromise. The role of low dose systemic or catheter directed thrombolysis in other patient subgroups is uncertain. After a diagnosis of pulmonary embolism, all patients should be assessed for risk of recurrent venous thromboembolism to guide duration of anticoagulation. Patients with a venous thromboembolism associated with a strong, transient, provoking risk factor can safely discontinue anticoagulation after three months of treatment. Patients with an ongoing strong risk factor, such as cancer, or unprovoked events are at increased risk of recurrent events and should be considered for extended treatment. The use of a risk prediction score can help to identify patients with unprovoked venous thromboembolism who can benefit from extended duration therapy. Despite major advances in the management of pulmonary embolism, up to half of patients report chronic functional limitations. Such patients should be screened for chronic thromboembolic pulmonary hypertension, but only a small proportion will have this as the explanation of their symptoms. In the remaining patients, future studies are needed to understand the pathophysiology and explore interventions to improve quality of life.

Introduction

Venous thromboembolism, which includes deep venous thrombosis (DVT) and pulmonary embolism, is the third most common cardiovascular disorder and affects up to 5% of the population during their lifetime. 1 The increased sensitivity of imaging modalities has more than doubled rates of hospital admission for pulmonary embolism in the past 10 years, although the case fatality rate has remained stable or decreased. 2 3 4 Embolization of a DVT in the lower extremity into the pulmonary arteries is thought to be the most common mechanism for pulmonary embolism. Registry studies found that up to 17% of patients die within three months of diagnosis of venous thromboembolism, 5 although many of these deaths may be due to associated comorbidities rather than direct causation. For those patients included in the more recent large randomized controlled trials (RCTs), the three month all cause mortality has been approximately 2%. 6 7 8 9

Careful clinical assessment is needed for diagnosis of pulmonary embolism, as the presentation can mimic other common medical conditions. Clinical probability scores in combination with D-dimer testing improve the use and interpretation of diagnostic imaging. 10 Important recent advances in diagnosis of pulmonary embolism have been the use of clinical probability adjusted, or age adjusted, D-dimer interpretation. 11 12 13 Only a small proportion of patients with acute pulmonary embolism will have high risk features associated with short term clinical deterioration, but identification of such patients and consideration of therapies in addition to anticoagulation, such as thrombolysis, are important. 14 15 16 Various risk prediction scores, serum biomarkers, and imaging abnormalities such as right ventricular strain can identify patients at higher short term risk for all cause mortality. 10 14 16 What interventions can be made to alter this prognosis remains unclear.

The major advance in management for patients with pulmonary embolism in the past decade has been the introduction of direct oral anticoagulants (DOACs). This class of drugs includes direct Xa inhibitors (apixaban, edoxaban, rivaroxaban) and a direct thrombin inhibitor (dabigatran). Large RCTs have shown these therapies to be non-inferior to vitamin K antagonists (warfarin). 6 7 8 17 Rates of major bleeding seem to be similar or reduced in patients treated with DOACs compared with warfarin, but whether this is a class effect or whether differences exist between drugs is uncertain. Duration of anticoagulation should be determined after weighing the risk of recurrent venous thromboembolism against the risk of bleeding, along with the associated morbidity and mortality of each outcome. In the era of DOAC therapy, weighing the risk of recurrent venous thromboembolism against that of bleeding remains a challenge as data on bleeding risk and direct comparisons between types and doses of DOACs are lacking. This review is aimed at clinicians caring for patients with pulmonary embolism and researchers interested in recent advances in its management.

Epidemiology

The annual incidence of pulmonary embolism in the population is 1 per 1000 people, but this increases sharply with age, from 1.4 per 1000 people aged 40-49 to 11.3 per 1000 aged 80 years or over. 1 18 19 Recurrent venous thromboembolism occurs in 30% of people, making the attack rate (including incident and recurrent venous thromboembolism) higher, estimated as up to 30 per 1000 person years. 19 The influence of race on venous incidence of thromboembolism is uncertain, but incidence may be higher in white and African-American populations and lower in Asians and Native Americans. 19 Overall, the incidence of venous thromboembolism in men is slightly higher than in women, but the balance changes according to age categories. 19 Among women under 45 years or over 80 years, the incidence of venous thromboembolism is higher than in men. This interaction with age and sex is likely related to estrogen and pregnancy related risk factors at a young age and longer life expectancy of women at advanced ages. Vital registration data indicate that women aged 15-55 and over 80 years have an excess pulmonary embolism related mortality compared with men. 20 Although increased incidence of pulmonary embolism in women among both of these age groups may be contributing to this, whether true sex and/or gender differences exist in case fatality rates remains to determined. Data from registry studies have suggested a higher in-hospital and 30 day pulmonary embolism related mortality in women, 21 whereas other studies have not observed a difference. 22 Subgroup analyses of RCTs comparing warfarin and DOAC therapy have not suggested a difference.

Fifty per cent of venous thromboembolism events are associated with a transient risk factor, such as recent surgery or hospital admission for medical illness, 20% are associated with cancer, and the remainder are associated with minor or no risk factors and are thus classified as unprovoked. 23 Box 1 summarizes common risk factors for venous thromboembolism. 19 24 Despite comprehensive literature on the epidemiology of venous thromboembolism and its risk factors, public awareness is poor compared with other health conditions with comparable incidence. This was illustrated in an international survey of more than 7000 people in nine countries. Half of respondents had no awareness of venous thromboembolism conditions and risk factors, and less than 30% knew the signs and symptoms of venous thromboembolism. 25

Transient risk factors for venous thrombosis 16

Strong risk factor (odds ratio >10).

Hip or leg fracture

Hip or leg joint replacement

Major general surgery

Major trauma

Spinal cord injury

Moderate risk factor (odds ratio 2-9)

Arthroscopic knee surgery

Central venous lines

Congestive heart or respiratory failure

Hormone replacement therapy

Oral contraceptive therapy

Paralytic stroke

Previous venous thromboembolism

Thrombophilia

Weak risk factor (odds ratio <2)

Bed rest >3 days

Immobility due to sitting (eg, prolonged road or air travel)

Increasing age

Laparoscopic surgery (eg, cholecystectomy)

Pregnancy (antepartum)

Varicose veins

Sources and selection criteria

We searched Ovid Medline, Cochrane CENTRAL, and other non-indexed citations from 1 January 2010 to 7 August 2019 to find English language systematic reviews, meta-analyses, and RCTs that evaluated management of pulmonary embolism. We included clinical practice guidelines (American College of Chest Physicians, American Society of Hematology, and European Society of Cardiology), as well as screening them to identify additional studies. We used Ovid Medline and PubMed for dedicated search strategies of selected topics thought not to be included in the above search. These topics included inferior vena cava filters, bleeding and anticoagulation, post-thrombotic syndrome, post-pulmonary embolism syndrome, chronic thromboembolic pulmonary hypertension, quality of life and patient experience, cancer, inherited thrombophilia, and antiphospholipid syndrome. A health sciences librarian did all the searches. Additional references were suggested during the peer review process.

Two authors (LD and LAC) independently evaluated the 360 non-duplicate references retrieved and identified 162 articles as potentially related to our overview. We focused our search on systematic reviews and meta-analyses judged to be of medium or high quality by the AMSTAR tool or as of acceptable quality by the SIGN-50 tool. 26 27 When multiple systematic reviews or meta-analyses covered the same topic, we chose the study with the best methodological quality; when studies had similar quality, we chose the most recent. If topic advances were not fully covered by a systematic review, meta-analysis, or RCT, we included observational studies or expert consensus and opinion. In the end, 11 endorsed clinical practice guidelines/consensus statements, 24 systematic reviews/meta-analysis, 25 randomized trials, 39 prospective studies, and 21 retrospective/secondary analysis studies informed our overview ( fig 1 ). We also included six actively recruiting clinical trials, identified using NCT registration numbers (clincaltrials.gov). These registered clinical trials were either selected by the authors or suggested through the peer review process as having the potential to affect the field, and the conclusions of this review, on completion. After this review was accepted for publication, one of these clinical trials, CARAVAGGIO, was completed and its results published; we updated the manuscript to include the details of this trial and its results.

Fig 1

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Prompt recognition of a constellation of nonspecific signs and symptoms is needed for diagnosis of pulmonary embolism. Prompt initiation of anticoagulation while awaiting investigations is prudent because of the high risk of early mortality with untreated pulmonary embolism. 28 29 30 Although this approach for starting anticoagulation in patients in whom a pulmonary embolism is suspected has been shown to be safe in outpatient settings, 31 risks of bleeding and overuse of diagnostic tests remain. Inappropriately proceeding down a diagnostic pathway for pulmonary embolism may also distract clinicians from identifying the alternative causes of the symptoms.

Clinical probability scores

Clinical probability scores can be used to assign a pre-test probability for pulmonary embolism. Consideration of the probability of pulmonary embolism before testing (that is, pre-test probability) avoids unnecessary testing and is critical to the interpretation of results. This was first illustrated in the PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) study. A high probability planar ventilation-perfusion lung scan was almost as likely to give a false positive result as a true positive one if the pre-test probability was low, with 44% having no evidence of pulmonary embolism on angiography. Conversely, with a low probability ventilation-perfusion lung scan and a high pre-test probability, 60% had pulmonary embolism by angiography. 32

The Geneva and Wells rules are among the most commonly cited clinical probability scores ( table 1 ). 10 34 37 Both the Geneva rule and the Wells rule have been studied in more than 55 000 patients and have been shown to be reliable, accurate, and superior to a gestalt, non-standardized, clinical assessment. 37 An adaption of the Wells rule, keeping three items only (clinical signs of DVT, hemoptysis, and whether pulmonary embolism is the most likely diagnosis), the YEARS rule, has been evaluated in one observational study of 3465 patients with suspected pulmonary embolism. 13 In this study, pulmonary embolism was excluded if patients had either absence of all three criteria and a D-dimer less than 1000 ng/mL or one or more criteria and a D-dimer less than 500 ng/mL. Of the patients in whom pulmonary embolism was ruled out at baseline and remained untreated, 0.61% (95% confidence interval 0.36% to 0.96%) were diagnosed as having venous thromboembolism during the three month follow-up. Limitations of this study include that investigators were not blinded to the D-dimer results when making the assessment of the most likely diagnosis, small numbers of patients with cancer, and the absence of a control arm.

Comparison of pulmonary embolism clinical probability scores

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Despite the routine use of clinical probability scores, only 8% of patients in the US and 27% in Europe investigated for pulmonary embolism will have the diagnosis confirmed. 38 To overcome this, the pulmonary embolism rule-out criteria (PERC rule) were studied in a crossover cluster RCT of 1916 patients who were judged by treating physicians to have a gestalt probability of pulmonary embolism of less than 15%. 39 The PERC rule consists of eight clinical variables (hypoxia, unilateral leg swelling, hemoptysis, previous venous thromboembolism, recent surgery or trauma, age >50, hormone use, tachycardia), and further testing (D-dimer and/or imaging) was withheld if all eight variables were absent. This study showed that in patients deemed to be at very low risk of pulmonary embolism by gestalt, the PERC rule was non-inferior to standard of care for the primary outcome of venous thromboembolism rate during three months of follow-up (mean difference 0.2, one sided upper 95% confidence limit 1.6%). The PERC rule should not be applied to patients at higher risk of pulmonary embolism, defined as gestalt pre-test probability of pulmonary embolism higher than 15%.

D-dimer testing

Physiologically, the activation of coagulation and generation of cross linked fibrin simultaneously leads to the activation of fibrinolysis. The D-dimer is a degradation product of fibrinolysis and is increased in patients with acute venous thromboembolism as well other non-thrombotic disorders. 40 D-dimer is a helpful diagnostic tool, and a negative value in combination with a low clinical probability score is useful for excluding a diagnosis of venous thromboembolism. D-dimer should not be used as a screening tool in patients in whom venous thromboembolism is not clinically suspected. Clinicians should assess the clinical pre-test probability of pulmonary embolism before ordering D-dimer testing, as knowledge of D-dimer results can influence the assessment of the clinical probability score. 41

D-dimer is a sensitive but not specific diagnostic test. Improvements to the specificity can be made by using a dichotomized cut-off value according to the pre-test probability. A recent observational study of 2017 patients with suspected pulmonary embolism showed that a cut-off of 1000 ng/mL in patients with a low pre-test clinical probability score (traditional Wells) and 500 ng/mL in patients with a moderate clinical probability score could safely exclude pulmonary embolism without the need for further diagnostic imaging. 11 All other patients (high clinical probability score) underwent diagnostic imaging. In this study, no patients with low or moderate clinical probability score had a recurrent venous thromboembolism event in the three months of study follow-up (0%, 95% confidence interval 0.00% to 0.29%) and the dichotomized D-dimer cut-off strategy reduced the use of diagnostic imaging by 17.6% (15.9% to 19.2%) compared with the reanalysis of results with a single 500 ng/mL cut-off. Alternatively, D-dimer concentrations increase with age, and specificity can be improved with an age adjusted cut-off value. 42 An observational study of 3346 patients evaluated an age adjusted D-dimer (500 µg/L cut-off for patients ≤50 or age×10 µg/L for patients >50 years), whereby patients with a negative D-dimer and an unlikely (Wells) or non-high (revised Geneva) clinical probability did not undergo diagnostic imaging. 12 This age adjusted D-dimer approach increased the number of patients in whom pulmonary embolism could be excluded without diagnostic imaging from 6% to 30% without additional false negative findings. The three month venous thromboembolism rate in patients with a D-dimer concentration higher than 500 μg/L but below the age adjusted cut-off was 1 in 331 patients (0.3%, 0.1% to 1.7%).

Imaging for suspected pulmonary embolism

The gold standard diagnostic test for pulmonary embolism has historically been interventional pulmonary angiography. This invasive procedure has been largely abandoned, and diagnostic management studies have used the clinical safety measurement of frequency of venous thromboembolism events in the three months after evaluation in patients in whom pulmonary embolism is considered ruled out. The target is to match what was historically observed in similar patients after a negative pulmonary angiography—that is, 1.6% (0.3% to 2.9%) venous thromboembolism rate in the three month follow-up period. 43 Planar ventilation-perfusion lung scans and computed tomography pulmonary angiography (CTPA) are validated imaging tests. Both should be used in combination with the probability scores and D-dimer testing to accurately interpret results, as both false negative and false positive results can be observed when test results are discordant with clinical probability scores ( fig 2 ). 44

Fig 2

Diagnostic work-up of patients with suspected pulmonary embolism (PE). CTPA=computed tomography pulmonary angiography; PERC=pulmonary embolism rule-out criteria; V/Q=ventilation-perfusion. Adapted from Wells PS, et al. Ann Intern Med 2018 44

On the basis of a meta-analysis of observational and randomized studies, a normal CTPA is associated with a pooled incidence of venous thromboembolism at three months of 1.2% (0.8% to 1.8%) and negative predictive value of 98.8% (98.2% to 99.2%). 45 A ventilation-perfusion lung scan in a validated diagnostic algorithm performs equally well as CTPA in the diagnosis of pulmonary embolism. 46 47 48 Patients with pulmonary embolism excluded by a diagnostic algorithm combining ventilation-perfusion lung scan, D-dimer, compression ultrasound, and clinical probability score had an incidence of venous thromboembolism at three months of 0.1% (0.0% to 0.7%) with a negative predictive value of 99.5% (99.1% to 100%). 48

An RCT comparing CTPA and ventilation-perfusion lung scanning found that CTPA detected 5% (1.1% to 8.9%) more pulmonary embolisms, but patients in whom pulmonary embolism was excluded by a diagnostic algorithm based on ventilation-perfusion lung scanning did not have a higher three month incidence of venous thromboembolism during follow-up: 2/561 (0.4%) patients randomized to CTPA versus 6/611 (1.0%) patients undergoing ventilation-perfusion lung scan (difference −0.6%, −1.6% to 0.3%). 46 This calls into question the clinical significance of these pulmonary embolisms “missed” by ventilation-perfusion lung scans. Nevertheless, the wide availability, fewer non-diagnostic results, and ability to provide alternative diagnoses have made CTPA the most common diagnostic modality. Important limitations to CTPA, however, should cause clinicians to reassess this shift in choice of tests, including exposure to ionizing radiation and risk of secondary malignancy, 49 renal toxicity with pre-existing renal disease, and risk of over-diagnosis and over-treatment of clinically insignificant pulmonary embolism.

Single photon emission computed tomography (SPECT) ventilation-perfusion scanning is proposed as an alternative to planar ventilation-perfusion scanning, as this technique may reduce the proportion of non-diagnostic results. The technique and diagnostic criteria for reporting SPECT ventilation-perfusion scans are variable and have not been validated sufficently. 16 On this basis, we suggest favoring planar ventilation-perfusion lung scans over SPECT.

Diagnosis of pulmonary embolism in pregnancy

Pregnancy and the postpartum period confer an increased risk of venous thromboembolism, but only 4-7% of women investigated are diagnosed as having pregnancy associated pulmonary embolism. 50 51 Diagnosing pulmonary embolism in pregnancy is challenging, as shortness of breath and lower extremity swelling are common complaints and D-dimer concentration is increased in normal pregnancies. Diagnostic management studies have either excluded or included very few pregnant women, and safe diagnostic strategies were lacking until recently. Two large observational studies specific to pregnant women have recently been published. The first evaluated the use of the modified Geneva score and a high sensitivity D-dimer in 441 pregnant patients. 51 Women with a low or intermediate clinical probability and negative D-dimer (<500 μg/L) had pulmonary embolism excluded; all others underwent bilateral lower limb compression ultrasonography and, if this was negative, CTPA. Although this approach was safe, with no venous thromboembolism events (0.0%, 0.0% to 1.0%), in three months of follow-up among untreated women in whom pulmonary embolism was excluded, the algorithm could avoid diagnostic imaging in only 10% of patients. This was because D-dimer testing was positive in 87% of women who underwent testing and was more likely to be positive with advanced gestation.

A second observational study of 510 pregnant women applied the YEARS probability score and D-dimer with a stratified cut-off (1000 ng/mL if no criteria were met or 500 ng/mL if one or more criteria were met). 50 Compression ultrasonography was performed only in women with symptoms of DVT. Using this approach, 39% of women were able to avoid diagnostic imaging, with an acceptably low three month venous thromboembolism incidence of 0.21% (0.04% to 1.2%). Furthermore, post hoc retrospective application of this pregnancy adapted YEARS algorithm to the cohort of patients in the first study showed similar findings, with 21% of women meeting criteria for exclusion of pulmonary embolism without diagnostic imaging and no venous thromboembolism events during follow-up. 52 Limitations of these studies include relative small sample sizes and possible bias for inclusion of patients at lower risk. Nevertheless, a pregnancy adapted YEARS algorithm seems to be safe and effective at reducing the need for diagnostic imaging in some patients.

Diagnostic imaging choices for suspected pulmonary embolism in pregnancy are similar to those in non-pregnant patients. Pregnancy alone does not increase the occurrence of non-diagnostic imaging results, and both ventilation-perfusion lung scans and CTPA are safe and accurate diagnostic imaging modalities in pregnancy. 53 54 Fetal exposure to radiation is well under acceptable limits for both tests. 53 Given the younger age, and thus longer lifetime risk for secondary malignancies, we favor the use of ventilation-perfusion lung scans in pregnant women, a position similar to the American Society of Hematology guidelines. 53 First investigating for DVT with compression ultrasonography can be considered in patients who have symptoms suggestive of a DVT. The absence of DVT does not exclude the need for chest imaging, but if a proximal DVT is confirmed then a presumptive diagnosis of pulmonary embolism may be made without dedicated imaging.

Thrombophilia testing

Family history of venous thromboembolism portends higher risk, 55 particularly when the venous thromboembolism is unprovoked or the patient is under 50 years of age. 56 Despite this, considerable controversy remains around the value of inherited thrombophilia testing (factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency), as evidence suggests that the presence of thrombophilia does not alter management. 56 Furthermore, thrombophilia testing does not identify all inherited causes of venous thromboembolism. 57 58 This is illustrated by the observation that only 30% of people with a family history of a first degree relative with venous thromboembolism will have a positive thrombophilia screen. 59

Patients who have a venous thromboembolism diagnosed in the context of a strong provoking risk factor, such as major surgery, are at a low risk for recurrence, and this risk is not significantly altered by the presence of an inherited thrombophilia. 56 Patients who have a venous thromboembolism that is classified as unprovoked are at a significant increased risk of recurrence, but testing for inherited thrombophilia has not been shown to alter this risk in a way that might guide decisions about duration of anticoagulation. 60 61 Relatives identified as asymptomatic carriers of thrombophilia are at increased lifetime risk of venous thromboembolism (factor V Leiden mutation: 0.58-0.67% per year; protein C deficiency: 1.0-2.5% per year; protein S deficiency: 0.7-2.2% per year; antithrombin deficiency: 4% per year), but half of all events occur with additional provoking risk factors. 62 The presence of a positive family history remains significant, as such patients are more likely to develop a venous thromboembolism event compared with those with an inherited thrombophilia with no family history. 59 62 How thrombophilia testing informs the care of family members without symptoms beyond consideration of the risk imposed by a positive family history is therefore unclear.

If thrombophilia testing is used, it should be done after completion of treatment for an acute venous thromboembolism event and preferably in the absence of anticoagulation therapy, as false positive results are associated with warfarin (protein C deficiency, protein S deficiency), heparin (lupus anticoagulant), and DOACs (lupus anticoagulant). 56 We suggest that inherited thrombophilia testing should not be done when venous thromboembolism is associated with a strong provoking factor, as such patients have a low risk of recurrent venous thromboembolism, even when an inherited thrombophilia is identified. 60 We also suggest that thrombophilia testing should not be done in patients with unprovoked venous thromboembolism who already have an indication for long term anticoagulation (based on sex or risk predictions scores). In the remaining patients with unprovoked venous thromboembolism and no indication for indefinite anticoagulation, we suggest discussing inherited thrombophilia testing with them. In most cases, testing will not change the decision on duration of anticoagulation, but rare exceptions include high risk inherited thrombophilia such as antithrombin deficiency, or combined thrombophilia. In the absence of high quality evidence, the patient’s preference should be considered in such decisions. Genetic counseling should be offered to patients undergoing testing, with acknowledgment of the psychological effects such results can have. 63 64 65 66

Antiphospholipid syndrome

Antiphospholipid syndrome is a thrombophilia that should be considered separately. It is acquired, so most affected people will not have a family history of venous thromboembolism. Antiphospholipid syndrome is thought to be associated with a high risk for both recurrent venous thromboembolism and arterial thrombosis. 67 The presence of persistently elevated antiphospholipid antibodies with a first venous thromboembolism is an acceptable indication for indefinite duration of anticoagulation. 16 67 A diagnosis of antiphospholipid syndrome is made on the basis of laboratory and clinical criteria. 68 Laboratory criteria include the presence of at least one associated antibody on two or more occasions and at least 12 weeks apart: lupus anticoagulant (detected according to the guidelines of the International Society on Thrombosis and Hemostasis (ISTH)), 69 anti-β2-glycoprotein I (>99th centile of controls), or anti-cardiolipin antibodies (>40 GPL units or >99th centile of controls). Clinical criteria include one or more episodes of arterial, venous, or small vessel thrombosis or one or more defined pregnancy morbidities. In patients presenting with an unprovoked venous thromboembolism event, 6% of patients overall and up to 19% of those under 50 years old will meet the criteria for antiphospholipid syndrome. 70 71

The identification of antiphospholipid syndrome may be important to guide decisions on choice of anticoagulant therapy. A randomized controlled, non-inferiority trial compared rivaroxaban and warfarin in patients with high risk antiphospholipid syndrome, defined as positive for all three laboratory criteria, for the primary outcome of cumulative incidence of thrombotic events, major bleeding, and vascular death. 72 This trial was terminated after 120 patients were enrolled, as interim analyses showed excess events in the rivaroxaban arm (hazard ratio 6.7, 95% confidence interval 1.5 to 30.5). All trial participants discontinued the assigned study drug and switched to a non-study vitamin K antagonist (VKA). Another non-inferiority RCT of 190 patients with thrombotic antiphospholipid syndrome (required one laboratory criterion: lupus anticoagulant, or moderate to high titer IgG anti-cardiolipin or anti-β2-glycoprotein I antibodies), randomized participants to rivaroxaban or warfarin. 73 The primary outcome of proportion of patients with new thrombotic events during three years of follow-up occurred more frequently in the rivaroxaban arm (risk ratio 1.83, 0.71 to 4.76). Most patients (96%) were positive for lupus anticoagulant, and 60% were triple positive. Both trials showed a trend of increased arterial rather than venous thrombotic events.

Given the high prevalence of antiphospholipid syndrome among patients under 50 years old with unprovoked venous thromboembolism, and implications for duration and choice of anticoagulation, screening for antiphospholipid syndrome should be considered in these patients. Further studies are needed to determine the efficacy of DOACs in lower risk antiphospholipid syndrome (for example, non-lupus anticoagulant, IgM class, and low titer antibodies) and to identify subpopulations of patients with antiphospholipid syndrome in whom DOACs might be acceptable (for example, non-arterial thrombotic history). Until such time, we discuss the risk and benefits of therapeutic options with patients with venous thromboembolism associated with antiphospholipid syndrome and suggest the use of VKAs over other therapies in most patients with antiphospholipid syndrome associated with lupus anticoagulant and triple positive serology.

Diagnosis of recurrent pulmonary embolism

Patients who have a history of a previous DVT or pulmonary embolism are at a lifetime increased risk of recurrent events. 29 74 Anticoagulation reduces the incidence of recurrent venous thromboembolism by about 80-85%. 75 Nevertheless, patients often present with symptoms of recurrent DVT and pulmonary embolism, and differentiating symptoms related to chronic complications of venous thromboembolism, such as post-thrombotic syndrome and post-pulmonary embolism syndrome, represents a diagnostic challenge. Because a history of previous venous thromboembolism is a variable in some clinical probability scores ( table 1 ), such patients are often categorized as having a high probability, necessitating further diagnostic imaging. The most commonly used clinical probability scores were derived in, and are therefore generalizable to, cohorts that included patients with previous venous thromboembolism. Additionally, the D-dimer concentration remains elevated in many patients after completion of a standard treatment course for acute venous thromboembolism, limiting its usefulness for excluding recurrent events. 76 77 Nevertheless, in a combined subgroup analysis of observational studies (1721 patients in total), patients with a previous history of venous thromboembolism and clinically suspected pulmonary embolism (306 patients) were safely managed using a clinical probability and D-dimer diagnostic approach (three month venous thromboembolism incidence in patients with pulmonary embolism excluded by negative D-dimer 0%, 0% to 7.9%). However, only 16% (compared with 33% of those without previous venous thromboembolism history) were able to have pulmonary embolism excluded without imaging tests. 78 Another observational study included 516 patients with clinically suspected recurrent pulmonary embolism while not on anticoagulation therapy. 79 This diagnostic strategy excluded pulmonary embolism on the basis of a Wells pulmonary embolism score of 4 or lower (“pulmonary embolism unlikely”) and a negative D-dimer test; all other patients underwent CTPA. The prevalence of pulmonary embolism in the study was 33%, and the primary outcome of three month recurrent venous thromboembolism in patients with pulmonary embolism excluded was 2.8% (1.2% to 5.5%). The strategy was able to exclude pulmonary embolism without imaging tests in only 17% of patients. Additionally, none of the patients was on anticoagulation at the time of D-dimer testing, so whether this strategy can be generalized to patients who are on anticoagulation is unknown. We support the position endorsed by the ISTH that a combination of low clinical probability score and negative D-dimer test can be used to exclude pulmonary embolism in patients with a history of previous venous thromboembolism, but patients with an intermediate or high clinical probability score should undergo diagnostic imaging. 76

As residual defects often persist on CTPA and ventilation-perfusion lung scans six to 12 months after the initial diagnosis, interpretation of diagnostic imaging for suspected recurrent events requires prudent comparison with previous imaging to prevent over-diagnosis. The rate of complete resolution on baseline imaging varies from about 50% to 84%. 80 81 82 83 Differentiating acute pulmonary embolism from residual thrombi is difficult, and inter-observer agreement between radiologists is poor. 82 Characteristics of thrombi such as density, intramural calcification, or eccentric filling defects have been proposed but never validated. 76 We would advise caution in relying on such descriptive features. The availability, and careful review with an experienced radiologist, of previous imaging and ideally baseline imaging performed six to 12 months after an acute pulmonary embolism is advised when evaluating a patient for recurrent pulmonary embolism and has been shown to be a safe and accurate approach. 84 We routinely do a baseline ventilation-perfusion lung scan six to 12 months after an acute pulmonary embolism. Although this may not be a widely adopted approach, the risk of radiation exposure with ventilation-perfusion lung scans is low and the availability of such baseline imaging has been shown to improve the interpretation of diagnostic tests for suspected recurrent venous thromboembolism. 84 85

Initial treatment for pulmonary embolism

Pulmonary embolism risk assessment.

Pulmonary embolism remains a heterogeneous condition, ranging from presentation with sudden death to incidental findings with no symptoms. Initial hemodynamic instability, defined as systolic blood pressure below 90 mm Hg for 15 minutes or more, is an important marker of prognosis. However, this presentation is uncommon, being found in only 5% of cases; the short term mortality exceeds 15%. 14 15 16 86 For the remaining 95% of cases, several risk prediction scores have been proposed to estimate the risk of an adverse outcome ( table 2 ). 33 88 89 90

Comparison of pulmonary embolism risk prediction scores

A systematic review assessing the characteristics and quality of pulmonary embolism risk prediction scores identified 17 models in the literature. 91 Of these, the Pulmonary Embolism Severity Index (PESI) and the simplified-PESI (sPESI) had the most robust evidence and validation. Both risk prediction scores were able to differentiate between low and high risk of 30 day mortality in patients with pulmonary embolism. 91 The PESI and the Hestia criteria have been used in randomized studies to select patients with low risk pulmonary embolism suited to outpatient care (discussed below). 92 93 Biomarkers have also been studied. A systematic review of cardiac troponin as a predictor of early mortality showed that in patients otherwise classified as being at low risk by the PESI or sPESI score, the presence of a positive troponin had a pooled fivefold increased odds of 30 day mortality (odds ratio 4.79, 1.11 to 20.68), although the wide confidence interval casts doubt on the reliability of this estimate. 94

Other prognostic markers have been proposed for risk stratification, including B-type natriuretic peptide and N-terminal pro-b-type natriuretic peptide (NT-proBNP). Evidence of right ventricular dysfunction by echocardiography and CTPA are also indicators of worse prognosis. 16 95 The combination of the prognostic markers of positive cardiac troponin and right ventricular dysfunction was used in an RCT of 1005 patients identified as having “intermediate risk” pulmonary embolism who were candidates for thrombolysis therapy. 96 The results of the thrombolysis arm are discussed below in the section “Thrombolytic therapy for pulmonary embolism.” In the control arm, a 5% rate of hemodynamic decompensation (25/499 patients) was seen within the first seven days; most of these patients (23/499) went on to need rescue thrombolytic therapy. Although this observation might justify the combination of right ventricular dysfunction and cardiac troponin as predicators of early decompensation, whether clinical characteristics alone would have also identified these patients at high risk is unclear. Although opinion on their usefulness diverges, right ventricular imaging and cardiac biomarkers may be considered for selecting patients who need cardiac monitoring, should close follow-up be unavailable.

Outpatient versus inpatient management of acute pulmonary embolism

Risk stratification has been used to identify patients with a low short term mortality risk to select for outpatient management. The availability of DOACs has simplified outpatient management of pulmonary embolism because some DOACs do not require initial self-administration of parenteral therapies. RCTs have compared outpatient versus inpatient management of pulmonary embolism and found no difference in outcomes in selected patients. A randomized controlled non-inferiority trial allocated 344 patients with low risk pulmonary embolism (PESI class I or II; table 2 ) to inpatient or outpatient treatment, with patients in both arms receiving low molecular weight heparin before transition to an oral agent. 92 No significant difference was seen in the primary outcome of three month incidence of recurrent venous thromboembolism in outpatients versus inpatients (difference 0.6%, 95% upper confidence limit 2.7%, meeting non-inferiority margin of 4%). The Hestia criteria ( table 2 ) have been combined with cardiac troponin and NT-proBNP, with no added benefit of either marker seen compared with the Hestia criteria alone. 93 97 An RCT of 114 patients with low risk pulmonary embolism, no Hestia criteria, and a negative troponin reported a reduction in the primary outcome of time spent in the hospital for venous thromboembolism or bleeding events 30 days after randomization (difference 28.8 (95% confidence interval 16.2 to 41.5) hours lower in outpatient arm). No difference was seen in the three month event rate of venous thromboembolism (predefined secondary outcome). 93 A non-inferiority RCT of 550 patients with no Hestia criteria and negative NT-proBNP compared inpatient and outpatient treatment. The composite primary outcome was 30 day pulmonary embolism or bleeding related mortality, cardiopulmonary resuscitation, or intensive care unit admission. 97 Although the lower than expected positive NT-proBNP concentrations (12% v 40% expected) prevented the trial from being powered to conclude non-inferiority, the primary endpoint occurred in none of the 275 patients (0%, 0% to 1.3%) who had NT-proBNP testing, compared with 3/275 patients (1.1%, 0.2% to 3.2%) in the direct discharge group (P=0.25). The authors speculate that the lower than expected positive biomarkers observed could be because the Heista criteria alone identified a low risk population, so lower amounts of NT-proBNP were detected. On the basis of this evidence, we support the recommendations for outpatient management of pulmonary embolism. 14 16 The identification and outpatient management of appropriate pulmonary embolisms will represent a significant cost savings without compromise to patient safety. 98

Subsegmental pulmonary embolism

The increased use and sensitivity of CTPA has seen an increase in single or multiple pulmonary emboli isolated to the smaller, subsegmental pulmonary arteries. 99 Despite this increase, overall pulmonary embolism related mortality has not changed, and this may account for the decrease in case fatality. 100 101 102 The clinical significance of subsegmental pulmonary emboli remains uncertain, and recommendations are extrapolated mainly from historical ventilation-perfusion lung scan trials.

In the PIOPED study, 17% of patients had defects isolated to the subsegmental pulmonary arteries, which corresponds to a “low probability” ventilation-perfusion lung scan. 32 In observational studies, these low probability ventilation-perfusion patients were not treated if bilateral leg compression ultrasonography and serial compression ultrasonography were performed. 48 This was shown to be a safe strategy and remains the current management of such patients. 16 A systematic review and meta-analysis of observational studies and RCTs showed that the rate of subsegmental pulmonary embolism was higher when multi-row detector computed tomography was used compared with single detector computed tomography, but the three month incidence of recurrent venous thromboembolism in patients left untreated was the same in both groups (0.9% (0.4% to 1.4%) and 1.1% (0.7% to 1.4%) for single and multi-row detectors respectively), suggesting that the extra subsegmental pulmonary embolisms detected may not have the same clinical significance. 99 Similarly, another systematic review and meta-analysis of observational studies and RCTs showed no difference between patients with subsegmental pulmonary embolism who were treated with anticoagulation and those not treated for the pooled outcomes of three month incidence of recurrent venous thromboembolism (5.3% (1.6% to 10.9%) treated, 3.9% (4.8% to 13.4%) untreated) and all cause mortality (2.1% (3.4% to 5.2%) treated, 3.0% (2.8% to 8.6%) untreated). 103 The diagnosis of subsegmental pulmonary embolism is complicated by low inter-observer agreement between radiologists and the recognition that many subsegmental pulmonary embolisms are interpreted as false positives by more experienced radiologists. 100 Collectively, this has led to the recommendation that subsegmental pulmonary embolism in the absence of DVT may not need to be treated with anticoagulation. 14 Until further research is completed, we suggest that isolated subsegmental pulmonary embolism on CTPA, in the absence of cancer or high risk features such as poor cardiopulmonary reserve, may be approached as one would a non-diagnostic ventilation-perfusion lung scan: with baseline and serial bilateral leg compression ultrasonography and no anticoagulation treatment unless DVT is found. An ongoing observational study is assessing the safety of such a management strategy (clinicaltrials.gov NCT01455818 ).

Choice of anticoagulation for acute pulmonary embolism

Anticoagulation therapy for confirmed acute pulmonary embolism is the mainstay of treatment and can be divided into three phases: initial phase from zero to seven days, long term therapy from one week to three months, and extended therapy from three months to indefinite. 14 Box 2 shows anticoagulation options and dosing during each phase. Parenteral anticoagulation with low molecular weight heparin (LMWH), fondaparinux, or intravenous unfractionated heparin is typically used in patients admitted to hospital for initial management of pulmonary embolism. Stable patients on discharge from hospital or those patients suitable for outpatient treatment from the time of diagnosis of acute pulmonary embolism may be treated with DOACs. DOACs are given at fixed doses and do not necessitate routine laboratory monitoring ( table 3 ). 105 Each DOAC has been deemed non-inferior to the VKA/LMWH combination in phase III RCTs for the prevention of symptomatic recurrent venous thromboembolism in patients with an acute venous thromboembolism). DOACs also have significantly fewer major bleeding events compared with VKAs ( table 4 ). 6 7 8 17 Limitations of these trials include heterogeneous populations and lack of direct comparisons between DOACs. An RCT comparing rivaroxaban and apixaban for patients with acute venous thromboembolism is ongoing ( NCT03266783 ), evaluating the differences in clinically relevant bleeding with these anticoagulants.

Phases of pulmonary embolism treatment 104

Initial (0-7 days).

Apixaban 10 mg BID for 7 days

Rivaroxaban 15 mg BID for 21 days

LMWH/fondaparinux for minimum 5 days* and INR ≥2 for 2 days

Long term (1 week to 3 months)

Apixaban 5 mg BID

Dabigatran 150 mg BID

Edoxaban 60 mg daily†

Rivaroxaban 20 mg daily

Warfarin for INR 2-3

Extended (3 months to indefinite)

Apixaban 5 mg BID or 2.5 mg BID‡

Acetylsalicylic acid 81-100 mg daily, if anticoagulation not possible

Rivaroxaban 20 mg daily or 10 mg daily‡

BID=twice daily; INR=international normalized ratio; LMWH=low molecular weight heparin

*LMWH is needed for 5-10 days before starting dabigatran or edoxaban

†30 mg daily if creatinine clearance is 30-50 mL/min or weight <60 kg

‡Dose reduction may be considered after 6 months of therapy

Characteristics of direct oral anticoagulant drugs

Phase III randomized controlled trials comparing direct oral anticoagulants and vitamin K antagonists

Until the past decade, VKAs were the only oral anticoagulants available for treatment of venous thromboembolism, used concurrently with parenteral anticoagulation for at least five days and until two consecutive international normalized ratio readings are between 2 and 3. Although VKA use has diminished with the availability and relative simplicity of DOACs, they remain a critical part of pulmonary embolism management in patients with severe renal insufficiency, antiphospholipid syndrome, 72 73 or inability to cover the cost of DOACs.

Treatment of cancer associated pulmonary embolism

Patients with cancer have a sevenfold increased risk for venous thromboembolism, with an overall absolute risk of 7% within the first year of a cancer diagnosis and up to 20% depending on type of cancer and treatments used. 108 109 110 Pulmonary embolism may be symptomatic or found incidentally on imaging to assess response to cancer treatment. Symptomatic or incidental pulmonary embolisms have similar high risk for recurrence. 111 Major bleeding complications are also more common with venous thromboembolism in patients with cancer. 112 113 Treatment of acute symptomatic and incidental pulmonary embolism is individualized according to risk of recurrent pulmonary embolism and bleeding. Prolonged use of LMWH dominated the cancer associated venous thromboembolism field for a long time, on the basis of the results of trials comparing LMWH and VKAs. 114 Since then, four RCTs have compared DOACs and LMWH in patients with cancer associated venous thromboembolism. The HOKUSAI VTE Cancer RCT randomized 1050 patients with cancer and acute venous thromboembolism and showed that edoxaban (after a five day lead-in with LMWH) was non-inferior to LMWH for the primary outcome of recurrent venous thromboembolism or major bleeding during 12 month follow-up (hazard ratio 0.97, 95% confidence interval 0.70 to 1.36; P=0.006 for non-inferiority). 115 A non-significant lower venous thromboembolism rate was seen (difference in risk −3.4 (−7.0 to 0.2) percentage points), but the major bleeding rate was significantly higher (difference in risk 2.9 (0.1 to 5.6) percentage points) in the edoxaban treated patients. Major bleeding events were mostly seen in the subgroup of patients with upper gastrointestinal tract malignancies.

A second RCT, SELECT-D, compared rivaroxaban and LMWH for the acute treatment of cancer associated venous thromboembolism in 406 patients. This pilot trial was originally designed to inform feasibility of recruiting patients to a phase III RCT. It was powered to estimate venous thromboembolism recurrence rates at six months to within an 8% width of the 95% confidence interval within each arm, assuming a recurrent venous thromboembolism rate of 10% at six months. As a result of slow recruitment, it was later modified to within 9% width. The cumulative venous thromboembolism recurrence rate at six months was 11% (7% to 16%) for dalteparin and 4% (2% to 9%) for rivaroxaban, with fewer recurrent venous thromboembolisms in patients treated with rivaroxaban (hazard ratio 0.43, 0.19 to 0.99). A non-significant increase in major bleeding was seen in patients treated with rivaroxaban (hazard ratio 1.83, 0.68 to 4.96) and a significant increase in clinically relevant non-major bleeding with rivaroxaban (3.76, 1.63 to 8.69). 116 A planned interim safety analysis identified a non-significant difference in major bleeding between arms in patients with esophageal cancers, and these cancers were later excluded from the trial. Unfortunately, slow recruitment in the SELECT-D pilot trial resulted in an inability to definitively compare the efficacy and safety of rivaroxaban and LMWH.

Two RCTs have compared apixaban and LMWH for the treatment of cancer associated venous thromboembolism. The ADAM VTE trial randomized 300 patients to either apixaban or LMWH for six months’ treatment of cancer associated venous thromboembolism. 117 Recurrent thrombosis was more common in the LMWH group (hazard ratio 0.099, 0.013 to 0.780). No differences were seen in safety outcomes of major bleeding or clinically relevant non-major bleeding rates at 6% in each group. The CARAVAGGIO trial randomized 1170 patients to apixaban or LMWH for six months’ treatment. 118 Apixaban was non-inferior to LMWH for the primary outcome of recurrent venous thromboembolism during the trial period of six months (hazard ratio 0.63, 0.37 to 1.07; P<0.001 for non-inferiority). No difference in major bleeding, the primary safety outcome, was observed (hazard ratio 0.82, 0.40 to 1.69). 118

Caution should be applied in making indirect comparisons of the major bleeding rate in CARAVAGGIO with those in other trials, as important differences in enrolled patients exist. Notably, CARAVGGIO excluded patients with either primary or metastatic central nervous system disease and acute leukemia. There was also an imbalance with less upper gastrointestinal malignancies in the apixaban arm than in the LMWH arm (4.0% v 5.4%), whereas HOKUSAI VTE had an imbalance in the opposite direction for edoxaban compared with LMWH (6.3% v . 4.0%).

Consensus from Canadian clinical experts provides a treatment algorithm for patients with cancer and acute venous thromboembolism, considering the risk of bleeding, informed patient preferences, and reimbursement of drugs ( fig 3 ). 112 Of note, this consensus statement was made before the publication of the ADAM VTE and CARAVAGGIO trials, the results of which would also support apixaban for the treatment of cancer associated venous thromboembolism. In general, patients with cancer associated pulmonary embolism without contraindication to anticoagulation are assessed for bleeding risk on the basis of a previous history of bleeding, comorbidities, and type of malignancy. Drug-drug interactions are another consideration, particularly for DOACs. All DOACs are substrates of P-glycoprotein; apixaban and rivaroxaban are also substrates of cytochrome P450 (CYP3A4), whereas edoxaban and dabigatran are not. Determination of clinically relevant drug interactions is complex in patients with cancer, as they are often treated with many anticancer therapies that may compete for a common metabolic pathway. The choice of anticoagulant should be made on an individual basis and in consultation with a pharmacist for assessment of drug-drug interactions. 112 A list of common drug-drug interactions for direct Xa inhibitors can be found in the Canadian expert consensus. 112 The initial phase of cancer associated pulmonary embolism treatment requires use of parenteral anticoagulation (LMWH, fondaparinux) or rivaroxaban in patients without significant renal impairment, according to the algorithm proposed. The choice of long term anticoagulant can include LMWH, edoxaban, or rivaroxaban over VKAs, which are inferior to LMWH. VKAs may be used if LMWH or DOACs are unavailable or contraindicated, such as with severe renal impairment or drug-drug interactions. Duration of therapy for acute venous thromboembolism in cancers patients is usually six months, and extended treatment is individualized on the basis of the patient’s cancer status and treatments ( box 3 ). An ongoing RCT is comparing low dose apixaban with standard dose apixaban in cancer patients treated beyond six months ( NCT03692065 ).

Fig 3

Suggested algorithm for management of cancer associated thrombosis. DOAC=direct oral anticoagulant; LMWH=low molecular weight heparin. *Consider risk factors for bleeding including gastrointestinal (GI) toxicity (previous GI bleed, treatment associated with GI toxicity), thrombocytopenia (<50 000 platelets/mL), renal impairment, recent and/or life threatening bleeding, intracranial lesion, and use of antiplatelet agents. Adapted from Carrier M, et al. Curr Oncol 2018 112

Phases of cancer associated pulmonary embolism treatment

LMWH/fondaparinux for minimum 5 days*

Apixaban 10 mg BID for 7 days†

Long term (1 week to 6 months)

Apixaban 5 mg PO BID†

Edoxaban 60 mg daily‡

VKA for INR 2-3

Extended (6 months to indefinite)

BID=twice daily; INR=international normalized ratio; LMWH=low molecular weight heparin; VKA=vitamin K antagonist

*LMWH is needed for 5-10 days before starting edoxaban

†Not included in original Canadian expert consensus recommendations

‡30 mg daily if creatinine clearance 30-50 mL/min or weight <60 kg

Treatment of pregnancy associated pulmonary embolism

DOACs and fondaparinux cross the placenta and should be avoided in pregnancy. Unfractionated heparin and LMWH are safest during pregnancy as they do not cross the placenta; LMWH is the mainstay of treatment owing to its once daily dosing and self-administered subcutaneous route. Management of anticoagulation around the time of delivery requires close coordination with a multidisciplinary team of obstetrics, anesthesia, thrombosis, and maternal fetal medicine. A recent RCT of 3062 low risk pregnancies showed that scheduled induction of labor is safe, does not increase the risk for cesarean section delivery, and had a small benefit on the primary outcome of perinatal death or severe neonatal complications (relative risk 0.80, 0.64 to 1.00). 119 In patients with an acute venous thromboembolism event in the current pregnancy that occurred more than a month before the expected delivery date, we suggest a scheduled induction of labor with the last dose of LMWH administered 24 hours before. Stopping LMWH 24 hours before delivery allows the safe use of neuro-axial anesthesia if needed. 120 121 In the absence of any postpartum hemorrhage, LMWH is restarted six hours after delivery and continued for at least six weeks post partum. In patients who have an acute pulmonary embolism within one month of expected delivery, we also suggest scheduled induction of labor but administration of unfractionated heparin at therapeutic dose until active labor to avoid prolonged interruptions of therapy. If pulmonary embolism occurred less than two weeks from time of delivery, an inferior vena cava (IVC) filter may be considered. 122 Post partum, anticoagulant treatment options for women who are breast feeding include unfractionated heparin, LMWH, VKA, fondaparinux, or danaparoid. DOACs concentrate in breast milk and are contraindicated but can be considered in women who are not breast feeding or after completion of breast feeding in those who have an indication for longer term treatment. Antepartum and postpartum venous thromboembolism prophylaxis with LMWH are recommended for future pregnancies. 53

Thrombolysis for acute pulmonary embolism

Thrombolytic therapy, either systemic (most common) or directed by a catheter into the pulmonary arteries, can be used to accelerate the resolution of acute pulmonary embolism, lower pulmonary artery pressure, and increase arterial oxygenation. 123 Five per cent of patients with acute pulmonary embolism will present with hemodynamic compromise with systolic blood pressure persistently less than 90 mm Hg; they represent the subgroup at the highest risk for early mortality from pulmonary embolism, thus standing to benefit the most from thrombolytic therapy. 124 Bleeding is the major limitation of thrombolytic therapy, with major bleeding rates reported to be 10% or greater. 125 Overall, a systolic blood pressure persistently less than 90 mm Hg for at least 15 minutes and without high risk for bleeding is considered to be an indication for immediate treatment with systemic thrombolytic therapy. 14 15 This recommendation, however, is based on poor quality evidence, likely because of challenges in studying patients presenting with acute instability.

The results of the International Cooperative Pulmonary Embolism Registry (ICOPER), showed no benefit in terms of 90 day mortality with thrombolytic therapy in hemodynamically unstable pulmonary embolism but should be interpreted with caution as only 32% of all such patients received thrombolysis and selection bias is likely present. 124 A systematic review identified 18 randomized trials using thrombolytic therapy for the treatment of pulmonary embolism, including both hemodynamically stable and unstable pulmonary embolism. 123 Overall a reduction in death with thrombolytic therapy was observed (odds ratio 0.51, 0.29 to 0.89; P=0.02; 1898 participants; low quality evidence), but this overall effect was lost when studies with a high risk of bias were excluded (odds ratio 0.66, 0.42 to 1.06; P=0.08; 2054 participants).

The use of thrombolytic therapy in selected hemodynamically stable patients with high risk features has been better studied in clinical trials. The largest RCT to evaluate the benefit of thrombolysis in hemodynamically stable patients was the Pulmonary Embolism Thrombolysis (PEITHO) trial, which randomized 1005 patients with right ventricular dysfunction on either CTPA or echocardiogram or an elevated troponin to receive thrombolysis (tenecteplase) in addition to unfractionated heparin, compared with unfractionated heparin alone. 96 This study showed a benefit in the study’s composite primary outcome of death or hemodynamic decompensation within seven days (odds ratio 0.44, 0.23 to 0.87; P=0.02) but at a significant cost of major bleeding (major extracranial bleeding: odds ratio 5.55, 2.3 to 13.39; P<0.001). The most notable finding of this trial was that no difference in overall death was seen between the two groups, perhaps because patients randomized to the heparin only group successfully received rescue thrombolysis on development of hemodynamic decompensation. This would suggest that a strategy of close observation of such patients with escalation to systemic thrombolysis in those who decompensate is worthy of study. Three year follow-up in PEITHO showed no effect of thrombolysis therapy on residual dyspnea, right ventricular dysfunction, or overall mortality. 126

Catheter directed thrombolysis (CDT) is an alternative method for delivery of thrombolysis with potentially a lower risk of bleeding (one third the dose of thrombolytic drug compared with systemic delivery). This approach has been studied in an RCT of 59 patients with acute pulmonary embolism without evidence of hemodynamic compromise on presentation, and CDT showed a benefit in the primary outcome of improved right ventricular function (right ventricular/left ventricular ratio) at 24 hours (mean difference 0.30 (SD 0.20) versus 0.03 (0.16), heparin and CDT respectively; P<0.001). 127 Cohort and registry studies have shown improvement in surrogate outcomes of right ventricular function but no difference in recurrent pulmonary embolism or mortality. 15 Major bleeding rates are variable across studies but reported by some to be similar to those with systemic thrombolysis. 128 129 The role for CTD remains unclear, and we do not recommend its routine use except in experienced centers when a patient has hemodynamic compromise and a high risk of bleeding and therapy can be started without delay.

A network meta-analysis of all RCTs that compared recanalization procedures for acute pulmonary embolism (full dose systemic thrombolysis, low dose systemic thrombolysis, and catheter directed thrombolysis) found no significant benefit on overall mortality for any thrombolysis methods (full dose systemic thrombolysis: odds ratio 0.60, 0.36 to 1.01; low dose thrombolysis: 0.47, 0.14 to 1.59; catheter directed thrombolysis: 0.31, 0.01 to 7.96) and a significantly increased risk of bleeding, especially with full dose systemic thrombolysis (odds ratio 2.00, 1.06 to 3.78). 125 For patients presenting with persisting hemodynamic instability for at least 15 minutes, in the absence of high quality evidence, but also considering the high short term mortality of this group, we suggest the use of systemic thrombolysis in patients without absolute contraindication. 16 For patients with persisting hemodynamic instability but at high risk or with contraindications to systemic thrombolysis, we suggest that catheter directed thrombolysis may be considered on an individual case basis, where available. For all other patients deemed to be at high risk for short term deterioration (see “Pulmonary embolism risk assessment” above), we suggest observation in a monitored setting with thrombolytic therapy reserved for hemodynamic deterioration.

Surgical embolectomy

Surgical embolectomy with cardiopulmonary bypass can be performed in patients with acute pulmonary embolism associated with hemodynamic instability and contraindication to thrombolytic therapy. 14 16 Published case series have shown variable results, with perioperative mortality ranging from 4% to 59%. 130 131 Advanced age, pre-surgical cardiac arrest, and pre-surgical thrombolytic therapy are associated with worse outcomes. Extracorporeal membrane oxygenation (ECMO) either alone or as a bridge to surgical embolectomy has also shown benefit in case reports and small case series. 130 ECMO requires continuous anticoagulation and can induce a consumptive coagulopathy, resulting in high risk of bleeding. In a patient with significant hemodynamic instability and contraindication to thrombolysis, surgical embolectomy and/or ECMO may be considered.

Vena cava filters

IVC filters were first introduced in 1973 and designed to mechanically trap venous emboli from the lower extremities to prevent pulmonary embolism. 122 Since this time, the use of IVC filters has dramatically increased, despite a lack of evidence for an effect on venous thromboembolism related mortality. 132 Guidelines from major clinical societies differ in their suggested indication for IVC filters but generally agree on their use in patients with an acute proximal DVT or pulmonary embolism and a contraindication to anticoagulation. 122 The use of IVC filters for other indications, such as failure of anticoagulation, massive pulmonary embolism clot burden with residual DVT, severe cardiopulmonary disease, use before thrombolysis, or prophylaxis in patients at high risk, has expanded greatly in recent years but is not driven by evidence. 122 133

Pre-emptive placement of a permanent IVC filter in addition to standard anticoagulation in patients at high risk with acute proximal DVT was investigated in the Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study, an RCT of 400 patients, which showed a reduction in the primary outcome of early pulmonary embolism diagnosed within the first 12 days (odds ratio 0.22, 0.05 to 0.90) but no difference in mortality (odds ratio 0.99, 0.29 to 3.42). 134 Longer term follow-up data showed similar results, with reduction of pulmonary embolism in the IVC filter arm but a significant increase in recurrent DVT and no difference in overall mortality. 47 A follow-up RCT, PREPIC-2, studied removable IVC filters in 399 patients with high risk pulmonary embolism and showed no benefit in the use of the filter combined with standard anticoagulation compared with anticoagulation alone on the primary outcome of recurrent pulmonary embolism at three months (relative risk 2.00, 0.51 to 7.89; P=0.50). 135 We suggest that IVC filters should be restricted to patients with an acute proximal DVT or pulmonary embolism in whom full dose anticoagulation cannot be given because of uncontrollable active bleeding or a high risk for life threatening bleeding (for example, coagulation defect, severe thrombocytopenia, recent intracerebral hemorrhage, or cerebral lesion at high risk of bleeding) or urgent surgery requiring interruption of anticoagulation. In such patients, the safety of starting or resuming anticoagulation should be assessed frequently. Once full dose anticoagulation can be restarted without recurrence of major bleeding, the IVC filter should be promptly removed to reduce the chance of IVC filter related complications, which are increased over time. 122

Duration of treatment for pulmonary embolism

The duration of treatment depends on the presence or absence of risk factors at the time of diagnosis of the index pulmonary embolism (see box 1 ). The ISTH Scientific Subcommittee suggests evaluating patients’ risk for recurrent venous thromboembolism. 14 In patients with less than 5% risk at one year or less than 15% at five years, the recommendation is to stop anticoagulation. In pulmonary embolism provoked by major transient risk factors such as major surgery, the risk of recurrent pulmonary embolism at one year is less than 1%, favoring discontinuation of anticoagulation after three months. In those with minor transient risk factors such as hormone associated pulmonary embolism, the risk of recurrent venous thromboembolism is approximately 15% at five years and consideration of the risks of anticoagulation related major bleeding is important when recommending extended treatment in this intermediate group.

In patients without an identifiable risk factor (unprovoked pulmonary embolism), a recent systematic review and meta-analysis of 18 studies (RCTs and observational studies) evaluated the risk of recurrent venous thromboembolism in patients with a first unprovoked venous thromboembolism. 74 In total, 7515 patients were included, and all completed at least three months’ anticoagulation before discontinuing therapy. In the first year after stopping anticoagulation, the pooled rate of recurrent venous thromboembolism was 10.3 (95% confidence interval 8.6 to 12.1) events per 100 person years and the rate of recurrent pulmonary embolism was 3.3 (2.4 to 4.2) events per 100 person years. Table 5 shows the cumulative incidence of recurrent venous thromboembolism and recurrent pulmonary embolism. The case fatality rate of recurrent venous thromboembolism was 3.8% (2.0% to 6.1%). These data suggest that patients with a first unprovoked venous thromboembolism are at substantial risk for recurrent thrombosis, and this should guide decisions on extended anticoagulation therapy. Intermediate duration anticoagulation, such as extending the initial treatment period to one or two years before discontinuing therapy, does not reduce the subsequent risk of recurrent venous thromboembolism after anticoagulation is discontinued. 136

Risk of recurrent venous thromboembolism (VTE) and pulmonary embolism (PE) after discontinuing anticoagulation* 74

Risk stratification for patients with unprovoked venous thromboembolism may also help to determine the risk of recurrent thrombosis. Prognostic markers of recurrent venous thromboembolism include male sex, advanced age, 137 138 inherited thrombophilia, 70 obesity, 70 persistently positive D-dimer, 77 139 and residual pulmonary obstruction on ventilation-perfusion lung scan. 140 Individually, these risk factors are insufficient to recommend long term anticoagulation; however, risk prediction models incorporating various combinations have been proposed. 137 138 The largest prospectively validated (2785 patients) clinical decision rule is the “Men Continue and HERDOO-2.” 75 141 In the derivation cohort of this prediction rule, stratifying men into high and low risk categories was not possible; men had an annual risk of recurrent venous thromboembolism of 13.9% (10.8% to 17.0%) while off anticoagulation, so they remained on anticoagulation in the validation cohort. Women, on the other hand, were stratified into risk groups, such that anticoagulation could be discontinued in women with 0 or 1 HERDOO points (hyperpigmentation, edema or redness of either leg, D-dimer >250 μg/L, obesity (body mass index >30), older age (≥65 years)). The annual risk of recurrent venous thromboembolism in women at low risk was 1.6% (0.3% to 4.6%) in the derivation cohort and 3% (1.8% to 4.8%) in the validation cohort. Women with 2 or more HERDOO points were deemed to be at high risk and had an annual recurrent venous thromboembolism rate of 14.1% (10.9% to 17.3%) in the derivation cohort and remained on anticoagulation in the validation study. Limitations to this rule include the misclassification of women at high and low risk of recurrent venous thromboembolism risk with use of non-VIDAS d -Dimer assays (bioMérieux, Marcy L’Etoile, France), 142 and D-dimer testing was done on anticoagulation at six months after the initial venous thromboembolism event. Use of the rule at other time points or off anticoagulation has not been validated. Anticoagulant options for extended venous thromboembolism treatment are shown in box 2 .

Oral anticoagulation reduces the risk of recurrent venous thromboembolism only during therapy. Identifying patients with unprovoked index venous thromboembolism who would benefit from prolonged anticoagulation for extended treatment and secondary prevention needs to be balanced with risk of bleeding while on anticoagulation. Risk factors for bleeding include age over 75 years, history of bleeding, chronic liver disease, chronic renal disease, previous stroke, and use of concurrent antiplatelet agents or non-steroidal anti-inflammatory drugs. 16 As the bleeding risks and associated case fatality rates are lower for DOACs than VKAs, 143 144 when possible, DOACs should be considered over VKAs.

Box 2 shows the DOAC dosing options for extended treatment, including continuation of the same dosing as for long term treatment or reduced dosing for rivaroxaban and apixaban. The EINSTEIN CHOICE RCT compared rivaroxaban 20 mg daily and rivaroxaban 10 mg daily against aspirin 100 mg daily for extended treatment of venous thromboembolism in 3400 participants who completed at least six to 12 months of anticoagulation for acute venous thromboembolism. 145 The trial was not sufficiently powered to compare the different doses of rivaroxaban with each other. For the primary efficacy outcome of recurrent/fatal venous thromboembolism, each dose of rivaroxaban was associated with fewer events compared with aspirin (hazard ratio 0.34 (0.20 to 0.59) for rivaroxaban 20 mg versus aspirin and 0.26 (0.14 to 0.47) for rivaroxaban 10 mg compared with aspirin). The primary safety outcome of major bleeding was not different for either dose of rivaroxaban compared with aspirin (hazard ratio 2.01 (0.50 to 8.04) for rivaroxaban 20 mg compared with aspirin and 1.64 (0.39 to 6.84) for rivaroxaban 10 mg compared with aspirin). Limitations of EINSTEIN CHOICE are centered on the predominantly provoked venous thromboembolism population (60% of participants). The benefit of extended therapy in this population is less clear, as the risk of recurrent venous thromboembolism is lower in patients with provoked index venous thromboembolism. Whether rivaroxaban 10 mg daily is as effective as 20 mg daily in unselected high risk patients with unprovoked venous thromboembolism is also unknown.

The AMPLIFY EXT RCT compared two doses of apixaban, 5 mg twice daily and 2.5 mg twice daily, with placebo for 12 months for prevention of recurrent venous thromboembolism/all cause mortality. 146 Participants were randomized after completing six to12 months of therapy for acute venous thromboembolism and received either dose of apixaban or placebo for 12 months. Apixaban at both doses resulted in fewer recurrent primary outcome events compared with placebo (hazard ratio 0.36 (0.25 to 0.53) for apixaban 5 mg versus placebo and 0.33 (0.22 to 0.48) for apixaban 2.5 mg versus placebo). Major bleeding was the primary safety outcome and occurred with similar frequency in each apixaban group (hazard ratio 0.25 (0.03 to 2.24) for apixaban 5 mg versus placebo and 0.49 (0.09 to 2.64) for apixaban 2.5 mg versus placebo). More than 90% of participants in AMPLIFY EXT had unprovoked index venous thromboembolism, providing reassurance that both doses of apixaban reduce the risk of recurrent venous thromboembolism in this high risk patient population, without increasing bleeding events. Unfortunately, the study was not sufficiently powered to compare the apixaban doses with each other. Ongoing studies such as RENOVE ( NCT03285438 ) are evaluating extended therapy of full dose DOAC compared with reduced dose DOAC for patients with unprovoked index venous thromboembolism. In the meantime, patients’ preferences and regular evaluation of bleeding risks should be incorporated into decisions about extended therapy. We recommend annual reassessment of risks of bleeding and recurrent venous thromboembolism to inform decisions about prolonged anticoagulation.

In cancer associated pulmonary embolism, cancer is a major persistent risk factor and the need for extended anticoagulation therapy, beyond six months, is suggested for patients with active cancer (metastatic disease) or receiving chemotherapy. 112 Box 3 shows the options for extended therapy. To ensure that the benefit of continuing anticoagulation outweighs the potential harm of bleeding, we suggest that the decision to continue anticoagulation should be regularly reassessed. Figure 4 summarizes our suggested approach to duration of anticoagulant treatment. 147

Fig 4

Approach to duration of treatment of venous thromboembolism (VTE). *If transient risk factor is non-surgical (eg, immobilization, pregnancy, or estrogen therapy), extended treatment can be considered given the safety profile of direct oral anticoagulants. †According to “Men continue and HERDOO2” risk prediction score: low=women with 0-1 points; high risk=all men and women with ≥2 points. ‡Bleeding risk according to HAS-BLED score: low risk 0-2 points or high risk ≥3 points. Adapted from Tritschler T, et al. JAMA 2018 147

Long term effect of pulmonary embolism

Post-pulmonary embolism syndrome.

As many as 50% of patients report long term sequelae after pulmonary embolism. 148 149 150 Post-pulmonary embolism syndrome has been defined by suboptimal cardiac function, pulmonary artery flow dynamics, or pulmonary gas exchange at rest or during exercise, in combination with dyspnea, decreased exercise tolerance, or diminished functional status or quality of life, without an alternative explanation. 148 149 At the extreme end, chronic thromboembolic pulmonary hypertension (CTEPH) occurs in an estimated 3% of patients surviving after a six month treatment period for acute pulmonary embolism. 151 The exact pathophysiology of why CTEPH occurs in a minority of patients remains unknown. Risk factors for development of CTEPH after acute pulmonary embolism include diagnostic delay, high thrombus load, recurrent symptomatic pulmonary embolism, pulmonary hypertension or right ventricular dysfunction at baseline, and failure to achieve thrombus resolution. 148 152 153 A diagnosis of CTEPH is confirmed by showing a mean pulmonary artery pressure above 25 mm Hg combined with thrombotic pulmonary vascular obstructions. Planar ventilation-perfusion lung scanning is the preferred imaging modality, with high sensitivity and specificity for CTEPH. 15 Bilateral pulmonary endarterectomy through the medial layer of the pulmonary arteries is a curative treatment for CTEPH, but most patients need lifelong anticoagulation because of the risk of recurrent venous thromboembolism. 15

A second subset of patients is those with evidence of chronic thromboembolic disease without pulmonary hypertension. Cardiopulmonary functional testing suggests that this is an intermediate clinical phenotype in response to exercise. 154 The relation between residual pulmonary obstruction and the patient’s risk of developing CTEPH and how the prognosis differs from those with functional symptoms without evidence of residual pulmonary obstruction remain unclear. An observational study, the Prospective Evaluation of Long-term Outcomes After Pulmonary Embolism (ELOPE), followed 100 unselected patients with an acute pulmonary embolism and did cardiopulmonary exercise testing at one and 12 months. 150 Consistent with self-reported symptoms at one year, almost 50% of these patients had evidence of diminished exercise capacity. The observed reduced cardiopulmonary exercise capacity correlated well with several quality of life measurements and the six minute walk test. Baseline residual pulmonary obstruction was not associated with the exercise limitation, and nor were pulmonary function testing or echocardiographic results. 155 Predictors of exercise limitations were age, body mass index, and smoking history. These observations led the investigators to speculate that general deconditioning may be the cause of the patient’s reported dyspnea and exercise limitation. The absence of association with baseline residual clot burden and cardiopulmonary exercise capacity is also consistent with the long term follow-up study of patients with pulmonary embolism who had systemic thrombolysis, as no benefit was seen on reported dyspnea or exercise capacity. 126

Post-pulmonary embolism syndrome describes a heterogeneous consolidation of symptoms and objective findings that has an important effect on the quality of life of patients with pulmonary embolism. Following patients beyond the acute pulmonary embolism period and screening for persisting dyspnea and functional limitations at three to six months is recommended. An ongoing observational study is evaluating a CTEPH clinical prediction score to select patients for screening with echocardiography ( NCT02555137 ). Until these results are available, we continue to screen all patients reporting persisting dyspnea with a ventilation-perfusion lung scan to evaluate for persistent mismatched defects and transthoracic echocardiogram for pulmonary hypertension. If these are found, these patients are referred to a CTEPH expert center for further diagnostic work-up and treatments. Targeted cardiopulmonary rehabilitation and lifestyle modifications may be offered to the remaining patients, although future research is needed to determine the benefits of such programs.

Psychological impact and quality of life

The diagnosis of a pulmonary embolism has a significant psychological effect on patients, who often refer to such an event as a near-miss death experience. The above described ELOPE study followed a cohort of patients with acute pulmonary embolism over one year and showed an acute decline in both generic and pulmonary embolism specific quality of life scores, but these scores then improved over the one year follow-up. 156 Cancer patients with venous thromboembolism also experience a decline in quality of life scores. 157 Qualitative interviews of patients six to 12 months after a diagnosis of venous thromboembolism reported a major theme of “life changing and forever changed” when describing their lived experience with venous thromboembolism. 158 Some patients also noted a “post-thrombotic panic,” describing feelings of hypervigilance and panic related to fear of illness recurring. A need for greater recognition of patients’ psychological wellness and research into potential targeted supports clearly exists.

Table 6 summarizes the guidelines that seem to be the most relevant, updated, and endorsed by leading international societies concerning management of patients with pulmonary embolism. 14 16 159 Of these, the guidelines from the European Society of Cardiology (ESC) and the American Society of Cardiology (ASH) have been updated within the last one or two years and are thus based on the most recent clinical trials. The completed ASH guidelines are in progress, with six of 10 intended sections published at this time (prophylaxis for medical patients, 160 diagnosis, 161 anticoagulation therapy, 162 pediatrics, 163 heparin induced thrombocytopenia, 164 and pregnancy 53 ). The remaining four sections are expected to be released later in 2020 (treatment, cancer, thrombophilia, prophylaxis in surgical patients). The completed ASH guidelines will represent the most comprehensive and updated guideline set. The guidelines released by the American College of Chest Physicians in 2016 are a partial update of the comprehensive 2012 guidelines. 165 The field of pulmonary embolism has had several important advances in the four years since this release.

Comparison of guideline recommendations from ASH*, CHEST†, and ESC‡ for diagnosis and treatment of pulmonary embolism

Emerging treatments

Anticoagulant therapies targeting coagulation factors IX, XI, and XII are under research and development. 166 167 Of these, factor XIa inhibition is most developed and includes targeted strategies such as antisense oligonucleotide agents to reduce hepatic biosynthesis, aptamers to target DNA or RNA expression, and monoclonal antibodies and small molecules that block activity of factor XIa. 168 169 Two phase II RCTs of novel factor XI inhibitors have been published, both testing various doses after elective knee arthroplasty for the primary outcome of new venous thromboembolism (symptomatic and asymptomatic). Büller et al randomized 300 patients to either 200 mg or 300 mg of FXI-ASO, given as a series of subcutaneous injections staring 36 days preoperatively, or enoxaparin prophylaxis. 170 The 200 mg regimen was non-inferior and the 300 mg regimen superior to enoxaparin (P<0.001). Weitz et al randomized 813 patients post-elective knee arthroplasty to enoxaparin, apixaban, or single intravenous infusions of the factor XIa inhibitor osocimab (BAY1213790) at various dose and schedules (preoperative/postoperative). 171 In this open label dose finding study, osocimab at doses of 0.6 mg/kg, 1.2 mg/kg, and 1.8 mg/kg given postoperatively met criteria for non-inferiority compared with enoxaparin for the primary outcome of new venous thromboembolism (symptomatic or asymptomatic), and the preoperative 1.8 mg/kg dose of osocimab met criteria for superiority compared with enoxaparin (risk difference 10.6, 95% confidence interval –1.2 to 22.4; P=0.07). Further studies are needed to determine the true efficacy and bleeding risk of these novel anticoagulants.

The management of pulmonary embolism has changed considerably over the past decade, most substantially driven by the introduction of direct oral anticoagulation therapies. The convenience of use, lack of routine laboratory monitoring, and lower bleeding rates have allowed a greater acceptance by patients compared with VKAs. Extended treatment duration in selected patients with pulmonary embolism has had a significant effect on risk of recurrent venous thromboembolism. Other important management updates include a recognition of over-investigation and perhaps over-treatment of pulmonary embolism in some patients. The use of clinical probability scores and advances in the interpretation of D-dimer results reduces the use of diagnostic imaging to exclude pulmonary embolism. Recognition of subsegmental pulmonary embolism as a distinct entity and careful evaluation of need for anticoagulation have been important to avoid over-diagnosis and over-treatment. Despite a decade of advances, however, pulmonary embolism continues to have important long term consequences for patients, including chronic dyspnea, diminished exercise capacity, and effects on quality of life. Future research is needed to identify targeted interventions and supports.

Glossary of abbreviations

ASH—American Society of Cardiology

CDT—catheter directed thrombolysis

CTEPH—chronic thromboembolic pulmonary hypertension

CTPA—computed tomography pulmonary angiography

DOAC—direct oral anticoagulant

DVT—deep venous thrombosis

ECMO—extracorporeal membrane oxygenation

ESC—European Society of Cardiology

ISTH—International Society on Thrombosis and Hemostasis

IVC—inferior vena cava

LMWH—low molecular weight heparin

NT-proBNP—N-terminal pro-b-type natriuretic peptide

PERC—pulmonary embolism rule-out criteria

PESI—Pulmonary Embolism Severity Index

pro-BNP—pro-B-type brain natriuretic peptide

RCT—randomized controlled trial

SPECT—Single photon emission computed tomography

sPESI—simplified Pulmonary Embolism Severity Index

VKA—vitamin K antagonist

How patients were involved in the creation of this article

The authors of this clinical review are members of Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) network. This network includes patient partner members. Three CanVECTOR patient partners were consulted for the preparation of the manuscript and were asked to review a proposed outline of topics to include and provided their contributions and feedback. Specifically, patients were asked to review the manuscript outline with the following question in mind: “If your clinicians were to read one review paper for the purpose of updating their knowledge of pulmonary embolism management, which topics do you feel are most important to include?” Additions to the manuscript as a direct result of this engagement with patient partners included a discussion of thrombophilia testing, with specific reference to benefits of thrombophilia testing in patients with identified transient provoking risk factors; a discussion of the detailed management of pregnancies in patient with pulmonary embolism; and a discussion of the psychological impact of a diagnosis of pulmonary embolism in survivors. The final manuscript of this article was reviewed and approved by one lead patient partner from this group.

Questions for future research

Can the use of clinical probability score and D-dimer testing be optimized for the diagnosis of pulmonary embolism in subgroups of patients such as those with a previous history of pulmonary embolism and pregnant women?

What is the appropriate management of a patient with pulmonary emboli located to within the subsegmental pulmonary arteries?

How can clinicians recognize and manage the long term sequelae of pulmonary embolism such as chronic thromboembolic pulmonary hypertension and post-pulmonary embolism syndrome?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: LD and LAC did the primary literature search in collaboration with a health information librarian. LD was the lead author of the manuscript, and LAC wrote the sections on choice of anticoagulation for acute pulmonary embolism, treatment of cancer associated pulmonary embolism, and duration of treatment for pulmonary embolism. MAF guided the writing of the full manuscript. All authors reviewed the full manuscript and contributed to its content and references.

Funding: LAC is supported by Heart and Stroke Foundation of Canada National New Investigator and Ontario Clinician Scientist Phase I award. LD, LAC, and MAF are investigators of the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network; the Network receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654). CanVECTOR’s Patient Partners platform provided support for patient engagement activities..

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.

Provenance and peer review: Commissioned; externally peer reviewed.

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case study of pulmonary embolism

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  • Published: 29 July 2022

A multitask deep learning approach for pulmonary embolism detection and identification

  • Xiaotian Ma 1 ,
  • Emma C. Ferguson 2 ,
  • Xiaoqian Jiang 1 ,
  • Sean I. Savitz 3 &
  • Shayan Shams 4  

Scientific Reports volume  12 , Article number:  13087 ( 2022 ) Cite this article

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  • Computational biology and bioinformatics
  • Computed tomography
  • Image processing
  • Machine learning
  • Medical imaging

Pulmonary embolism (PE) is a blood clot traveling to the lungs and is associated with substantial morbidity and mortality. Therefore, rapid diagnoses and treatments are essential. Chest computed tomographic pulmonary angiogram (CTPA) is the gold standard for PE diagnoses. Deep learning can enhance the radiologists’workflow by identifying PE using CTPA, which helps to prioritize important cases and hasten the diagnoses for at-risk patients. In this study, we propose a two-phase multitask learning method that can recognize the presence of PE and its properties such as the position, whether acute or chronic, and the corresponding right-to-left ventricle diameter (RV/LV) ratio, thereby reducing false-negative diagnoses. Trained on the RSNA-STR Pulmonary Embolism CT Dataset, our model demonstrates promising PE detection performances on the hold-out test set with the window-level AUROC achieving 0.93 and the sensitivity being 0.86 with a specificity of 0.85, which is competitive with the radiologists’sensitivities ranging from 0.67 to 0.87 with specificities of 0.89–0.99. In addition, our model provides interpretability through attention weight heatmaps and gradient-weighted class activation mapping (Grad-CAM). Our proposed deep learning model could predict PE existence and other properties of existing cases, which could be applied to practical assistance for PE diagnosis.

Introduction

Pulmonary embolism (PE) refers to blood clots in the pulmonary arterial system of the lungs, which usually originate in the deep veins of the legs that break loose and travel to the blood vessels of the lung where they become lodged 1 . PE results in decreased blood flow and oxygen to the lung as well as decreased oxygen levels to other organs in the body 1 , 2 . PE is associated with significant morbidity and mortality, and it is the third most common cause of cardiovascular death with an incidence of one case per 1,000 persons in the United States annually 3 , 4 . Numerous risk factors predispose patients to the development of PE, including immobilization, recent surgery, history of clotting disorders, malignancy, obesity, pregnancy, cigarette smoking, certain medications such as birth control pills, medical conditions such as heart disease, among others 1 , 4 , 5 . Early identification and prompt treatment can greatly reduce the risk of death. Thus, accurate diagnosis is crucial in these patients 1 , 4 , 5 , 6 .

Computed tomographic pulmonary angiography (CTPA) is currently the most common imaging modality to diagnose pulmonary embolism 7 . The radiologists’sensitivity for detecting PE is reported to range from 0.67 to 0.87, with a specificity ranging from 0.89 to 0.99 8 , 9 , 10 , 11 . Deep Learning methods have been developed and showed promising results in detecting PE with a high accuracy, which could further assist radiologists’ decisions 8 . For example, Tajbakhsh et al. 12 used a 3D convolutional neural network (CNN) with manually extracted features of CT scans called vessel-aligned multi-planar image representation to predict the presence of pulmonary embolism, achieving sensitivity factors predispose of 83% at 2 false positives per volume. Yang et al. 13 performed a two-stage convolutional neural network with a candidate proposal and a false positive removal subnet. It achieved a sensitivity of 75.4% at two false positives per scan at 0 mm localization error. Instead of using the whole 3D CT scan as an input, Huang et al. 14 used sliced windows as inputs to 3D CNNs as an end-to-end PE detection solution. This approach reached an area under the receiver operating characteristic curve (AUROC) of 0.84 on the hold-out internal test set and 0.85 on an external dataset for PE detection. Moreover, Huang et al. 15 proposed a multimodal fusion with deep learning models, combining CTPA image data and electronic medical records. The best model achieved an AUROC of 0.947 on the entire hold-out test set. However, all these studies only considered datasets with a binary classification indicating the existence of PE. The RSNA Pulmonary Embolism CT (RESPECT) dataset 16 introduced a more challenging problem by containing several study-level labels to predict. Xu’s method 17 achieved first place in the corresponding Kaggle competition 18 . Their proposed model used a CNN network to extract features for slices and then utilized RNN to process sequences of features for final prediction. However, this solution lacked comprehensive evaluations and had relatively low AUROC scores (Table  1 ). Suman et al. 19 also proposed a similar pipeline on the RESPECT dataset and tested their model on a curated external dataset, where the AUROC of positive studies reached 0.949. However, the curated dataset was balanced in positive and negative samples, which was unlikely in real scenarios and publicly unavailable, thus could not be used to compare as a baseline.

In this work, we develop a model that not only detects PE using 3D CTPA images but also predicts the position of PE (left, right, or central), PE condition (acute or chronic), and whether the right-to-left ventricle diameter (RV/LV) ratio is greater or less than 1 in a specific CT image (RV/LV ratio \(\ge 1\) suggests the presence of right heart strain) using the RESPECT dataset. Our proposed model consists of a two-phase pipeline to robustly detect and identify PE position, condition and other properties. The first phase uses a 3D CNN for feature extraction and a temporal convolutional network (TCN) 20 with attention mechanisms in the second phase to perform sequential learning. First, we split the 3D CT scan image into smaller 3D windows to train a deep 3D CNN model. This can capture local contextual information of 3D windows containing several 2D slices. The second-phase model utilizes the learned features in the first step to learn the PE attribute at a study level, we treat the selected features from 3D windows as a sequence and use TCN for sequential learning. In addition, PE only exists in a small subset of studies in our dataset. We, therefore, utilize attention mechanisms to assign weights for features in a sequence, where higher weights indicate higher probabilities of the existence of PE. We train different attention modules for different attributes of PE, since each attribute may focus on different subsets of the whole scan. Besides, integration of CNN and the attention layer introduces interpretability to our model by highlighting the specific region that our model focuses on for prediction. The results of the two phases are reported in the “ Results ” section, and the classification performances, interpretation outcomes, limitations, and contributions are discussed in the “ Discussion ” section. The details of our dataset, model, and implementation are described in the “ Methods ” section.

Since the data are imbalanced, it would be improper to evaluate the model by prediction accuracy. Thus, we draw the receiver operating characteristic (ROC) curves for each study-level label and compute the AUROC as well. In addition, we produce and examine the sensitivity vs. specificity plots to determine the thresholds of positivity for nine study-level labels. Besides the study-level results obtained after the whole pipeline, ROC curves, AUROC scores, and sensitivity vs. specificity plots are used to evaluate the second-phase training that classifies 3D windows for the window-level label and studies for the nine study-level labels.

First phase: feature extraction

figure 1

t-SNE plot for all the extracted features of the training set from the first-phase training. The features are extracted from the fine-tuned 3D ResNet-18 model and are 512-d vectors, which are then embedded in the 2D space by t-SNE for visualization. The two groups of positive (orange) and negative (blue) samples are separated well in the 2D space.

The target of the first-phase training is to learn the features for 3D CT scan windows that will be used as inputs for the second phase. Therefore, the learned features from the test samples, extracted from the penultimate layers, are visualized in a 2D embedding space by t-distributed stochastic neighbor embedding (t-SNE) 21 . The two classes are separated well as visualized in Fig. 1 . We further analyze the separation by Manhattan distances in the 512-d feature space. We calculate the means for positive samples and negative samples in the 512-d space, denoted as CP and CN respectively. The average Manhattan distance from all the positive samples to CP is 70.15, and that from all the negative samples to CN is 75.70. The distance between CP and CN is 97.21, which indicates that the positive and negative samples are separated well in the 512-d feature space. These well-separated and distinctive clusters among embedded features obtained in the first phase indicate the high quality of feature selection and information embedding in the first-phase model. Therefore, these features could be utilized further in the downstream second-phase training. In addition, the ARUOC on the test set for window-level classification of the first-phase training is 0.9134.

Second phase: fine-grained classification

The second-phase learning takes the features of 3D windows of a CT image as inputs and predicts the window-level labels and the study-level labels, providing the final prediction of the PE detection task.

Prediction performance indicated by ROC curves and AUROCs

figure 2

Plots of ROC curves. ROC curves for the window-level ( a ) and nine study-level ( b ) predictions on the test set in the second phase. The values of AUROCs are reported in the parentheses.

The ROC curves of the window-level label and nine study-level labels on the test set for the second training are shown in Fig. 2 . The AUROC on the test set for the window-level label increases from 0.9134 of the first-phase training to 0.9258 after the second-phase training. Most of the study-level labels are predicted with AUROCs above 0.85. The AUROCs for central PE and right PE are 0.9477 and 0.9233, respectively. This high performance demonstrates that the model has a great advantage in not only predicting the existence of PE, but also the properties of PE. Table 1 shows the classification performance comparison using AUROC on the same hold-out test set between our model and two previous approaches: (1) Xu’s method 17 in terms of the window-level label and nine study-level labels; and (2) PENet 14 in terms of the window-level label and one study-level label indicating negative for PE. Both models are re-trained using the same training and validation set as ours. The comparison shows that we outperformed their results for all labels by a large margin.

Sensitivities and specificities

figure 3

Sensitivity vs. specificity plots. Sensitivity (blue) vs. specificity (orange) for the window-level label (‘pe_present_on_window’on the top indicating whether the PE is present in a certain window) and nine study-level labels over the test set.

Figure 3 shows the sensitivity vs. specificity plots of the test set on the window-level label (whether PE exists) and nine study-level labels. The sensitivities and specificities are calculated as follows:

We select the probability thresholds according to the sensitivity vs. specificity plots of the validation set, and the selected thresholds aim to maximize both sensitivity and specificity. For example, the probability threshold of 0.15 for left PE results in a sensitivity of 0.81 and a specificity of 0.86. The thresholds for the nine study-level labels are reported in Table 2 . We can see in Fig. 3 that the sensitivity of detecting PE from a window level reaches 0.86 with a specificity of 0.85, and 0.82 with a specificity of 0.90 on our test set, which is competitive with the radiologists’sensitivity for detecting PE ranging from 0.67 to 0.87 with a specificity of 0.89 to 0.99 generally 8 .

Our proposed two-phase deep learning model for PE detection and identification of its properties could be a helpful tool for radiologists. This method can help to predict the presence of PE, highlighting regions of interest with varying degrees of certainty so that the patient receives a faster and more accurate diagnosis. This tool can help to identify life-threatening PEs, specifically those that are central and acute. It is essential to identify these PEs early since they are associated with higher mortality. This tool can also help rule out PE and different subtypes of existing PE, thereby allowing radiologists to prioritize studies and triage patient care appropriately.

figure 4

Interpretation with Grad-CAM and attention weights. True positive ( a – d ) and false negative ( e , f ) samples of Grad-CAM and original image for positional labels. For each sample, the processed CT image (right) and the corresponding attention-mapped image are paired (left). The red arrow points to the precise location of the PE identified by an experienced radiologist. The heatmap below shows the attention weights of all windows in the study containing the image above, while the orange square marks the exact window that includes the image. Darker colors in the heatmap illustrate larger attention weights.

To introduce interpretability and highlight the features selected by the model during prediction, we use Grad-CAM 22 . Here, we focus on the position of the present PE and show selected samples of the true-positive and false-negative results according to the probability thresholds determined in Table 2 . Figure 4 illustrates the selected Grad-CAM images and original images for the three positional labels: central, left, and right PE. In addition to the Grad-CAM visualization, we also show the attention weights as the saliency map over the sequences of 3D windows, where darker colors indicate higher attention weights.

Figure 4 a–d show the true positive samples. This demonstrates that the model could locate the position of a PE properly. Figure 4 a,b are the right lower lobe sub-segmental PEs. The PE in Fig. 4 a is located in a peripheral pulmonary artery branch. It is centrally located in the artery and almost completely occludes the blood vessel, indicating that it is acute. The PE in Fig. 4 b is also acute, and it occludes the right lower lobe pulmonary artery branch. Figure 4 c indicates a tiny, left lower lobe pulmonary embolism in a peripheral branch that is acute and does not occlude the vessel. Figure 4 d shows a large PE within the left main pulmonary artery, which is acute and occludes the blood vessel. This kind of centrally located PEs is associated with a higher mortality rate. The attention maps of all the examples above show that the attention weights over the corresponding windows are high, leading our model to pay more attention to those windows with PE present. Some of the selected windows may not have the exact highest attention weight in the sequence, which seems to be a “shift”, but they are generally much higher than the vicinity and are very close to the highest weights if not the same. Also, one sequence could have more than one window showing defects, and we only selected one of the windows to illustrate the details, because it involves great human labor to annotate the actual defects, and we could only select a small subset of the images for annotation instead of annotating all of them. Although our model achieves promising results, there are still many false-negative samples that we need to inspect. Figure 4 e,f are two examples of false-negative predictions. Our model fails to detect a small left lower lobe segmental and sub-segmental PE located in Fig. 4 e. It does not occlude the blood vessel, and contrast passes around it. In addition, the attention map shows that our model fails to pay attention to the corresponding window that contains this image. Figure 4 f displays a right upper lobe segmental PE that is acute but not detected by our model. The attention map shows that the attention weight of the corresponding window are not the highest.

This study also has important limitations. The Grad-CAM for interpretability is only performed on the first-phase training, not going through the parameters of the sequential model in the second phase. In addition, the study-level labels are hierarchical, and some labels may be directly determined by others. For example, a study labeled negative for PE should also be labeled negative for left PE. However, in our model, we do not consider the dependency between the labels and the predicted study-level labels could be inconsistent.

In conclusion, our contribution can be summarized as follows:

Our two-phase method can detect PE and predict several attributes of existing PE at a study level.

We split each 3D CT scan image into several smaller windows, ensuring that the model learns local contextual information.

By implementing multitask attention mechanisms before predicting the study-level labels of PE, our proposed model could focus on specific items in a sequence corresponding to certain attributes for a certain label instead of the whole sequence for all the labels.

We also visualize and interpret our model using gradient-weighted class activation mapping (Grad-CAM) 22 and label-specific attention heatmaps to provide insight into the modeling process, alleviating the“black-box”problem of deep learning models.

Our proposed deep learning approach could be a useful tool to facilitate radiologists in PE diagnosis. Future works will include designing more efficient 3D CNN to extract informative features, applying better sequential models for the second-phase learning, and solving the hierarchical dependency of the property labels.

This section will introduce our method in terms of its architecture (3D CNN in the first phase for feature detection and TCN for classification in the second phase) and various modules (attention mechanism, loss functions, and interpretation methods). Briefly, the first-phase training extracts features for 3D windows, and the second-phase training takes the extracted features from 3D windows as sequential inputs for final prediction.

The utilized dataset is obtained from the Kaggle competition RSNA STR Pulmonary Embolism Detection 16 , 18 . There are 7279 studies in total, and each study consists of multiple 2D slices. The number of 2D slices ranges from 63 to 1083 for the whole dataset, but in 80% of studies, the number of 2D slices ranges from 190 to 296. The dataset has both study-level and slice-level labels. Each slice has a label indicating whether there are any forms of PE present in the slice, while each study has another nine labels indicating other aspects of PE at a study level, such as whether the study is negative for PE, the position of PE (left, right, central), the RV/LV ratio (greater or less than 1), whether the PE is acute or chronic, and whether the PE is indeterminate. The whole dataset is split into 1000 validation studies, 1000 test studies, and 5292 train studies. The positive rates for the nine study-level labels on the train, validation, and test set are reported in Table 3 .

Data processing

figure 5

Illustration of data processing. ( a ) Localizing the lung areas according to lung segmentation masks. ( b ) Splitting the whole 3D CT scan into smaller 3D windows. ( c ) Converting single-channel images into 3-channel images.

Figure 5 illustrates the data processing steps. Each study contains an average of 246 slices, and the slices are sorted by the z-axis position from bottom to top to ensure the orders. The raw DICOM pixels are transformed to Hounsfield unit (HU) according to the intercept and slope from the raw data for each study: \(\text {HU pixel} = \text {raw pixel} \times \text {slope} + \text {intercept}\) . Since each slice has a different thickness, we also resample the slices in each study to ensure the thicknesses are in the same magnitude, i.e., 1 mm for all three dimensions. The labels are also resampled in the same way as the corresponding slices. In addition, lung segmentation 23 is performed on each slice to decrease the noise, and then we localize the lung area in each study by a 3D bounding box derived from the segmentation masks (Fig.  5 a). The labels are also truncated, and only those for the slices inside the bounding box remain.

Furthermore, we treat the processed slices in each study as a 3D image and then split the whole image into several small 3D windows (Fig.  5 b). Each window contains 10 slices, and the shape is thus \(10 \times H \times W\) , where H and W are the height and width of the slices, respectively. We transform each 3D window into three channels by clipping the HU pixel according to different window levels (Fig.  1 c) 24 . In practice, we set the window level ( L ) and window width ( W ) tuples ( L ,  W ) of the boundaries to be \((-600, 1500)\) (lung), (100, 700) (PE), and (40, 400) (mediastinal) 6 . The upper and lower boundaries for clipping the image are \(L \pm W / 2\) respectively, which are \((-1350, 150)\) , \((-250, 450)\) , and \((-160, 240)\) . The clipped image is then normalized to the range of [0, 1].

First phase: 3D CNN

figure 6

Illustration of the overall pipeline. ( a ) First-phase training framework to extract features. ( b ) Second-phase sequential training architecture. ( c ) Details of temporal neural network (TCN) 20 in training phase 2. ( d ) Attention mechanism used in training phase 2.

Figure 6 shows the overall pipeline that we used for training. The model in the first phase is a 3D CNN extracting features from 3D windows of pre-processed image slices (Fig. 6 a). The average number of split 3D windows in each study is 32. If one of the slices in a window has PE on it, the label for the window is 1, otherwise 0. The purpose of the first-phase training is to learn features that could capture useful information from the 3D windows and then send them into the second phase for further training. As a result, we use the pre-trained 3D ResNet-18 model 25 provided by PyTorch 26 . The 3D ResNet-18 model, which is a simple and effective backbone for classifying videos or 3D images and is efficient to implement, meets the purpose of the first phase well to extract informative features (as shown in Fig. 1 ). We then fine-tune the pretrained 3D ResNet-18 model by replacing the output of the last layer with a scalar to fit our binary labels and retraining the model initialized by pretrained weights using the 3D image windows (i.e., a cubic extracted from the original image) of our own dataset. After training, we extract the outputs of penultimate layers as learned features for the 3D windows, which are treated as inputs to the second phase of the model for sequential learning. The size of the extracted feature is 512 which is pre-defined in the 3D ResNet-18 architecture. As a result, we get a 512-d feature for each 3D window. More implementation information is reported in the “ Implementation details ” section.

Loss function

The loss function for the first phase is the binary cross-entropy loss. For each 3D window \(\mathbf {I} \in \mathbb {R}^{C \times D \times H \times W}\) , the output logit is thus \(z \in \mathbb {R}\) , and the ground truth label is \(y \in \{0, 1\}\) . The loss for window i can be described as

where \(\sigma (\cdot )\) is the sigmoid function. For each mini-batch of size M , the loss function is then defined as

Second phase: sequential model with attention

The second phase (Fig. 6 b) of training uses the features extracted in phase 1 from 3D windows of a CT image in each study as sequential inputs. The sequence length is set to 40. If a sequence has less than 40 elements, zeros are padded to the end of the sequence; otherwise, the sequence is resized to the length of 40. To extract more information from the context, we subtract each feature of a certain 3D window from the features of its two neighbors and use these two differences as additional inputs by concatenating them to the original feature to form a new 1536-d feature. Then the sequences of new features are sent to a TCN 20 to capture the overall sequential information. Afterward, the outputs of TCN are used for slice-level prediction, i.e., predicting whether there exists PE on each slice. Meanwhile, nine attention heads are attached to the outputs of the TCN for the downstream prediction of nine study-level labels. Finally, the sum of the outputs of TCN weighted by the attention scores is treated as final embeddings, and we predict each of the nine study-level labels by a two-layer multilayer perceptron (MLP). More implementation information is reported in the “ Implementation details ” section.

Temporal convolutional neural network (TCN)

The basic residual block of TCN is shown in Fig. 6 c. It uses dilated convolutional layers to increase the receptive field. In addition, the inputs of the block are added to the outputs as the original residual block 27 . This allows the block to learn residuals to the identical mapping instead of the entire transformation, which could ensure the stabilization of deeper networks and increase the expressive power 20 , 27 . Each block consists of two dilated convolution layers with dilation d and kernel size k , and each layer is followed by weight normalization, ReLU activation, and dropout. If the output and the residual input have different dimensions, a convolution layer with a kernel size equal to 1 will be added to ensure the dimensions are the same when adding. Then the basic residual block is stacked by n levels, and for the i -th level’s block, the dilation is set to be \(d=2^i\) . In our implementation, the kernel size is \(k=3\) , the number of levels is \(n=2\) , and the dropout ratio is 0.2. The padding for each convolution operation is \((k-1) \cdot d\) and the stride is 1 to make sure the output has the same sequence length as the input. The number of output channels is 128. After transpose, we get 128-d embeddings from the input 1536-d features. The embeddings are either used to classify window-level labels or are sent into several attention mechanisms to obtain study-level predictions.

Attention mechanism

The input feature sequences are treated as both keys and values in the attention mechanism (Fig. 6 d). We denote the feature sequence after the TCN as a matrix \(\mathbf {X} \in \mathbb {R}^{n \times d}\) , where n is the length of the sequence, and d is the dimension of each feature in the sequence (in this case, \(n=40\) and \(d=128\) ). We set the query vector \(\mathbf {w}_q \in \mathbb {R}^d\) as a parameter to learn through the training, which has the same dimension of each feature. The attention weights \(\mathbf {a} \in \mathbb {R}^n\) are obtained from the activation of dot product of keys and queries, and the outputs \(\mathbf {e} \in \mathbb {R}^d\) are the weighted sums of the inputs by attention weights on the sequence level:

In the “ Visualization and interpretation ” section, we also use the attention weights to illustrate the importance of each 3D window that contributes to a certain output label.

The loss function for each predicted label is the binary cross-entropy loss as used in the first phase. Suppose in a mini-batch containing M studies and each study containing \(N_i\) windows, \(z_{ij} \, (j = 1,2,\ldots ,N_i)\) denotes the output logit for the window j in study i , and \(z_{ik} \, (k = 1,2,\ldots ,9)\) denotes the logit for the study-level label k in study i . The window-level loss for the 3D window j in study i is defined as

where w is the weight and \(q_i\) is the proportion of positive image windows in study i . The study-level loss of study i for the k -th study-level label is

where \(w_k\) is the weight for the label k which is pre-defined in the Kaggle competition’s evaluation method, accounting for the relevant importance of the label 28 . Thus, for a mini-batch containing M studies with \(N_i\) windows in study i , the final loss for a mini-batch is

Visualization and interpretation

We first capture the attention weights on 3D windows for each of the nine labels. This helps us focus on specific features in the sequences and thus directs us to the original 3D window corresponding to those features. Furthermore, we use Grad-CAM 22 to visually explain the 3D CNN with those selected windows as inputs. Grad-Cam is a localization technique for CNN-based networks, which computes the gradients flowing into the final convolutional layer from a certain target to output heatmaps that highlight specific areas of interest. These areas of interest could be interpreted as the important regions in an image which the network focuses on to predict the target.

Implementation details

figure 7

Bar charts of hyperparameter tuning. ( a ) First phase. We tune the batch size (8 and 16) based on AUROC and the optimal one is 16. ( b ) Second phase. We tune the dropout ratio (0 and 0.2) and the number of output channels in TCN (64 and 128) based on loss value. The optimal combination is that the dropout ratio is 0.2 and the number of output channels in TCN is 128.

The two-phase models are trained and tested using a single NVIDIA A100 Tensor Core GPU. The optimizer used for the first-phase training is Adam with a learning rate of 0.0004, and the batch size is 16 selected by hyperparameter tuning (Fig. 7 a). We train the model 20 epochs and select the one with the maximum AUROC on the validation set among all the AUROCs of 20 epochs for testing. We also resize the original 2D image slices to \(224 \times 224\) and then apply 3D random crop and \(15^{\circ }\) rotation to the 3D windows to get \(10 \times 192\times 192\) 3D images when training, while we directly resize each 2D image slices to \(192 \times 192\) for validation and testing. For the second-phase training, we use Adam optimizer with an initial learning rate 0.0005 decayed every 20 training steps by a multiplicative factor 0.9. The batch size is 64 and the number of epochs for training is 200. We select the dropout ratio as 0.2 and the number of output channels in TCN as 128 by hyperparameter tuning (Fig. 7 b). The model with the minimum loss value on the validation set among all the losses of 200 epochs is selected for testing. To select the best model on validation set, we compare the loss in each epoch with the minimum one in all previous epochs, and save the model if the loss in the current epoch is less than the previous minimum one, instead of using early stopping or performing manually via observation.

Statistical analysis

The evaluation of the first-phase training includes the t-SNE analysis of the extracted features from the training set, and the evaluation of the second-phase training includes the AUROC, sensitivity, and specificity. The 95% DeLong confidence intervals for AUROCs are calculated to measure the variability. We also draw the plots of ROC and sensitivity vs. specificity for all the labels on the test set to better display our results. In addition, the probability thresholds for predicting positive samples are determined by the sensitivities and specificities on the validation set, which ensure high sensitivities while keeping reasonable specificities.

Data availability

The data that support the findings of this study are obtained from Radiological Society of North America (RSNA) and are publicly available from RSNA STR Pulmonary Embolism Detection Kaggle competition ( https://www.kaggle.com/competitions/rsna-str-pulmonary-embolism-detection/data) . We also acquired institutional review board approval under protocol HSC-SBMI-13-0549. Since it is a public dataset, we do not need to go through ethical approval.

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Acknowledgements

X.J. is CPRIT Scholar in Cancer Research (RR180012), and he was supported in part by Christopher Sarofim Family Professorship, UT Stars award, UTHealth startup, the National Institute of Health (NIH) under award number R01AG066749 and U01TR002062.

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Xiaotian Ma & Xiaoqian Jiang

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X.M. conducted the experiments. X.M. and E.F. led the writing of the paper. X.J., S.S., and S.S. were responsible for the investigation, conceptualization, and methodology of the project. E.F. and S.S. clinically validated the results. All contributed to writing the paper and conducted the final approval of the version to be published. All authors agreed to submit the report for publication.

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Ma, X., Ferguson, E.C., Jiang, X. et al. A multitask deep learning approach for pulmonary embolism detection and identification. Sci Rep 12 , 13087 (2022). https://doi.org/10.1038/s41598-022-16976-9

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case study of pulmonary embolism

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Life after pediatric pulmonary embolism

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Marilyn J. Manco-Johnson; Life after pediatric pulmonary embolism. Blood 2024; 143 (7): 569–570. doi: https://doi.org/10.1182/blood.2023023264

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Massive, submassive, right heart strain, heart failure…these words inject fear and terror into the hearts of parents upon hearing test results diagnosing and characterizing pulmonary embolism (PE) in their child or adolescent. In this issue of Blood , Bastas and colleagues 1 address practical questions about life after pediatric PE related to how comfortably children are able to breath and how active they are able to be.

In a comprehensive long-term follow-up of 150 children and teens (<18 years, median age 16) with PE, the study showed a low rate of mortality (5%), recurrence (9%), and thrombus nonresolution (29%). Similarly, rates of chronic thromboembolic pulmonary hypertension (0.7%), post-PE cardiac impairment (0.7%), and post-PE chronically abnormal echocardiograms (4%) were low. These data are comparable to numerous previous reports. 2-10 The original contributions of this study from Bastas et al are the comprehensive post-PE exercise tolerance testing, stratification of outcomes in children by the presence or absence of underlying conditions, and determination of alternative explanations for abnormal findings. Two-thirds of the group without underlying conditions were female, of whom 70% were using oral contraceptives, while the group with underlying conditions (autoimmune, cancer, infections, cardiac disease and other) had more cases of hospital-acquired thrombosis and major thrombophilia. Overall, the study determined subjective dyspnea in about a quarter of children in follow-up ≥3 months following PE, with no difference related to the presence of underlying condition, but only 1% had persistent PE-related dyspnea when other potential causes were excluded (see figure ). Similarly, ≥3 months after presentation with PE, 31% of the children had impaired aerobic capacity on exercise testing, again with no difference in underlying condition, in percent peak heart rate, peak workload in watts, peak oxygen saturation (SPO 2 ), or exercise-induced desaturation. Ultimately only 8.5% of children had functional exercise impairment. Most children with long-term functional impairment were found to have decreased exercise performance based on deconditioning with the prevalence of deconditioning and impaired exercise tolerance, higher in children with major underlying medical conditions.

Functional outcomes of PE in pediatric patients. Professional illustration by Patrick Lane, ScEYEnce Studios.

Functional outcomes of PE in pediatric patients. Professional illustration by Patrick Lane, ScEYEnce Studios.

PE has a high risk of dire outcomes in older adults with half of adults suffering post-PE syndrome with chronic thromboembolic pulmonary hypertension, cardiac impairment, or functional impairment. The Bastas study on pediatric PE gives encouraging results that the outcome of PE in most pediatric patients is excellent, despite a high proportion of short-term abnormal test results, with a very low rate of long-term poor cardiopulmonary function or diminished aerobic capacity. This is likely due to the healthy heart and lungs of the pediatric patients prior to the episode of PE.

The article by Bastas et al has implications for immediate application to clinical practice. Despite frequent symptomatic and testing abnormalities at diagnosis and short-term follow-up, ultimately most of the abnormal outcomes were exercise intolerance related to deconditioning, often in the setting of severe underlying conditions that precluded active exercise. This article should inform pediatric practice to encourage return to aerobic sports and activities following PE as soon as physically feasible (usually starting gradually 4 weeks after presentation) in those who were previously able to participate, to focus enhanced outcome surveillance and intervention on children with preexisting conditions and to encourage children, adolescents and their parents that the outlook for future cardiopulmonary function and sports participation following PE is bright. Additionally, while this study is not the first to implicate oral contraceptives in adolescent female PE, it should resurrect a discussion of whether the use of progesterone only hormonal therapies in young teenaged girls is warranted to decrease this rare but potentially serious thrombotic complication.

Unanswered questions center around the best approaches for exercise rehabilitation in both previously well children and adolescents as well as those with significant debilitating medical conditions following an episode of PE. Also unknown are the long-term adult cardiopulmonary ramifications of pediatric PE. Finally, the psychosocial issues for parents allowing their children to return to strenuous sports and activities following a frightening intensive care unit stay for PE deserve to be explored. PE remains a serious condition that is increasing in pediatric patients, but the current study adds to our knowledge base guiding efforts to optimize functional outcomes.

Conflict-of-interest disclosure: The author declares no competing financial interests.

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Factors Associated with Acute Pulmonary Embolism in Patients with Hypoxia After off-Pump Coronary Artery Bypass Grafting: A Case-Control Study

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  • 1 Department of Endocrinology, Tianjin Chest Hospital, Tianjin, 300070, People's Republic of China.
  • 2 Department of Cardiac Surgery, Tianjin Chest Hospital, Tianjin, 300070, People's Republic of China.
  • 3 Department of Imaging, Tianjin Chest Hospital, Tianjin, 300070, People's Republic of China.
  • PMID: 38343756
  • PMCID: PMC10859096
  • DOI: 10.2147/JMDH.S447534

Purpose: This study aims to explore the factors linked to the occurrence of acute pulmonary thromboembolism (PE) within a cohort of patients exhibiting hypoxic saturation (oxygen saturation levels falling below 93%), subsequent to undergoing off-pump coronary artery bypass grafting (OPCABG).

Methods: A retrospective case-control study was conducted. A total of 296 patients met the inclusion and exclusion criteria, divided into PE group (100 cases) and non-PE group (196 cases) according to whether they had PE or not. The preoperative and postoperative information of patients were collected and statistically analyzed.

Results: The results from a multivariate logistic regression analysis indicated the following factors were independently linked to PE following OPCABG: history of smoking (OR = 3.019, 95% CI, 1.437-6.634, P = 0.004), preoperative arterial oxygen partial pressure ≤78.9 mmHg (OR = 3.686, 95% CI, 1.708-8.220, P = 0.001), presence of postoperative lower extremity deep venous thrombosis (OR = 4.125, 95% CI, 1.886-9.310, P < 0.001), elevated postoperative D-dimer levels >6.76 mg/l (OR = 8.078, 95% CI, 3.749-18.217, P <0.001), postoperative NT-BNP levels (OR = 1.001, 95% CI: 1.000-1.001, P = 0.011), and elevated postoperative pulmonary arterial pressure >33.0 mmHg (OR = 10.743, 95% CI: 3.422-37.203, P < 0.001). The developed nomogram exhibited a high predictive accuracy with an area under the curve of 0.913 (95% CI: 0.878-0.948).

Conclusion: When patients have a history of preoperative smoking, decreased preoperative arterial oxygen pressure, postoperative lower limb DVT, increased postoperative pulmonary artery pressure, and elevated postoperative D-Dimer and NT pro-BNP levels, it is recommended to take perioperative preventive measures, timely diagnostic evaluation, and if necessary, anticoagulant treatment. In addition, the results of this study may improve the diagnostic sensitivity of medical staff for postoperative PE in OPCABG, thereby increasing the detection rate and potentially reducing the need for excessive medical imaging procedures.

Keywords: case-control study; off-pump coronary artery bypass grafting; prediction model; pulmonary embolism; risk factor.

© 2024 Yu et al.

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Case Reports in Oncology

Introduction

Case presentation, statement of ethics, conflict of interest statement, funding sources, author contributions, data availability statement, pulmonary tumor thrombotic microangiopathy in a patient with rapid progressive triple-negative breast cancer.

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Fiona Rudolf , Albert Baschong , Deniz Bilecen , Nicola Aceto , Marcus Vetter; Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Rapid Progressive Triple-Negative Breast Cancer. Case Rep Oncol 3 January 2024; 17 (1): 277–282. https://doi.org/10.1159/000535873

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Introduction: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of metastatic carcinoma, which occurs in patients with pulmonary arterial hypertension, and is mostly fatal. Circulating tumor cell clusters have been recognized as critical factors during breast cancer progression. Case Presentation: An 80-year-old woman with triple-negative breast cancer was admitted to our hospital with progressive dyspnea and lower back pain. Breast cancer treatment included mastectomy, neoadjuvant and adjuvant chemotherapy as well as adjuvant radiotherapy, receiving her last cycle of radiotherapy 8 days before death. At admission, D-dimers were strongly elevated and platelets were low. NT-pro-BNP was moderately elevated. A CT scan of the chest did not show pulmonary embolism but revealed interlobular septal thickening, centrilobular consolidation, and distension of the pulmonary arteries. Moreover, new skeletal and most likely lymphatic metastasis was described. Treatment with oxygen and oral glucocorticoids was initiated, assuming radiotherapy-induced pneumonitis. Due to low expression of PD-L1 and her markedly bad performance status, tumor-specific therapy was not possible, and the treatment regimen was changed to best supportive care. The patient died 8 days after admission. Autopsy revealed numerous events consistent with tumor emboli in the pulmonary vessels, suggesting PTTM. Conclusion: PTTM is a rare and mostly fatal complication in malignant breast cancer. As an early detection is difficult, further investigation is needed. Circulating tumor cluster cells may be one way to detect PTTM early and improve patients’ survival.

Triple-negative breast cancer is a type of breast cancer that does not express the estrogen receptor and progesterone receptor and lacks gene amplification of the epidermal growth factor 2 (HER2). The standard treatment for triple-negative breast cancer is surgery, followed by chemotherapy and/or radiation therapy. Newer therapy regimens include immunotherapy. The mortality rate from triple-negative breast cancer has been declining over the past few decades [ 1 ]. One end-stage manifestation of malignancies is a pulmonary tumor embolism. This is a clot, containing embolized tumor cells, that originates in a tumor and lodges in the lungs. They are considered to be relatively rare, being detected in about 5% of breast cancer patients [ 2 ].

Activation of the coagulation system on the surface of the pulmonary embolic tumor clot and intimal proliferation is a syndrome called pulmonary tumor thrombotic microangiopathy (PTTM), which is a rare and severe complication and can lead to pulmonary hypertensive arteriopathy, first described in 1990 by von Herbay et al. [ 3, 4 ]. Typical symptoms include cough, dyspnea, and other signs of right heart failure [ 5, 6 ]. Antemortem diagnosis is difficult due to nonspecific symptoms and lack of clear radiological findings. Treatment options for a pulmonary tumor embolism and PTTM, respectively, consist of treatment of the primary tumor; further supportive measures are application of oxygen and intravenous glucocorticoids. The role of anticoagulants and thrombolytic therapy is not clear in this context. There is no certain way to prevent a pulmonary tumor embolism, but early detection and treatment of breast cancer may help reduce the risk [ 7 ]. Detection of circulating tumor cells (CTCs) and CTC clusters is a newer method for cancer monitoring [ 8 ], and an association between the presence of CTC clusters and microembolism has been found [ 9 ].

We present a case of PTTM in the setting of triple-negative breast cancer treated at the Cantonal Hospital of Basel-Land, a secondary care hospital with approximately 300 beds in Northwestern Switzerland. With this case report, we would like to recall this rare diagnosis and present newer diagnostic possibilities using detection of CTCs. The CARE Checklist has been completed by the authors for this case report, attached as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000535873 ).

An 80-year-old woman was admitted to the emergency department of our hospital with dyspnea and without other respiratory symptoms or fever. She had back pain, which started 1 week before admission, radiating in the right knee. She had similar complaints a year before, due to a herniated disc. The patient’s past medical history included triple-negative, node-positive cancer of the right breast (cT3 cN1 cM0 G2, estrogen receptor- and progesterone receptor-negative, HER2-negative, PD-L1-negative, BRCA-negative) diagnosed 7 months earlier. After eleven cycles of chemotherapy with paclitaxel and carboplatin, a mastectomy was performed. Subsequently, she received adjuvant chemotherapy with capecitabine and percutaneous radiotherapy of the right breast inclusive of axillary, paraclavicular and parasternal lymphatic drainage. When radiotherapy was completed, she had shortness of breath on light exertion. At admission, tachypnea was present with a respiratory rate of 24 breaths per minute and an oxygenation saturation of 89% breathing ambient air. The heart rate was 78 beats per minute, and blood pressure 160/76 mm Hg. The hemoglobin level was 11.2 g/dL, and the platelet count was 68,000/mm 3 . The white blood cell count was 7,400/mm 3 , with 79.6% neutrophils. Serum C-reactive protein was elevated (80 mg/L), and the sodium level was decreased (125 mmol/L), diagnosed as syndrome of inadequate antidiuretic hormone secretion. A pronounced D-dimer elevation (55 μg/mL) was also detected. The patient’s characteristics are summarized in Table 1 .

Patients characteristics

LDH, lactate dehydrogenase.

A CT scan with pulmonary embolism detection program of the chest revealed smooth interlobular septal thickening with centrilobular consolidation and pleural effusions, as shown in Figure 1 . Angiography of the greater pulmonary arteries was negative for pulmonary embolism, and there were no signs of acute right heart failure, but signs of chronic pulmonary arterial hypertension were evident. Additionally, progressive mediastinal lymphadenopathy and right mammary soft tissue thickening, highly suspicious for a locoregional recurrence of the breast cancer, were detected. Further, the CT scan showed multiple metastases and suspect sclerotic lesions in the thoracic spine.

CT scan of the chest demonstrating (blue) thickened interlobular septa, (red) centrilobular faint compression.

CT scan of the chest demonstrating (blue) thickened interlobular septa, (red) centrilobular faint compression.

Advanced tumor progression was suspected, but neither chemotherapy (due to the poor condition [ECOG 3] and low platelets) nor immunotherapy (due to low PD-L1 expression in a previous biopsy) nor an antibody-drug conjugate (due to hematotoxicity) was a causative treatment option. Symptomatic treatment for the respiratory distress consisted of oxygen, inhalation therapy with anticholinergic and beta-agonist bronchodilators, as well as oral corticosteroids. A follow-up CT scan of the chest 7 days later showed regressive pulmonary congestion. The platelets continued to decrease with a count of 22,000/mm 3 7 days after admission. The patient’s condition massively deteriorated under the initiated therapy, and finally, end-of-life-care was initiated, given a situation with rapidly progressive carcinoma. The patient died 8 days after admission.

An autopsy was then performed, revealing numerous tumor embolisms in the small- and medium-sized pulmonary vessels, partly with associated thrombi indicating PTTM ( Fig. 2 ). In addition, advanced metastatic disease with manifestations in the liver, non-regional lymph nodes, visceral pleura, all vertebral bodies, both suprarenal glands, and the mucosa of the stomach was found. The histomorphology was consistent with the pre-diagnosed triple-negative breast cancer.

Histology of pulmonary vessels. a, b Multiple tumor cells within the lumen of pulmonary vessels and thrombus formation (H and E, ×100). c, d High-power field of an obstructed small pulmonary vessel (H and E, EVG ×400). Legend: black arrows point at embolized tumor cell clusters; x: artery, +: clot, *: bronchioles.

Histology of pulmonary vessels. a , b Multiple tumor cells within the lumen of pulmonary vessels and thrombus formation (H and E, ×100). c , d High-power field of an obstructed small pulmonary vessel (H and E, EVG ×400). Legend: black arrows point at embolized tumor cell clusters; x: artery, +: clot, *: bronchioles.

Diagnosis of PTTM is difficult and mainly postmortem. Most cases are described as gastric carcinoma, followed by breast carcinoma and lung carcinoma; histologically, mostly adenocarcinoma [ 10 ].

PTTM is characterized by an embolization of the pulmonary vasculature through CTCs [ 3, 10 ]. Histologically, fibrocellular intimal proliferation of small pulmonary vessels can be seen. This eventually can lead to stenosis and occlusion of the pulmonary vessels through the tumor cells themselves and through local release of tissue factors, leading to thrombosis due to activation of the coagulation system [ 5, 11, 12 ]. CTCs and CTC clusters are associated with severe outcome with rapid progression and early death in patients with metastatic breast cancer [ 13 ]. Recently, Gkountela et al. [ 14 ] demonstrated that the ability of CTCs to form clusters has been linked to increased metastatic potential. Furthermore, there is an association between CTCs, circulating tumor microemboli, and intravascular coagulation activation in progressive breast cancer [ 9, 12 ]. In this patient, detection of CTCs and CTC clusters was not performed, but retrospectively, it might have been a relevant additional diagnostic test.

An increase in lactate dehydrogenase, thrombocytopenia, and elevated D-dimers is a common constellation in PTTM. Low platelets and high D-dimers were both detected in our patient. Lactate dehydrogenase could not be determined in our case due to hemolysis. Although there is no pathognomonic imagining, ground glass opacities, septal thickening, and lymphadenopathy are radiological findings of PTTM that can occur in a CT scan of the chest. In addition, the source of the primary malignancy may influence radiological findings [ 10 ]. Clinical presentation, laboratory results, and CT findings of this patient are thus consistent with PTTM.

Patients’ critical condition, in particular at the PTTM onset, and diagnostic difficulties make it complex to initiate adequate treatment, which is nota bene only based on case reports. Although there is no standard treatment regimen available, therapeutic options include pulmonary vasodilators, chemotherapy, and anti-inflammatory/antiproliferative approaches with the aim to decrease pulmonary hypertension and tumor load [ 3, 15 ]. In our case, the patient’s poor condition only allowed anti-inflammatory and supportive measures.

This case shows a typical course of PTTM with unclear diagnosis antemortem and rapidly worsening clinical condition. Further investigation in pathophysiological pathways, diagnostic and therapeutic features are desirable for a better assessment and outcome in these patients.

Written informed consent was obtained from the patient for the publication of this case report including any accompanying images. The authors have no ethical conflicts to disclose. The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical approval is not required for this study in accordance with local guidelines.

Related to the present work, the authors disclose no potential conflicts of interest. The authors declare that they have no competing interests.

No funding was received.

F.R. and M.V. wrote the manuscript. A.B. contributed to the histological sections. D.B. contributed to the radiological sections. N.A. critically reviewed the report. All the authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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Acute pulmonary embolism.

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  • Continuing Education Activity

Acute pulmonary embolism is a common clinical condition with a variable clinical presentation, making its diagnosis challenging. This activity outlines the clinical features, diagnosis, and treatment of acute pulmonary embolism and highlights the role of the interprofessional healthcare team in improving the care and outcomes of patients with pulmonary embolism.

  • Identify the etiology of acute pulmonary embolism.
  • Describe the pertinent findings for the diagnosis of patients with acute pulmonary embolism.
  • Explain the management options available for acute pulmonary embolism.
  • Outline the importance of collaboration and coordination among the interprofessional team members to diagnose and manage acute pulmonary embolism early and enhance the delivery of care for patients.
  • Introduction

Pulmonary embolism (PE) occurs when there is a disruption to the flow of blood in the pulmonary artery or its branches by a thrombus that originated somewhere else. In deep vein thrombosis (DVT), a thrombus develops within the deep veins, most commonly in the lower extremities. PE usually occurs when a part of this thrombus breaks off and enters the pulmonary circulation. Very rarely, PE can occur from the embolization of other materials into the pulmonary circulation such as air, fat, or tumor cells. [1] The spectrum of PE and DVT combined is referred to as venous thromboembolism (VTE).

Most pulmonary embolisms originate as lower extremity DVTs. Hence, risk factors for pulmonary embolism (PE) are the same as risk factors for DVT. Virchow's triad of hypercoagulability, venous stasis, and endothelial injury provides an understanding of these risk factors.

Risk factors can be classified as genetic and acquired. Genetic risk factors include thrombophilia such as factor V Leiden mutation, prothrombin gene mutation, protein C deficiency, protein S deficiency, hyperhomocysteinemia, among others. Acquired risk factors include immobilization for prolonged periods (bed rest greater than three days, anyone traveling greater than 4 hours, whether by air, car, bus, or train), recent orthopedic surgery, malignancy, indwelling venous catheter, obesity, pregnancy, cigarette smoking, oral contraceptive pill use, etc. [2] [3] [4] [5]

Other predisposing factors for VTE include:

  • Fracture of lower limb
  • Hospitalization for heart failure or atrial fibrillation/flutter within the previous three months
  • Hip or knee replacement
  • Major trauma
  • History of previous venous thromboembolism 
  • Central venous lines
  • Chemotherapy
  • Congestive heart failure or respiratory failure
  • Hormone replacement therapy 
  • Oral contraceptive therapy
  • Postpartum period
  • Infection (specifically pneumonia, urinary tract infection, and HIV)
  • Cancer (highest risk in metastatic disease)
  • Thrombophilia
  • Bed rest greater than three days

Cancer carries a high risk for thrombus formation and hence, PE. Pancreatic cancer, hematological malignancies, lung cancer, gastric cancer, and brain cancer carry the highest risk for VTE. [6]  Infection anywhere in the body is a common trigger for VTE. [7]  Myocardial infarction and congestive heart failure(CHF) increase the risk of PE. Also, patients with VTE were found to have an increased risk of subsequent stroke and myocardial infarction. [8] [9]

Types of Pulmonary Embolism

It is extremely crucial to divide PE based on the presence or absence of hemodynamic stability.

Hemodynamically unstable PE (previously called massive or high-risk   PE) is PE which results in hypotension (as defined by systolic blood pressure (SBP) less than 90 mmHg or a drop in SBP of 40 mm Hg or more from baseline or hypotension that requires vasopressors or inotropes), the old term "massive" PE does not describe the size of the PE but describes its hemodynamic effect. Patients with hemodynamically unstable PE are more likely to die from obstructive shock (i.e., severe right ventricular failure).

Hemodynamically stable PE is a spectrum ranging from small, mildly symptomatic or asymptomatic PE (low-risk PE or small PE) to PEs, which cause mild hypotension that stabilizes in response to fluid therapy, or those who present with right ventricle dysfunction (submassive or intermediate-risk PE), but is hemodynamically stable.

  • Epidemiology

The incidence of pulmonary embolism (PE) ranges from 39 to 115 per 100 000 population annually; for DVT, the incidence ranges from 53 to 162 per 100,000 people. [10]  After coronary artery disease and stroke, acute pulmonary embolism is the third most common type of cardiovascular disease. [11]  The incidence of PE is noted to be more in males as compared to that in females. [12]  Overall, PE related mortality is high, and in the United States, PE causes 100,000 deaths annually. [12]  However, the mortality rates attributable to PE can be challenging to estimate accurately because many patients with sudden cardiac death are thought to have had a thromboembolic event like PE. It is important to note that the case-fatality rates of PE have been decreasing; this might be from the improvement in diagnostic modalities and initiation of early intervention and therapies.

  • Pathophysiology

Pulmonary embolism occurs when clots break off and embolize into the pulmonary circulation.

Pulmonary emboli are typically multiple, with the lower lobes being involved more frequently than the upper, and bilateral lung involvement being more common. [13]

Large emboli tend to obstruct the main pulmonary artery, causing saddle embolus with deleterious cardiovascular consequences. In contrast, smaller sized emboli block the peripheral arteries and can lead to pulmonary infarction, manifested by intra-alveolar hemorrhage. Pulmonary infarction occurs in about 10% of patients.

PE leads to impaired gas exchange due to obstruction of the pulmonary vascular bed leading to a mismatch in the ventilation to perfusion ratio because alveolar ventilation remains the same, but pulmonary capillary blood flow decreases, effectively leading to dead space ventilation and hypoxemia.

Also, mediators, such as serotonin, are released, which cause vasospasm and further decreased pulmonary flow in unaffected areas of the lung. Local accumulation of inflammatory mediators alters lung surfactant and stimulates respiratory drive resulting in hypocapnia and respiratory alkalosis. [14]

In PE, pulmonary vascular resistance (PVR) increases due to the mechanical obstruction of the vascular bed with thrombus and hypoxic vasoconstriction. Pulmonary artery pressure (PAP) increases if thromboemboli occludes greater than 30% to 50% of the total cross-sectional area of the pulmonary arterial bed.

Increased PVR increases the right ventricular afterload, which impedes right ventricular outflow, which, in turn, causes right ventricular dilation and flattening or bowing of the interventricular septum. The desynchronization of the ventricles may be increased by the development of the right bundle branch block. The decreased RV outflow and concomitant RV dilation reduce left ventricular filling, thereby compromising cardiac output. [15]  As a result, LV filling is reduced in early diastole, and this leads to a reduction in the cardiac output (CO), and cause systemic hypotension and hemodynamic instability. Right ventricle (RV) failure due to acute pressure overload is the primary cause of death in severe PE. Given the above pathophysiological considerations, clinical symptoms, and signs of overt RV failure and hemodynamic instability, are indicative of a high risk of early (in-hospital or 30 day) mortality.

  • History and Physical

A timely diagnosis of a pulmonary embolism (PE) is crucial because of the high associated mortality and morbidity, which may be prevented with early treatment. It is important to note that 30% of untreated patients with pulmonary embolism die, while only 8% die after timely therapy. [16] [17]  Unfortunately, the diagnosis of PE can be difficult due to the wide variety of nonspecific clinical signs and symptoms in patients with acute PE.

The most common symptoms of PE include the following: dyspnea, pleuritic chest pain, cough, hemoptysis, presyncope, or syncope. Dyspnea may be acute and severe in central PE, whereas it is often mild and transient in small peripheral PE. In patients with preexisting heart failure or pulmonary disease, worsening dyspnea may be the only symptom. Chest pain is a frequent symptom and is usually caused by pleural irritation due to distal emboli causing pulmonary infarction. [18]  In central PE, chest pain may be from underlying right ventricular (RV) ischemia and needs to be differentiated from an acute coronary syndrome or aortic dissection.

Less common presentations include arrhythmias (e.g., atrial fibrillation), syncope, and hemodynamic collapse. [19]  Hemodynamic instability is a rare but essential form of clinical presentation, as it indicates central or extensive PE with severely reduced hemodynamic reserve. Syncope may occur and may be associated with a higher prevalence of hemodynamic instability and RV dysfunction. [20]  It is essential to recognize that patients with large PE may, at times, be asymptomatic or have mild symptoms. Many times, PE may be asymptomatic or discovered incidentally during diagnostic workup for another disease.

Apart from symptoms of PE, it is crucial to look for the risk factors for venous thromboembolism (VTE) to determine the clinical probability of a PE.

On examination, patients with PE might have tachypnea and tachycardia, which are common but nonspecific findings. Other examination findings include calf swelling, tenderness, erythema, palpable cords, pedal edema, rales, decreased breath sounds, signs of pulmonary hypertension such as elevated neck veins, loud P2 component of second heart sound, a right-sided gallop, and a right ventricular parasternal lift might be present on examination.

PE is a well-recognized cause of sudden cardiac arrest (8%). [21] A massive PE leads to an acute right ventricular failure, which presents as jugular venous distension, parasternal lift, third heart sound, cyanosis, and shock. If a patient with PE who has tachycardia on presentation develops sudden bradycardia or develops a new broad complex tachycardia (with right bundle branch block), providers should look for signs of right ventricular strain and possible impending shock. PE should be suspected in anyone who has hypotension with jugular venous distension wherein acute myocardial infarction, pericardial tamponade, or tension pneumothorax has been ruled out. [22]

Diagnostic Workup

Arterial Blood Gas (ABG) Analysis

Unexplained hypoxemia with a normal chest radiograph should raise the clinical suspicion for pulmonary embolism (PE). Widened alveolar-arterial gradient for oxygen, respiratory alkalosis, and hypocapnia are commonly seen findings on ABG, as a pathophysiological response to pulmonary embolism. It is important to note that hypercapnia, respiratory, or lactic acidosis is not common but can be present in patients with massive PE associated with obstructive shock and respiratory arrest.

Brain Natriuretic Peptide (BNP)

Elevated BNP has limited diagnostic importance in patients suspected of having PE. [23]  Right ventricle pressure overload because of acute PE is associated with more myocardial stretch, which then releases B-type natriuretic peptide (BNP) and N-terminal (NT)-proBNP. Thus, the levels of natriuretic peptides in blood reflect the severity of RV dysfunction in acute PE. [24]

Serum troponin I and T levels are beneficial prognostically but not diagnostically. [25] [26]  As markers of right ventricular dysfunction, troponin levels are elevated in 30 to 50 percent of patients with moderate to large PE and are linked to clinical deterioration and death after PE. [27]  

D-dimer 

D-dimer levels are elevated in plasma whenever there is an acute thrombotic process in the body because of the activation of coagulation and fibrinolysis pathways at the same time. D-dimer testing has high negative predictive value; hence, a normal D-dimer level makes acute PE or DVT unlikely. But since the positive predictive value of elevated D-dimer levels is low, D-dimer testing is not useful for confirmation of PE. As many D-dimer assays are available, providers should become aware of the diagnostic performance of the test used in their clinical setting. The quantitative enzyme-linked immunosorbent assay (ELISA) has a diagnostic sensitivity of at least 95%. It can be used to exclude the diagnosis of PE in patients with either low or intermediate pretest probability. A negative ELISA D-dimer, along with low clinical probability, can exclude PE without further testing in approximately 30% of suspected patients. 

The specificity of D-dimer decreases steadily with age to approximately 10% in patients greater than 80 years of age. The use of age-adjusted cut-offs for patients older than 50 may improve the performance of D-dimer testing in the elderly. In one study, the use of the age-adjusted cut-off instead of the standard D-dimer cut-off of 500 ng/mL or more increased the number of patients in whom the possibility of PE could be ruled out from 6.4% to 30%, without additional false-negative findings. [28]

The formula is age (years) x 10 mcg/L for patients more than 50 years of age. Example: Patient age 75 = age-adjusted d-dimer of 750 mcg/L.

Electrocardiography (ECG)

ECG abnormalities, in patients with suspected PE, are nonspecific. [29]  The most common ECG findings in PE are tachycardia and nonspecific ST-segment and T-wave changes, S1Q3T3 pattern, right ventricular strain, and new incomplete right bundle branch block are uncommon.

Chest Radiograph (CXR)

In PE, CXR is usually normal or might show nonspecific abnormalities such as atelectasis or effusion. It helps to rule out alternative diagnoses in patients presenting with acute dyspnea.

Hampton's hump is a shallow, hump-shaped opacity on CXR in the periphery of the lung, with its base lying against the pleural surface and hump towards the hilum (Figure 1). Westermark's sign is the sharp cut-off of pulmonary vessels with distal hypoperfusion in a segmental distribution within the lung; both of these findings are rare but specific for acute PE. [30] 'Westermark sign' may be seen in up to 2% of the cases. This finding is a result of a combination of dilation of the pulmonary artery proximal to the thrombus and the collapse of the distal vasculature (figure 2).

Computed Tomographic Pulmonary Angiography (CTPA)

Multidetector CTPA is the diagnostic modality of choice for patients with suspected PE. It allows appropriate visualization of the pulmonary arteries down to the subsegmental level. [31] The PIOPED (Prospective Investigation On Pulmonary Embolism Diagnosis) II study showed a sensitivity of 83% and a specificity of 96% for CTPA in PE diagnosis. [32] PIOPED II also highlighted the pretest clinical probability influence on the predictive value of CTPA. A normal CTPA had a high negative predictive value for PE 96% and 89% in patients with a low or intermediate clinical probability, respectively, but its negative predictive value was only 60% if the pretest probability was high. In contrary to this, the positive predictive value of a positive CTPA was high (92% to 96%) in patients with an intermediate or high clinical probability, but much lower (58%) in patients with a low pretest likelihood of PE. [32]  Therefore, providers should consider further testing in case of discordance between clinical judgment and the CTPA result.

The present data suggest that a negative CTPA result is adequate for the exclusion of PE in patients who have a low or intermediate clinical probability. Besides, it remains controversial whether patients with a negative CTPA and a high clinical probability should be further investigated.

CTPA may be relatively contraindicated in moderate to severe iodinated contrast allergy or renal insufficiency (eGFR less than 30 mL/min per 1.73-meter square). The risk of these contraindications must be measured against the clinical significance of performing the CTPA examination and the availability of other imaging modalities (e.g., V/Q scan). If clinically feasible, CTPA should be postponed for premedication for a history of allergy or intravenous hydration for renal insufficiency.

CTPA can detect RV enlargement and other indicators of RV dysfunction. Enlarged RV has prognostic value, and it is supported by the results of a prospective multicentre cohort study in 457 patients. [33]  In that study, RV enlargement (RV/LV ratio ≥0.9) was a strong and independent predictor of a severe in-hospital outcome, both in the overall population and in hemodynamically stable patients.

Lung Scintigraphy

The planar ventilation/perfusion scan (V/Q scan) is an established diagnostic test for suspected PE. V/Q scanning is mostly performed for patients in whom CTPA is contraindicated or inconclusive, or when additional testing is needed. A normal chest radiograph is usually required before V/Q scanning. Scans performed on patients with abnormal chest radiographs are most likely to be false positives because the images do not appear normal or low probability of PE in such patients.

For those with a normal chest radiograph, V/Q scanning remains the test of choice for the diagnosis of PE in pregnancy. Other groups of patients include those who have a history of contrast medium-induced anaphylaxis and patients with severe renal failure. [34]

Planar lung scan results are frequently classified into three-tiers: normal scan (excluding PE), high-probability scan (considered diagnostic of PE in most patients), and nondiagnostic scan. [34] [35]  Multiple studies have suggested that it is safe to withhold anticoagulant therapy in patients with a normal perfusion scan. [36] An analysis from the PIOPED II study advocated that a high-probability V/Q scan can confirm PE. However, the positive predictive value of a high-probability V/Q scan is not enough to confirm the PE diagnosis in patients with a low clinical probability. [37]  The high frequency of nondiagnostic scans is a limitation because they indicate the necessity for further diagnostic testing. 

Pulmonary Angiography

In pulmonary angiography, contrast is injected via a catheter introduced into the right heart under fluoroscopy, which was the gold standard in the past for the diagnosis of PE. The diagnosis of acute PE is made on the evidence of a thrombus either as amputation of a pulmonary arterial branch or filling defect. [38] With the widespread emergence of CTPA, pulmonary angiography is infrequently used and reserved for rare circumstances for patients with a high clinical probability of PE, in whom CTPA or V/Q scanning is nondiagnostic. Pulmonary angiography seems to be inferior to CTPA, and its results are operator dependent and highly variable. [39]  Therefore, catheter-based pulmonary angiography is performed in patients who need therapeutic benefit since it helps with diagnosis as well as therapeutic interventions aimed at clot lysis.

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) has been assessed for several years regarding suspected PE. However, the results of large-scale studies show that this technique, although promising, is not recommended as a first-line test for the diagnosis of PE due to its low sensitivity, low availability in most emergency settings, and the high proportion of inconclusive MRA scans. [40]  But it may be an imaging option for diagnosis of PE in patients in whom neither CTPA nor V/Q scan can be performed. Potential advantages include no exposure to radiation. MR pulmonary angiography was studied prospectively in 371 adults with suspected PE. Among the 75 percent of patients who had technically adequate images, MRPA alone showed a sensitivity and specificity of 78 percent and 99 percent, respectively. [40]  Among the 48 percent of patients with technically adequate images, MR pulmonary angiography and MR pulmonary venography have shown a sensitivity and specificity of 92 percent and 96 percent, respectively.

Echocardiography

Transthoracic echocardiography can very rarely diagnose PE definitively when the thrombus is visualized in the proximal pulmonary arteries. The diagnosis of PE on echocardiography is supported by the presence of clot in the right heart or new right heart strain, especially in hemodynamically unstable patients with suspected PE wherein echocardiogram may be useful to establish a possible diagnosis and justify the emergency use of thrombolytic therapy.

There are significant considerations with using echocardiography to establish a diagnosis of PE. Given the peculiar shape of the RV, there is no single echocardiographic parameter that gives quick and accurate information on RV size or function. That is why echocardiographic criteria for the diagnosis of PE have varied between different studies. Because of the negative predictive value of 40% to 50%, a negative result cannot exclude PE. [41] [42]  On the other hand, signs of RV overload or dysfunction may also be present without acute PE, and may be due to coexisting cardiac or respiratory disease. [43]

RV dilation is seen in 25% or more of patients with PE on echo and is useful for risk stratification of the disease. [44]  More specific echocardiography findings confer a high positive predictive value for PE, even in the presence of preexisting cardiorespiratory illness. This includes, the combination of a pulmonary ejection acceleration time (measured in the RV outflow tract) less than 60 ms with a peak systolic tricuspid valve gradient less than 60 mmHg ('60/60' sign), or McConnell sign (with depressed contractility of the RV free wall compared to the RV apex), is suggestive of PE. [45] . An RV/LV diameter ratio 1.0 or more and tricuspid annular plane systolic excursion (TAPSE) less than 16 mm are the findings for which an association with unfavorable prognosis has most frequently been reported. [46]

Compression Ultrasonography (US)

PE originates from a lower limb DVT in a majority of patients, and only rarely from upper-limb DVT (mostly following venous catheterization). In one study, DVT was found in 70% of patients with proven PE. [47]  Compression US has a sensitivity of more than 90% and a specificity of about 95% for proximal symptomatic DVT. [48]  A finding of proximal DVT in patients suspected of having PE is considered sufficient to warrant anticoagulant treatment without further testing. [49] It is important to note that, due to the low sensitivity of compression ultrasonography, it is reserved for patients in whom definitive imaging (e.g., CTPA, V/Q scanning) is contraindicated or indeterminate. [50]

Wells criteria and Geneva score are scoring systems most commonly used to estimate the pretest probability of having a PE. This allows the classification of patients with suspected PE into categories of clinical or pretest probability, based on which the diagnostic tests are chosen and interpreted.

The Revised Geneva Clinical Prediction Rule

Items/Clinical decision rule points (Original version)(Simplified version)

  • Previous PE or DVT-3/1
  • 75–94 beats per minute-3/1
  • ≥95 beats per minute-5/2
  • Surgery or fracture within the past month-2/1
  • Hemoptysis-2/1
  • Active cancer-2/1
  • Unilateral lower-limb pain-3/1
  • Pain on lower-limb deep palpation and unilateral edema-4/1
  • Age >65 years-1/1

Clinical Probability

Three-level score

  • Low/0–3/0–1
  • Intermediate/4–10/2–4
  • High/≥11/≥5

Two-level Score

  • PE-unlikely/0–5/0–2
  • PE-likely/≥6/≥3

Wells Criteria and Modified Wells Criteria

Items/Scores

  • Clinical symptoms of DVT-3.0
  • Other diagnoses less likely than pulmonary embolism-3.0
  • Heart rate >100 beats per min-1.5
  • Immobilization for three or more days or surgery in the previous four weeks-1.5
  • Previous history of DVT-PE1.5
  • Hemoptysis-1.0
  • Malignancy-1.0

Probability/ Score

Traditional Clinical Probability Assessment (Wells criteria)

  • High/>6.0
  • Moderate/2.0 to 6.0
  • Low/<2.0

Simplified Clinical Probability Assessment (Modified Wells Criteria)

  • PE likely/>4.0
  • PE unlikely/≤4.0

Since symptoms of PE are very nonspecific, The Pulmonary Embolism Rule-out Criteria (PERC) was developed for emergency department patients to select patients whose likelihood of having PE is so low that diagnostic workup should not even be initiated. [51]  They constitute variables significantly associated with the absence  of PE.

The PERC rule has eight criteria:

• Age <50 years

• Heart rate <100 beats per minute

• Oxyhemoglobin saturation ≥95 percent

• No hemoptysis

• No estrogen use

• No prior DVT or PE

• No unilateral leg swelling

• No surgery/trauma requiring hospitalization within the preceding four weeks

Patients having a low probability of PE who fulfill all eight criteria, the likelihood of PE is sufficiently low that further testing is not indicated.

PERC is only valid in clinical settings with a low prevalence of PE (<15 percent). [52]  In hospital settings with a higher prevalence of PE (>15 percent), the PERC-based approach has substantially weaker predictive value. [53]  Therefore, it should not be used in patients with an intermediate or high suspicion for PE or for inpatients suspected as having PE. 

Diagnostic Approach to Hemodynamically Stable Patients with Suspected Pulmonary Embolism

For most patients with suspected PE who are hemodynamically stable, an approach that combines clinical and pretest probability assessment, D-dimer testing, and definitive diagnostic imaging is usually applied.

For a Patient with a Low Probability of PE (Wells Score <2)

If PERC criteria are fulfilled, there is no need for further testing, and PE can be excluded. If PERC criteria are not met, then D-dimer should be obtained. If D-dimer is negative(<500 ng/ml), PE can be ruled out if D-dimer is positive (>500 ng/ml) in patients age <50 or high after age-adjusted D-dimer value, CT pulmonary angiography should be performed. If CTPA is inconclusive or contraindicated, V/Q scan should be performed.

For a patient with intermediate probability of PE (Wells score 2 to 6)

Measure D-dimer levels, if negative, PE can be excluded. If positive, then CTPA is done. If CTPA is inconclusive or contraindicated, V/Q scan should be performed.

For a Patient with a High Probability of PE (Wells Score >6)

CTPA should be performed emergently. Feasibility requires adequate scanner technology, and the patient must be able to lie flat, to cooperate with exam breath-holding instructions, have a body habitus that can fit into the scanner, and no contraindications for iodinated contrast. If inconclusive or not feasible, perform a V/Q scan. V/Q scan could be normal, ruling out PE. It could also have resulted as a "high probability for PE," which would be diagnostic of PE if V/Q scan results as intermediate probability, further testing with lower extremity compression ultrasonography with Doppler is appropriate.

For patients who are hemodynamically unstable and in whom definitive imaging is unsafe, bedside echocardiography or venous compression ultrasound may be used to obtain a presumptive diagnosis of PE to justify the administration of potentially life-saving therapies.

  • Treatment / Management

A) Initial Management 

1) The Supportive Measures

The initial approach to patients with pulmonary embolism (PE) should focus on supportive measures.

Supplemental oxygen is indicated in patients with oxygen saturation <90%. Mechanical ventilation (non-invasive or invasive) should be utilized in unstable patients, but providers should be mindful of the adverse hemodynamic effects of mechanical ventilation.

Acute RV failure is the leading cause of death in patients with hemodynamically unstable PE. Aggressive volume resuscitation in such patients can over distend the RV, worsen ventricular interdependence, and reduce cardiac output (CO). Hence, in patients with massive PE, intravenous fluid resuscitation should be tried only in patients with collapsible IVC/intravascular depletion. Vasopressors might be needed for hemodynamic support.

Mechanical cardiopulmonary support devices, such as extracorporeal membrane oxygenation (ECMO), may be used in hemodynamically unstable patients with pulmonary embolism.

2) Anticoagulation

It is vital to remember that the mainstay of treatment of acute PE is anticoagulation.

It is important to note that either low-molecular-weight heparin (LMWH) or fondaparinux or unfractionated heparin (UFH) can be used for anticoagulation in acute PE. LMWH and fondaparinux are preferred since they have a less incidence of inducing major bleeding and heparin-induced thrombocytopenia. [54] [55]  UFH is usually only used in patients with hemodynamic instability in whom primary reperfusion treatment might be required, or in patients with renal impairment. Newer oral anticoagulants (NOACs) and vitamin K antagonists(VKA) can also be used for anticoagulation in PE.

For patients with suspected PE, the treatment is stratified according to the type of PE ( whether it is hemodynamically stable or unstable PE) and according to the suspicion of PE in an individual patient. Patients are classified into low, intermediate, or high suspicion for PE based on either revised Geneva or Wells score.

Hemodynamically Stable Patients:

Patients with a high clinical suspicion for PE, anticoagulation is started even before diagnostic imaging is obtained. 

For patients with a low clinical suspicion for PE, if diagnostic imaging can be performed within 24 hours, then wait for imaging to establish a definitive diagnosis before starting treatment with anticoagulation.

For patients with an intermediate clinical suspicion for PE, if diagnostic imaging can be performed within 4 hours, then wait for imaging to establish a definitive diagnosis before starting treatment with anticoagulation.

For patients in whom anticoagulation is contraindicated, IVC filter placement should be considered once the diagnosis of PE is confirmed.

Hemodynamically Unstable Patients:

Patients with a high clinical suspicion for PE who are hemodynamically unstable, emergent CTPA, portable perfusion scanning, or bedside transthoracic echocardiography should be performed whenever possible.  Primary reperfusion treatment, usually, thrombolysis, is the treatment of choice for patients with hemodynamically unstable acute PE. Surgical pulmonary embolectomy or percutaneous catheter-directed therapy are alternative reperfusion options in patients with contraindications to thrombolysis. Following reperfusion treatment and hemodynamic stabilization, patients recovering from high-risk PE can be switched from parenteral to oral anticoagulation.

3) Reperfusion Strategies

Thrombolysis:

Thrombolysis has shown an effective reduction in pulmonary artery pressure and resistance in patients with PE when compared with UFH alone; these improvements are assessed by a decrease in RV dilation on echocardiography. [56] [57] Thrombolysis is preferred when therapy can be instituted within 48 hours of symptom onset, but it has still shown benefit in patients whose symptoms began less than 14 days ago. [58]  A meta-analysis suggested a significant reduction in mortality and recurrent PE with the use of thrombolytics. [59]

 Pulmonary Embolism Thrombolysis (PEITHO) trial identified the benefits of thrombolysis in hemodynamically stable patients with intermediate-risk PE. [60]  It demonstrated that thrombolysis was associated with a significant reduction in the risk of hemodynamic decompensation or collapse, but it also showed an increased risk of severe bleeding with thrombolytics. [60] [61]

Absolute contraindications to thrombolysis include any prior intracranial hemorrhage, known structural intracranial cerebrovascular disease (e.g., arteriovenous malformation), known malignant intracranial neoplasm, ischemic stroke within three months, suspected aortic dissection, active bleeding or bleeding diathesis, recent surgery encroaching on the spinal canal or brain, and recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injury.

Catheter-Directed Treatment:

Involves the insertion of a catheter into the pulmonary arteries, which is then used for ultrasound-assisted thrombolysis, suction embolectomy, rotational embolectomy, thrombus aspiration, or combining mechanical fragmentation with pharmacological catheter-directed thrombolysis. Different studies have shown a success rate of up to 87%  for catheter-directed therapies. [62] [63] Catheter-assisted embolectomy techniques carry the inherent risk of perforating the pulmonary arteries, leading to massive hemoptysis or cardiac tamponade. These complications are rare but fatal.

Surgical Embolectomy

It   is usually indicated in a patient with   hemodynamically unstable PE  in whom thrombolysis (systemic or catheter-directed) is contraindicated, or in patients who have failed thrombolysis. [64] [65] [66] Thrombolysis or surgical embolectomy, there was no difference in mortality between the two, but the thrombolysis group had a higher risk of stroke and re-intervention.

Vena Cava Filters

These block the path of travel of emboli and prevent them from entering the pulmonary circulation. Filters are indicated in patients with venous thromboembolism who have an absolute contraindication to anticoagulants, and in patients with recurrent VTE despite anticoagulation. Retrievable filters are preferred, such that once the contraindication has resolved, the filter can be removed, and patients should be anticoagulated. This is because, the Prevention of Recurrent Pulmonary Embolism by Vena Cava Interruption (PREPIC) study showed that the insertion of a permanent vena cava filter was associated with a significant reduction in the risk of recurrent PE and a substantial increase in the risk of DVT, without a remarkable difference in the risk of recurrent VTE or death. [67]

B) Chronic Treatment and Prevention of Recurrence

The aim of anticoagulation after the acute management of PE is to complete the treatment of the acute episode and also prevent the recurrence of VTE over the long-term. Clinical trials have assessed various durations of anticoagulant therapy with vitamin K antagonists (VKAs) for VTE. [68] [69] [70] The findings of these studies have concluded the following points. First, all patients with PE should receive three or more than three months of anticoagulant treatment. Second, after the anticoagulant treatment is stopped, the risk of recurrence is expected to be similar if anticoagulants are stopped after 3-6 months compared with longer treatment periods (e.g., 12-24 months). Third, extended oral anticoagulant treatment reduces the risk of recurrent VTE by ≤90%, but the risk of bleeding partially offsets this benefit. Oral anticoagulants are highly efficient in preventing recurrent VTE at the time of treatment, but after the discontinuation of treatment, they do not eliminate the risk of subsequent recurrence. [68] [68] [68]  It is important to note that about 30% of PEs are unprovoked. Unprovoked PE ( PE in the absence of an identifiable risk factor) is associated with a two- to three-fold increase in the risk of recurrence compared to patients who had a provoked PE. [71] Patients with persistent risk factors (e.g., cancer or elevated antiphospholipid antibodies) have a higher rater of recurrence than those with transient risk factors (e.g., immobilization, surgery, or trauma). [72]

In conclusion, the optimal duration of anticoagulation remains uncertain and has to be considered on a case to case basis. A minimum of 3 months is usually recommended, but a more extended period is required if the  PE was unprovoked or if there are persistent risk factors. [71] This need for longer anticoagulation should be assessed at the end of 3 months by considering the patient's bleeding risk. Those with a high bleeding risk can limit therapy to three months.

Special considerations are required for patients with active cancer, given their increased risk for a VTE event. Hence, cancer patients should receive an extended duration of anticoagulation if their bleeding risk remains acceptable ( low or moderate bleeding risk). For cancer patients with PE, LMWH, and DOACs (apixaban, rivaroxaban) are preferred over VKA. [73]

  • Differential Diagnosis

Since pulmonary embolism has a very heterogeneous clinical presentation ranging from dyspnea to sudden cardiac arrest. The differential diagnosis of PE is extensive and includes:

  • Acute coronary syndrome
  • Stable angina
  • Acute pericarditis
  • Congestive heart failure
  • Cardiac arrhythmias
  • Pneumonitis
  • Pneumothorax
  • Vasovagal syncope

Shock and right ventricular dysfunction confer a poor prognosis and predict mortality in patients diagnosed with PE. [52] Patients with pulmonary embolism and a coexisting deep vein thrombosis (DVT) are also at an increased risk for death. Several prognostic models have been designed, the Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are the most commonly used. PESI score predicts 30-day mortality in patients with an established diagnosis of PE. [74]  The principal strength of the PESI  and sPESI lies in the identification of patients at low risk for 30-day mortality (PESI classes I and II).

Original and simplified Pulmonary Embolism Severity Index

  • Parameter- original version [74] /simplified version [75]
  • Age-1 point (if age >80 years)
  • Male sex- +10 points/ –
  • Cancer- +30 points/1 point
  • Chronic heart failure- +10 points/1 point
  • Chronic pulmonary disease- +10 points/1 point                       
  • Pulse rate ≥110 b.p.m- +20 points/1 point
  • Systolic BP <100 mmHg- +30 points/1 point
  • Respiratory rate >30 breaths per min- +20 points/–
  • Temperature <36°C- +20 points/–
  • Altered mental status- +60 points/–
  • Arterial oxyhaemoglobin saturation <90%- +20 points/1 point 

Risk stratification in PESI

  • Class I: Points less than or equal to 65; low 30-day risk of mortality from 1 to 6 percent.
  • Class II: Points 66–85; low mortality risk from 1.7 to 3.5%
  • Class III: Points 86–105; moderate mortality risk from 3.2 to 7.1 percent.
  • Class IV: Points 106–125; high mortality risk from 4.0 to 11.4%.
  • Class V: Points more than 125; very high mortality risk from 10.0 to 24.5%.

Risk stratification in sPESI

If 0 points then 30-day mortality risk 1.0%

If one or more than one point(s) then 30-day mortality risk 10.9%

  • Complications

The major complications associated with pulmonary embolism (PE) include the following:

  • Recurrent thromboembolism
  • Chronic thromboembolic pulmonary hypertension
  • Right heart failure
  • Cardiogenic shock

PE, if left untreated, is associated with mortality of up to 30 percent. Studies have also suggested an increased risk of stroke, thought to be due to paradoxical embolism via a patent foramen ovale (PFO) in patients with acute PE. [76]

1) Recurrent Thromboembolism

In the one to two weeks following diagnosis, patients may deteriorate and experience recurrence. Inadequate anticoagulation is the most common reason for recurrent venous thromboembolism while on therapy. 

2) Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

The development of persistent or progressive dyspnea, particularly during the first three months to two years of diagnosis, should prompt the provider to investigate for the development of CTEPH (affects up to 5 percent of patients). Follow-up computed tomography, ventilation-perfusion scans, or echocardiography should be performed in patients who remain persistently symptomatic months to years after an acute PE. In CTEPH, these modalities demonstrate pulmonary hypertension.

On the V/Q scan, patients with CTEPH generally have at least one segmental or more significant mismatched ventilation-perfusion defects. For those patients with evidence of CTEPH on V/Q lung scanning, right heart catheterization and pulmonary angiography are indicated to confirm pulmonary hypertension, quantify the degree of pulmonary hypertension, exclude competing diagnoses, define the surgical accessibility of the obstructing thrombotic lesions, and confirm that an acceptable component of the elevated pulmonary vascular resistance is due to surgically accessible disease and not from distal obstruction or a secondary arteriopathy. For all patients with CTEPH, lifelong anticoagulant therapy is recommended. Also, early referral for evaluation for pulmonary thromboendarterectomy is highly recommended.

  • Pearls and Other Issues

A timely diagnosis of pulmonary embolism (PE) is crucial because of the high associated mortality and morbidity, which may be prevented with early treatment. Patients should be made aware of the signs and symptoms of VTE and PE since the incidence of recurrent thromboembolism is high. It is important to note that 30% of untreated patients with pulmonary embolism die, while only 8% die after timely therapy.

  • Enhancing Healthcare Team Outcomes

Some hospitals are establishing multidisciplinary pulmonary embolism response teams (PERTs) to facilitate prompt diagnosis and timely treatment of patients with pulmonary embolism. A PERT is a treatment model composed of providers from different specialties involved in the treatment of PE, including pulmonary, critical care, cardiology, and cardiothoracic surgery, among others. The establishment of PERT has proven effective in multiple studies by improving communication and coordinating treatment efforts among providers. [77]

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Electrocardiogram of a patient with pulmonary embolism showing sinus tachycardia of approximately 150 beats per minute and right bundle branch block. Contributed by Wikimedia Commons, Walter Serra, Giuseppe De Iaco, Claudio Reverberi and Tiziano Gherli (more...)

Transesophageal echocardiography, Thrombo embolism, Pulmonary artery, Pulmonary Embolism, Thromboembolic , Right Pulmonary artery, TE, RPA, Acute ECG segment elevation mimicking myocardial infarction in a patient with pulmonary embolism Contribute by (more...)

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Disclosure: Vrinda Vyas declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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