Summary for Pulmonary Embolism
Pulmonary embolism is a life-threatening medical condition due to blockage of pulmonary vessels by a thrombus originating typically in the leg’s deep veins. It can range from small asymptomatic clots to massive emboli that can cause sudden cardiovascular collapse and death. Several acquired and inherited risk factors precede its development. Age, obesity, pregnancy, surgery, immobilization, malignancies, and inherited thrombophilias are some of the most important risk factors. Pulmonary embolism has a vague clinical presentation and hence a puzzling diagnosis.
The gold standard diagnostic test is CTPA, done after weighing the likelihood of a pulmonary embolism via Wells criteria. Age-adjusted cut-off values for D-dimes are also crucial to reaching a diagnosis. Immediate initiation of anticoagulant therapy with either LMWH or DOAC is the first step in management. VTE prophylaxis should be considered for emboli formation. Warfarin or DOAC can be used for VTE prophylaxis. If anticoagulation is contraindicated, inferior vena cava filters can be used to prevent deep venous thrombosis from turning into a pulmonary embolism.
Introduction – Overview of Pulmonary Embolism
Pulmonary embolism comes under the umbrella of the term “venous thromboembolism” (VTE). The term “venous thromboembolism” has two most common manifestations: deep venous thrombosis (DVT) and pulmonary embolism. The American Lung Association defines pulmonary embolism as a sudden blockage in the pulmonary vessel due to a thrombus originating elsewhere (1). Most commonly, the thrombus originates from a deep vein in the leg (2).
Pulmonary embolism can range from small blood clots that are asymptomatic and can be managed on an outpatient basis to large clots that can cause sudden cardiovascular collapse (3). In the latter case, it is a medical emergency and a potentially life-threatening condition. Keeping a high index of diagnostic suspicion in patients with risk factors is crucial to early diagnosis and initiation of treatment.
Epidemiology of Pulmonary Embolism
The latest study reports an average incidence of pulmonary embolism as 60-120 per 100,000 persons yearly (2). In the United States, about 300,000 to 600,000 people are diagnosed with pulmonary embolism annually (4). 5% of hospitalized patients die due to pulmonary embolism (5). It is higher than the general population as hospitalized patients are mostly immobile and more prone to developing venous thrombosis, which can dislodge and cause a pulmonary embolism. Venous thromboembolism has been reported to affect 5% of the total population during their lifetime, and it is the third most common cardiovascular disorder (4, 6).
The incidence of clinically diagnosed DVT is approximately twice that of PE. Anderson et al. reported an incidence of first-time DVT of 48 per 100,000, compared with 23 per 100,000 for PE (32% of VTE cases).
The relative incidence of deep venous thrombosis (DVT) to pulmonary embolism is 2:1. The incidence of first-time DVT is 48 per 100,000 compared to 23 per 100,000 for PE (7).
Venous thromboembolism is a significant burden on the healthcare system and workforce. One study estimates that around 1.5 billion dollars are spent annually in the United States on treating and caring for patients with VTE (8).
Etiologies and Risk Factors of Pulmonary Embolism
There is a long list of acquired and inherited factors that put patients at risk of developing a pulmonary embolism.
Increasing age, obesity (9), varicose veins, personal history, and family history of venous thromboembolism are some of the most important risk factors for developing pulmonary embolism. The annual incidence of pulmonary embolism increases acutely with age. It is 1.4 per 1000 people in the age group 40-49 years. This drastically increases to 11.4 per 1000 in people above 80 years (6). It is widely thought that race influences the incidence of pulmonary embolism, but no specific trends could be defined. Men have a slightly higher risk of developing pulmonary embolism as compared to women, but this changes with age. Under 45 years of age, women are more likely to develop pulmonary embolism due to the thrombophilic propensity of estrogen.
There is an increased risk during pregnancy and 6 to 12 weeks postpartum due to a hypercoagulable state (6, 10). Women using estrogen-containing oral contraceptive pills (OCPs) have a 9 times greater likelihood of developing a fatal pulmonary embolism when compared to the control group (11).
Any major surgery, especially those lasting more than 30 minutes, predisposes the patient to develop a pulmonary embolism. Prolonged immobilization after surgeries, especially orthopedic surgeries, increases the venous stasis of blood, especially in the deep veins of the leg (12). Thrombi formed in the venous systems of the legs dislodge and block the pulmonary vessels resulting in a pulmonary embolism. A retrospective cohort study on more than 18000 patients with pulmonary embolism concluded that 23% had recent immobilization and 12% had recently undergone surgery. (13).
Polycythemia rubra vera, essential thrombocythemia, and some genetic disorders like protein C and protein S deficiency and anti-thrombin III deficiency increase the coagulability of blood, which in turn increases the risk of developing a pulmonary embolism (14, 15). Anti-phospholipid syndrome (APS) is also a significant risk factor that requires lifelong treatment.
Malignancies induce the activation of tumor-associated procoagulant factors. These factors result in the formation of blood clots which can lodge in the pulmonary vessels. About 20 to 30% of previously undiagnosed malignancies are unveiled by such thrombotic events (16).
Pathophysiology of Pulmonary Embolism
Most pulmonary emboli arise from thrombi in the deep veins of the legs. Rarely septic emboli may arise from tricuspid and pulmonary valve endocarditis.
Fat emboli originating due to fracture of the femur and amniotic fluid emboli are the least common (14, 15). Rudolf Virchow proposed a theory in which a triad of events precedes the formation of a thrombus. This triad is called Virchow’s triad, and it explains the pathophysiology of a VTE. Virchow’s triad consists of three events that precede the formation of a thrombus (17):
1) endothelial injury
3) venous stasis
In the presence of these events, a blood clot is formed, typically in the deep veins of the legs. In most cases, the blood clot is dissolved by the fibrinolytic system of the body, while in others, the pieces of the thrombus break away and get dislodged into the pulmonary vasculature. Mostly they are small asymptomatic clots, but sometimes they can be large emboli that block pulmonary blood flow and create a medical emergency (3).
Clinical Presentation and Symptoms of Pulmonary Embolism
The clinical presentation of pulmonary embolism is often vague and non-specific. The symptoms can vary depending on the number and size of the emboli. In the case of an acute massive pulmonary embolism, the patient can present with faintness or acute cardiovascular collapse, severe dyspnea, and crushing central chest pain (18). On examination, the patient will appear cyanotic and in severe distress with signs of a major circulatory collapse: tachycardia with hypotension and raised jugular venous pressure (JVP). On auscultation, a right ventricular gallop rhythm and a loud pulmonary component of the second heart sound is characteristic of a saddle embolus.
If there is a small or medium-sized clot, the patient complains of pleuritic chest pain, hemoptysis, and labored breathing. Examination findings include tachycardia, pleural rub, crackles, pleural effusion, and low-grade fever (19).
To reach a diagnosis, it is imperative to correlate the symptoms and examination findings with the aforementioned risk factors.
Diagnosis of Pulmonary Embolism
The diagnosis of a pulmonary embolism is challenging due to a non-specific presentation. The most trusted algorithm involves determining 2-level pulmonary embolism Well’s score (20) in all patients with suspected pulmonary embolism. Well’s score greater than 4 indicates the likelihood of a pulmonary embolism. Immediately, a CT Pulmonary Angiogram (CTPA) should be planned. Anticoagulants should be started while awaiting CTPA (19).
CT pulmonary angiogram (CTPA)
CTPA is the diagnostic test of choice in patients with suspected pulmonary embolism. However, this test is not recommended in patients with renal failure or allergic to the contrast dye. In such cases, ventilation-perfusion (V/Q) scanning can be done for diagnosis (Konst).
If the PE Well’s score is less than 4, then a D-dimer test should be performed. While awaiting the results, it is important to start interim anticoagulant therapy. A positive D-dimer is not specific for pulmonary embolism, as a positive result can also be obtained in cases of myocardial infarction, pneumonia, and sepsis.
Hence, it is still important to advise a CTPA if D-dimers are positive. D-dimer test has a very high negative predictive value for pulmonary embolism. If it is negative, other differentials should be explored. The new guidelines insist on using age-adjusted or clinical probability-adjusted D-dimer values as the cut-off rather than the fixed cut-off (19, 21).
Color Doppler Ultrasound of Leg Veins
This test is usually done if a CTPA is negative for an embolism, but there are clinical signs of venous thrombosis in the leg veins. Most pulmonary emboli are dislodged thrombi in the deep veins of the legs. If a proximal DVT is present in suspected patients, anticoagulant therapy should be initiated without further testing (22).
A chest X-ray may be normal or abnormal depending on the clot’s size and the presentation’s acuteness. In a massive pulmonary embolus, the chest X-ray is usually normal. This can help to exclude some key differentials like pneumonia or pneumothorax. However, in small or medium-sized emboli, the presentation is sub-acute. The chest X-ray may show some characteristic changes: pleuropulmonary opacities (wedge-shaped or horizontal linear opacities), pleural effusion, and an elevated hemidiaphragm are some common findings (23).
More often than not, an ECG is normal in case of a pulmonary embolism. It can help to rule out differentials like acute myocardial infarction (MI). In some cases, ECG may show sinus tachycardia and T-wave inversion. Like a saddle embolus, large emboli produce a characteristic ECG pattern, the S1Q3T3 pattern, which can aid in diagnosis (22).
Diagnosing a pulmonary embolism is puzzling as its clinical manifestations can mimic several other diseases. The differential diagnosis varies with the size of the clot. A massive clot can present with sudden cardiovascular collapse. The most likely differential will be an acute myocardial infarction or pneumothorax; pneumonia, pleuritis, or pericarditis are important differentials for patients with dyspnea and pleuritic chest pain.
Treatment and Management of Pulmonary Embolism
The patient should be given oxygen to maintain target oxygen saturation. Opioid analgesics can also be used for pain relief.
Low molecular weight heparin (LMWH)
Immediate anticoagulation therapy can be started with a low molecular weight heparin like enoxaparin. This can be continued for 5 days, after which a coumarin anticoagulant like warfarin can be added. The LMWH should be continued until the international normalized ratio (INR) is above 2 (19).
Direct oral anticoagulants (DOAC)
Diect oral anticoagualants (DOAC) like rivaroxaban and apixaban (factor Xa inhibitors) can be used as an alternative to LMWH. While the factor IIa inhibitor dabigatran should be used only after initial therapy for about five days with an LMWH.
Anticoagulant therapy should continue for 3 to 6 months if the risk factor for thromboembolism is removed (19, 21). If the risk factor cannot be removed, as in the case of malignancies, then lifelong anticoagulant therapy is recommended (19). The benefit of anticoagulation should be carefully weighed against the risk of bleeding by an experienced physician. The European Respiratory Society guidelines recommend indefinitely using a vitamin K antagonist (VKA) for patients with anti-phospholipid syndrome (21).
Thrombolysis occurs in patients presenting with acute hemodynamic instability due to a massive pulmonary embolism. Usually, it is reserved for patients with hypotension and no significant risk of bleeding (19). Thrombolysis is done with a tissue plasminogen activator (tPA) inhibitor, alteplase (21).
Surgical embolectomy is the removal of the embolus via a catheter. This is the alternative to thrombolytic therapy in a hemodynamically unstable patient. A surgical embolectomy should be done if there is a contraindication of thrombolysis or failed thrombolysis (21, 22).
Inferior vena cava filters should be considered in patients with recurrent VTE or contraindications to anticoagulant therapy. These vena cava filters prevent blood clots from traveling through the inferior vena cava from the deep leg veins and blocking the pulmonary vessels (18, 19, 21).
Prognosis and Complications of Pulmonary Embolism
Over the years, the prognosis of pulmonary embolism has improved largely due to better diagnostic tools and effective anticoagulation therapy. Once the anticoagulant therapy has been commended, the prognosis improves drastically. The prognosis is worst in patients with right ventricular dysfunction or cardiogenic shock. In a massive pulmonary embolism, acute dilatation of the right heart may lead to right heart failure. Patients with right ventricular dysfunction should be monitored via echocardiography at three months to assess evidence of chronic thromboembolic pulmonary hypertension (21, 22).
- American Lung Association. “Pulmonary Embolism (PE).” Lung.org, American Lung Association, https://www.lung.org/lung-health-diseases/lung-disease-lookup/pulmonary-embolism.
- Freund Y, Cohen-Aubart F, Bloom B. Acute Pulmonary Embolism: A Review. Jama. 2022 Oct 4;328(13):1336-45.
- Giordano NJ, Jansson PS, Young MN, Hagan KA, Kabrhel C. Epidemiology, Pathophysiology, Stratification, and Natural History of Pulmonary Embolism. Tech Vasc Interv Radiol. 2017 Sep;20(3):135-140. doi: 10.1053/j.tvir.2017.07.002. Epub 2017 Jul 5. PMID: 29029707.
- Essien EO, Rali P, Mathai SC. Pulmonary Embolism. Med Clin North Am. 2019 May;103(3):549-564. doi: 10.1016/j.mcna.2018.12.013. PMID: 30955521.
- Alikhan R, Peters F, Wilmott R, Cohen AT. Fatal pulmonary embolism in hospitalized patients: a necropsy review. Journal of clinical pathology. 2004 Dec 1;57(12):1254-7.
- Duffett L, Castellucci LA, Forgie MA. Pulmonary embolism: update on management and controversies. BMJ. 2020 Aug 5;370.
- White, R. H. (2003, June 17). The Epidemiology of Venous Thromboembolism. Circulation, 107(23_suppl_1). https://doi.org/10.1161/01.cir.0000078468.11849.66
- Park B, Messina L, Dargon P, Huang W, Ciocca R, Anderson FA. Recent trends in clinical outcomes and resource utilization for pulmonary embolism in the United States: findings from the nationwide inpatient sample. Chest. 2009 Oct 1;136(4):983-90.
- Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. A prospective study of risk factors for pulmonary embolism in women. Jama. 1997 Feb 26;277(8):642-5.
- Dado CD, Levinson AT, Bourjeily G. Pregnancy and Pulmonary Embolism. Clin Chest Med. 2018 Sep;39(3):525-537. doi: 10.1016/j.ccm.2018.04.007. PMID: 30122177; PMCID: PMC8018832.
- Parkin L, Skegg DC, Wilson M, Herbison GP, Paul C. Oral contraceptives and fatal pulmonary embolism. The Lancet. 2000 Jun 17;355(9221):2133-4.
- Nesheiwat F, Sergi AR. Deep venous thrombosis and pulmonary embolism following cast immobilization of the lower extremity. The Journal of Foot and Ankle Surgery: official publication of the American College of Foot and Ankle Surgeons. 1996 Nov 1;35(6):590-4.
- Nauffal D, Ballester M, Reyes RL, Jiménez D, Otero R, Quintavalla R, Monreal M, RIETE investigators. Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism. Journal of Thrombosis and Haemostasis. 2012 Sep 1;10(9):1752-60.
- Baker RJ. Treatment Considerations for Inherited Thrombophilia and Pulmonary Embolus. Archives of Surgery. 2001 Feb 1;136(2):237.
- Merli GJ. Pathophysiology of venous thrombosis, thrombophilia, and the diagnosis of deep vein thrombosis–pulmonary embolism in the elderly. Clinics in geriatric medicine. 2006 Feb 1;22(1):75-92.
- Canonico ME, Santoro C, Avvedimento M, Giugliano G, Mandoli GE, Prastaro M, Franzone A, Piccolo R, Ilardi F, Cameli M, Esposito G. Venous Thromboembolism and Cancer: A Comprehensive Review from Pathophysiology to Novel Treatment. Biomolecules. 2022 Feb 4;12(2):259. doi: 10.3390/biom12020259. PMID: 35204760; PMCID: PMC8961522.
- Kushner A, West WP, Khan Suheb MZ, Pillarisetty LS. Virchow Triad. 2022 Dec 10. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30969519.
- Stein PD, Beemath A, Matta F, Weg JG, Yusen RD, Hales CA, Hull RD, Leeper Jr KV, Sostman HD, Tapson VF, Buckley JD. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. The American Journal of Medicine. 2007 Oct 1;120(10):871-9.
- Lapner ST, Kearon C. Diagnosis and management of pulmonary embolism. BMJ. 2013 Feb 20;346.
- Söderberg M, Brohult J, Jorfeldt L, Lärfars G. The use of d‐dimer testing and Wells score in patients with high probability for acute pulmonary embolism. Journal of evaluation in clinical practice. 2009 Feb;15(1):129-33.
- Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jiménez D, Kucher N. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). European heart journal. 2020 Jan 21;41(4):543-603.
- Vyas V, Goyal A. Acute Pulmonary Embolism. 2022 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32809386.
- Forbes KP, Reid JH, Murchison JT. Do preliminary chest X-ray findings define the optimum role of pulmonary scintigraphy in suspected pulmonary embolism? Clinical radiology. 2001 May 1;56(5):397-400.