Pulmonary Embolism (PE)

1. 1. Poor HD. Pulmonary Thrombosis and Thromboembolism in COVID-19. Chest 2021;160(4):1471-1480. doi:10.1016/j.chest.2021.06.016

1. 1. Konstantinides SV, Meyer G, Becattini C, et al: 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405

2. 2. Jiménez D, Aujesky D, Moores L, et al: Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010;170(15):1383-1389. doi:10.1001/archinternmed.2010.199

3. 3. Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A, et al: Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. Eur Respir J 2017;49(2):1601792. doi:10.1183/13993003.01792-2016

Clinical probability of pulmonary embolism can be assessed by combining ECG and chest radiograph findings with findings from the history and physical examination. Clinical prediction scores, such as the Wells score or the revised Geneva score (1), or the Pulmonary Embolism Rule-Out Criteria (PERC) rule, may aid clinicians in assessing the chance that acute pulmonary embolism is present. These prediction scores assign points to a variety of clinical factors, with cumulative scores corresponding to designations of the probability of PE before testing (pretest probability). For example, the Wells score result is classified as likely or unlikely for PE. Clinical probability scoring has been best studied in patients presenting to the emergency department as opposed to those already hospitalized.

Clinical Calculators

Revised Geneva Score for Estimation of the Clinical Probability of Pulmonary Embolism in Adults

Clinical Calculators

PERC Rule for the Assessment of Possible Pulmonary Embolism

One of the important clinical criteria is a judgment of whether PE is more likely than an alternate diagnosis, and this determination is somewhat subjective. However, the clinical judgment of experienced clinicians is as sensitive as, or even more sensitive than, results from formal prediction scores. PE should probably be considered more likely if one or more of the symptoms and signs, particularly dyspnea, hemoptysis, tachycardia, or hypoxemia, cannot be explained clinically or by chest radiograph findings.

Pretest probability guides testing strategy and the interpretation of test results. In patients in whom the probability of PE is unlikely, only minimal additional testing (ie, D-dimer testing in outpatients) may be needed. In such cases, a negative D-dimer test (< 0.4 mcg/mL [< 2.2 nmol/L]) is highly indicative of the absence of pulmonary embolism. Conversely, if there is a high clinical suspicion of PE and the risk of bleeding is low, immediate anticoagulation should be considered while the diagnosis is confirmed with additional tests.

The PERC rule specifies 8 criteria. Presence of all these criteria in a patient who, based on clinical findings, is at low risk specifies that testing for PE is not indicated (2). The criteria are:

• Age < 50 years

• Heart rate < 100

• Oxygen saturation ≥ 95%

• No prior deep venous thrombosis or pulmonary embolism

• No unilateral leg swelling

• No estrogen use

• No hemoptysis

• No surgery or trauma requiring hospitalization within the past 4 weeks

Use of the PERC rule has been recommended as a way to decrease rates of testing for PE with conventional testing using D-dimer, but with similar rates of sensitivity and negative predictive values.

Clinical Calculators

PE Probability: Wells Score System

• Screening of outpatients with D-dimer testing if pre-test probability is low or intermediate

• If pretest probability is high or if the D-dimer result is elevated, CT angiography, or if renal insufficiency is present or when CT contrast is contraindicated, with ventilation/perfusion (V/Q) scanning

• Sometimes ultrasound of the legs or arms (to confirm deep venous thrombosis when lung imaging is delayed or prohibitive)

There is no universally accepted algorithm for the approach to suspected acute pulmonary embolism. Tests most useful for diagnosing or excluding PE are

• D-dimer testing

• CT angiography

• Ventilation/perfusion scanning

• Doppler ultrasound

Echocardiography may be useful to identify pulmonary embolism on the way to the lung (clot-in-transit) or to find evidence of new right ventricular dysfunction. Echocardiographic findings that may suggest pulmonary embolism include the 60/60 sign, which is the combination of a pulmonary artery acceleration time of < 60 milliseconds with a peak systolic tricuspid valve gradient of < 60 mm Hg (3), and the McConnell sign, which is depressed contractility of the RV free wall compared to the RV apex (4).

D-Dimer is a by-product of intrinsic fibrinolysis; thus, elevated levels occur in the presence of a recent thrombus. Historically, when pretest probability is considered low or intermediate, a negative D-dimer level (< 0.4 mcg/mL [< 2.2 nmol/L]) is highly sensitive for the absence of PE with a negative predictive value of > 95% (5); in most cases, this result is sufficiently reliable for excluding the diagnosis of PE in the emergency department or clinic. More recently, data have shown that age can elevate D-dimer levels, which can cause a false-positive test result. Therefore, in patients with a low or intermediate pretest probability of PE and age over 50 years, the most common correction factor is to use a cutoff value of age multiplied by 10 in ng/mL. However, elevated D-dimer levels are not specific for venous thrombus because many patients without deep venous thrombosis (DVT) or PE also have elevated levels (particularly in patients who are hospitalized). Therefore, further testing is required when the D-dimer level is elevated or when the pretest probability for PE is high.

CT angiography is the preferred imaging technique for diagnosing acute pulmonary embolism. It is rapid, accurate, and highly sensitive and specific. It can also give more information about other lung pathology (eg, demonstration of pneumonia rather than PE as a cause of hypoxia or pleuritic chest pain) as well as severity of PE (for example by the size of the right ventricle or the reflux into the hepatic veins). Although poor quality scans due to motion artifact or poor contrast boluses can limit the sensitivity of the examination, CT technology allows acquisition times of < 2 seconds, providing relatively motion-free images in patients with dyspnea. Fast scanning times allow the use of smaller volumes of iodinated contrast, which reduces the risk of acute kidney injury.

Pulmonary Embolism (Chest CTA)

Image

Image courtesy of Victor F. Tapson, MD.

The sensitivity of CT angiography is highest for pulmonary embolism in the main pulmonary artery or lobar or segmental vessels. Sensitivity of CT angiography is lowest for emboli in subsegmental vessels (about 30% of all pulmonary emboli). However, CT angiography is still the preferred means of diagnosing acute PE if there are no contraindications.

Ventilation/perfusion (V/Q) scans in pulmonary embolism detect areas of lung that are ventilated but not perfused. V/Q scanning takes much longer than CT angiography and is less specific. However, when chest radiograph findings are normal or near normal and no significant underlying lung disease exists, it is a highly sensitive test. V/Q scanning is particularly useful when renal insufficiency precludes the use of contrast agents, which are otherwise required for CT angiography, and in patients who are pregnant (6). In some hospitals, V/Q scanning can be done with a portable machine that provides 3 views of ventilation and perfusion, which is useful when a patient is too ill to move. Perfusion defects may occur in many other lung conditions (eg, COPD, pulmonary fibrosis, pneumonia, pleural effusion). Mismatched perfusion defects that may mimic PE may occur in pulmonary vasculitis, pulmonary veno-occlusive disease, and sarcoidosis.

Results are based on patterns of V/Q mismatch and reported as normal, low probability, intermediate probability, or high probability of pulmonary embolism.

The pretest clinical probability of a pulmonary embolism must be used together with the V/Q scan result to determine the need for treatment or further testing (7).

Pulmonary Embolism (Ventilation-Perfusion Scan)

The ventilation-perfusion scan demonstrates high probability for acute pulmonary embolism. The ventilation is relatively unaffected, while the perfusion images show large defects, particularly in the left lung. Image courtesy of Victor F. Tapson, MD.

Doppler ultrasound is a safe, noninvasive, portable technique for detecting leg or arm thrombi. A clot can be detected by showing poor compressibility of the vein or by showing reduced flow by Doppler ultrasound. The test has a sensitivity of > 95% and a specificity of > 95% for thrombus (8). Confirming DVT in the calf or iliac veins can be more difficult but can generally be accomplished. The ultrasound technician should always attempt to image below the popliteal vein into its trifurcation.

Absence of thrombi in the leg veins does not exclude the possibility of thrombus from other sources, such as the upper extremities or pelvic vasculature, but patients with suspected DVT and negative results on Doppler ultrasound have > 95% event-free survival, because thrombi from other sources are so much less common.

Although ultrasound of the legs or arms is not diagnostic for PE, a study that reveals leg or axillary-subclavian thrombus establishes the need for anticoagulation and may obviate the need for further diagnostic testing unless more aggressive therapy (eg, thrombolytic therapy) is being considered. Therefore, stopping the diagnostic evaluation after detection of DVT on ultrasound of the legs or arms is most appropriate for stable patients with contraindications to CT contrast and in whom V/Q scanning is expected to have low specificity (eg, in patients with an abnormal chest radiograph). In suspected acute PE, a negative ultrasound does not negate the need for additional studies.

Echocardiography may show a clot in the right atrium or ventricle, but echocardiography is most commonly used for risk stratification in acute PE. The presence of right ventricular dilation and hypokinesis may suggest the need for more aggressive therapy.

Cardiac biomarker testing is a useful means of stratifying mortality risk in patients with acute pulmonary embolism. Cardiac biomarker testing can be used as an adjunct to other testing if PE is suspected or proven. Elevated troponin levels signify right ventricular (or sometimes left ventricular) ischemia. Elevated brain natriuretic peptide (BNP) and pro-BNP levels may signify RV dysfunction; however, these tests are not specific for RV dysfunction or for PE.

Thrombotic disorder (thrombophilia) testing should not be done routinely. Testing should be considered for patients with unprovoked PE (ie, with no known risk factors or cause), especially if they are younger (age < 60 years), have recurrent PE, or have a positive family history. Certain thrombophilias, such as antiphospholipid syndrome, require disease-specific types of anticoagulation therapy.

Pulmonary arteriography is rarely needed to diagnose acute PE because noninvasive CT angiography has similar sensitivity and specificity. However, in patients in whom catheter-based thrombolytic therapy is being used, pulmonary angiography is useful for assessment of catheter placement and may be used as a rapid means of determining success of the procedure when the catheter is removed. Pulmonary arteriography is also used together with right-heart catheterization in assessing whether patients with chronic thromboembolic pulmonary hypertension are candidates for pulmonary endarterectomy.

1. 1. Le Gal G, Righini M, Roy PM, et al: Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 144:165–171, 2006.

2. 2. Kline JA, Courtney DM, Kabrhel C, et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost 6(5):772-780, 2008. doi:10.1111/j.1538-7836.2008.02944.x

3. 3. Kurzyna M, Torbicki A, Pruszczyk P, et al: Disturbed right ventricular ejection pattern as a new Doppler echocardiographic sign of acute pulmonary embolism. Am J Cardiol 90(5):507–511, 2002. doi:10.1016/s0002-9149(02)02523-7

4. 4. McConnell MV, Solomon SD, Rayan ME, et al: Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 78(4):469–473, 1996. doi:10.1016/s0002-9149(96)00339-6

5. 5. Bass AR, Fields KG, Goto R, Turissini G, Dey S, Russell LA: Clinical Decision Rules for Pulmonary Embolism in Hospitalized Patients: A Systematic Literature Review and Meta-analysis. Thromb Haemost 2017;117(11):2176-2185. doi:10.1160/TH17-06-0395

6. 6. Leung AN, Bull TM, Jaeschke R, et al: SI An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med 2011;184(10):1200-1208. doi:10.1164/rccm.201108-1575ST

7. 7. PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 263(20):2753–2759, 1990. doi:10.1001/jama.1990.03440200057023

8. 8. Habscheid W, Höhmann M, Wilhelm T, Epping J: Real-time ultrasound in the diagnosis of acute deep venous thrombosis of the lower extremity. Angiology 41(8):599–608, 1990. doi:10.1177/000331979004100803

Given the evolving therapeutic options and the lack of randomized controlled trials, choosing appropriate treatment for individual patients can be challenging. Many hospitals use a multidisciplinary group of clinicians (pulmonary embolus response team) to rapidly evaluate patients, determine the level of pulmonary embolism risk, and make the complex treatment decisions needed. These teams may be comprised of clinicians in pulmonary/critical care medicine, interventional cardiology, interventional radiology, cardiothoracic surgery, hematology, emergency medicine, and other specialties. Recent single-center studies published have shown lower rates of bleeding, shorter time to therapeutic anticoagulation, decreased 30-day mortality, and decreased use of IVC filters in patients whose care is managed by a PERT. The use of PERT in the management of acute PE is now recommended by the European Society of Cardiology (1, 2).

1. 1. Chaudhury P, Gadre SK, Schneider E, et al. Impact of Multidisciplinary Pulmonary Embolism Response Team Availability on Management and Outcomes. Am J Cardiol 2019;124(9):1465-1469. doi:10.1016/j.amjcard.2019.07.043

2. 2. Konstantinides SV, Meyer G, Becattini C, et al. 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). Eur Respir J 2019;54(3):1901647. doi:10.1183/13993003.01647-2019

Initial anticoagulation choices for acute PE include

• Intravenous unfractionated heparin

• Subcutaneous low molecular weight heparin

• Factor Xa inhibitors (oral apixaban, edoxaban, or rivaroxaban, or subcutaneous fondaparinux)

• Direct thrombin inhibitors (IV argatroban, oral dabigatran) for patients with heparin-induced thrombocytopenia

Intravenous unfractionated heparin has a short half-life (useful when the potential for bleeding is deemed higher than usual) and is reversible with protamine. An initial bolus of unfractionated heparin is given, followed by an infusion of heparin dosed by protocol to achieve an activated partial thromboplastin time (PTT) 1.5 to 2.5 times that of normal control. Therefore, unfractionated heparin requires ongoing hospitalization to administer. Further, the pharmacokinetics of unfractionated heparin are relatively unpredictable, resulting in frequent periods of over-anticoagulation and under-anticoagulation and necessitating frequent dose adjustments. Some clinicians prefer this IV unfractionated heparin regimen when thrombolytic therapy is given or contemplated or when patients are at risk of bleeding because if bleeding occurs, the short half-life means that anticoagulation is quickly reversed after the infusion is stopped.

Subcutaneous low molecular weight heparin has several advantages over unfractionated heparin including

• Superior bioavailability

• Weight-based dosing results in a more predictable anticoagulation effect than does weight-based dosing of unfractionated heparin, which allows for quicker time to therapeutic coverage

• Ease of administration (can be given subcutaneously once or twice a day)

• Decreased incidence of bleeding

• Potentially better outcomes

• The potential for patients to self-inject (thereby allowing earlier discharge from the hospital)

• Lower risk of heparin-induced thrombocytopenia compared with standard, unfractionated heparin

Low molecular weight heparins that can be used include dalteparin, enoxaparin, and tinzaparin.

In patients with renal insufficiency, dose reductions are needed, and subsequent verification of appropriate dosing should be done by checking serum factor Xa levels (target: 0.5 to 1.2 IU/mL measured at 3 to 4 hours after the fourth dose). Low molecular weight heparins are generally contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 mL/minute [0.5mL/second/m²]). Low molecular weight heparins are partially reversible with protamine.

Adverse effects of all heparins include

• Bleeding

• Thrombocytopenia (including heparin-induced thrombocytopenia with the potential for thromboembolism)

• Urticaria

• Anaphylaxis (rare)

Bleeding caused by over-heparinization with unfractionated heparin can be treated with a protamine infusion. Over-heparinization with a low molecular weight heparin can also be treated with protamine.

Fondaparinux is a factor Xa antagonist given subcutaneously. It can be used in acute DVT and acute PE instead of heparin or low molecular weight heparin. Outcomes appear to be similar to those of unfractionated heparin. Advantages include once or twice a day fixed-dose administration, no need for monitoring of the degree of anticoagulation, and lower risk of thrombocytopenia. The medication is contraindicated if creatinine clearance is < 30 mL/minute (0.5mL/second/m²).

The other factor Xa inhibitors, apixaban, rivaroxaban, and edoxaban, have the advantages of oral fixed dosing and the ability to be used as maintenance anticoagulants with no need for laboratory monitoring of the anticoagulant effect. They also cause few adverse interactions with other medications, although azole antifungal therapy and protease inhibitors will increase oral factor Xa inhibitor levels, and certain antiseizure medications and rifampin will decrease oral factor Xa inhibitor levels. Although rivaroxaban and apixaban do not require overlap with a parenteral anticoagulant when used as initial therapy, edoxaban requires use of a parenteral anticoagulant for 5 to 10 days.

Dose reductions are indicated for patients with renal insufficiency. Apixaban can be used in patients with renal insufficiency, and use is safe in patients undergoing hemodialysis.

Anticoagulation reversal of the oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) is possible with andexanet, although this medication is not widely used. Reversal of fondaparinux may be possible using recombinant activated factor VII (2). The half-lives of the factor Xa inhibitors are much shorter than the half-life for warfarin. If bleeding develops that requires reversal, use of 4-factor prothrombin complex concentrate can be considered, and hematology consultation is recommended.

The safety and efficacy of these medications in patients with PE complicated by severe cardiopulmonary decompensation have not been studied, and parenteral medications should be used for anticoagulation in these patients until there is significant improvement in cardiopulmonary function.

The direct thrombin inhibitor dabigatran is also effective for treatment of acute DVT and PE. Dabigatran requires overlap with a parenteral anticoagulant when used as initial therapy. Idarucizumab is effective at reversing dabigatran.

In patients with suspected or proven heparin-induced thrombocytopenia, intravenous argatroban or subcutaneous fondaparinux can be used for anticoagulation. Use of the direct oral anticoagulants (dabigatran, apixaban, edoxaban, rivaroxaban) in this situation has been found to be safe in a recent meta-analysis (3).

Maintenance anticoagulation is indicated to reduce the risk of clot extension or embolization and to reduce the risk of new clot formation. Medication choices for maintenance anticoagulation include

• Oral vitamin K antagonist (VKA) (warfarin in the United States)

• Oral factor Xa inhibitors (apixaban, rivaroxaban, edoxaban)

• Oral direct thrombin inhibitor (dabigatran)

• Rarely subcutaneous low molecular weight heparin or subcutaneous fondaparinux

Warfarin is an effective long-term oral anticoagulant option that has been used for decades, but it is inconvenient for a number of reasons. In most patients, warfarin is started on the same day as heparin (or fondaparinux) therapy used for initial anticoagulation. Heparin (or fondaparinux) therapy should be overlapped with warfarin therapy for a minimum of 5 days and until the international normalized ratio (INR) has been within the therapeutic range (2.0 to 3.0) for at least 24 hours.

The major disadvantages of warfarin are the need for periodic INR monitoring, with frequent dose adjustments, and medication, supplement, and food interactions. Physicians prescribing warfarin should be wary of such interactions; in a patient taking warfarin, virtually any newly ingested medication or substance should be checked.

Bleeding is the most common complication of warfarin treatment; patients > 65 years and those with comorbidities (especially diabetes, recent myocardial infarction, hematocrit < 30%, or creatinine > 1.5 mg/dL [>133 micromol/L]) and a history of stroke or gastrointestinal bleeding seem to be at greatest risk. Bleeding can be reversed with vitamin K and, in an emergency, with fresh frozen plasma or a concentrate formulation (prothrombin complex concentrates) that contains factor II (prothrombin), factor VII, factor IX, factor X, protein C, and protein S. Vitamin K may cause flushing, local pain, and, rarely, anaphylaxis.

Warfarin-induced necrosis, a devastating complication of warfarin therapy, is a paradoxical hypercoagulable state that can arise upon the initiation of warfarin therapy. Warfarin inactivates vitamin K-dependent clotting factors II, VII, IX, and X. At the same time, vitamin K-dependent proteins C and S are inactivated. This may cause a paradoxical hypercoagulable state in which microthrombi form in cutaneous and subcutaneous venules, resulting in skin necrosis. Based on these considerations and the development of more convenient oral anticoagulants, warfarin use has been declining substantially. However, cost considerations continue to make warfarin a reasonable treatment option for some patients.

The oral factor Xa inhibitor anticoagulants apixaban, edoxaban, and rivaroxaban can be used for both initial and maintenance anticoagulation therapy (see table Direct Oral Anticoagulants for Treatment of Venous Thromboembolism). These medications are more convenient than warfarin due to their fixed dosing and lack of need for laboratory monitoring, as well as having fewer interactions. In clinical trials, rivaroxaban (4, 5), apixaban (6), and edoxaban (7) were as effective (in non-inferiority analyses) as warfarin in preventing recurrent DVT and PE. A meta-analysis of large phase III randomized controlled trials found that rates of major bleeding, including intracranial hemorrhage, were significantly lower with oral factor Xa inhibitor anticoagulants than with warfarin (8). Another advantage of both rivaroxaban and apixaban is that dosages may be lowered after patients have been treated for 6 to 12 months (9).

One important caveat is that edoxaban requires that a preceding 5 to 10 days of initial heparin or low molecular weight heparin be given.

The direct thrombin inhibitor dabigatran can also be used for maintenance anticoagulation therapy. As with edoxaban, 5 to 10 days of treatment with unfractionated heparin or low molecular weight heparin is needed before dabigatran can be initiated. Clinically relevant bleeding is lower with dabigatran than with warfarin. The use of dabigatran as maintenance therapy has the same advantages and disadvantages as the use of the factor Xa inhibitors.

The need for initial heparin treatment before edoxaban or dabigatran is given is a reflection of the way the clinical trials were conducted.

Subcutaneous low molecular weight heparin has been used primarily for patients with cancer at high risk of pulmonary embolism or patients with recurrent pulmonary embolism despite the use of other anticoagulants. However, multiple recent trials of apixaban, edoxaban, and rivaroxaban have been completed in patients with cancer, and these agents are now recommended over low molecular weight heparin (10).

Aspirin has been studied for long-term maintenance therapy. It appears more effective than placebo but less effective than all other available anticoagulants. Rivaroxaban, 10 mg once/day, has proven more effective at reducing recurrent DVT/PE yet is as safe as aspirin in patients already treated with anticoagulation for 6 to 12 months (9).

Duration of maintenance anticoagulation for PE is dependent on a variety of factors (eg, risk factors for PE, bleeding risk) and can range from 3 months to lifelong therapy. Clearly transient risk factors (eg, immobilization, recent surgery, trauma) require only 3 months of treatment. Patients with unprovoked PE, those with more durable risk factors for PE (eg, cancer, thrombophilic disorder), and those with recurrent PE might benefit from lifelong anticoagulation provided the bleeding risk is low or moderate. In patients with unprovoked venous thromboembolism, annual assessment of bleeding risk versus clotting risk should be done and an informed joint decision regarding continuing anticoagulation reached.

Risk factors for bleeding include

• Age > 65 years

• Previous bleeding

• Thrombocytopenia

• Antiplatelet therapy

• Poor anticoagulant control

• Frequent falls

• Liver failure

• Alcohol overuse

• Recent surgery

• Reduced functional capacity

• Previous stroke

• Diabetes

• Anemia

• Cancer

• Renal failure

Low risk for bleeding is defined as no risk factors for bleeding, moderate risk for bleeding is defined as one risk factor, and high risk for bleeding is defined as two or more risk factors.

For patients in whom long-term anticoagulation is considered appropriate, after 6 months of treatment with rivaroxaban or apixaban, dosage decreases can be considered.

1. 1. Smith SB, Geske JB, Maguire JM, Zane NA, Carter RE, Morgenthaler TI. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 2010;137(6):1382-1390. doi:10.1378/chest.09-0959

2. 2. Yee J, Kaide CG. Emergency Reversal of Anticoagulation. West J Emerg Med 2019;20(5):770-783. doi:10.5811/westjem.2018.5.38235

3. 3. Nilius H, Kaufmann J, Cuker A, Nagler M. Comparative effectiveness and safety of anticoagulants for the treatment of heparin-induced thrombocytopenia. Am J Hematol 2021;96(7):805-815. doi:10.1002/ajh.26194

4. 4. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al: Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510, 2010. doi:10.1056/NEJMoa1007903

5. 5. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366 (14):1287–1297, 2012. doi:10.1056/NEJMoa1113572

6. 6. Agnelli G, Buller HR, Cohen A, et al: Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808, 2013. doi:10.1056/NEJMoa1302507

7. 7. Hokusai-VTE Investigators, Buller HR, Decousus H, et al: Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15): 1406–1415, 2013. doi:10.1056/NEJMoa1306638

8. 8. van Es N, Coppens M, Schulman S, et al: Direct oral anticoagulants compared with vitamin K antagonists for acute symptomatic venous thromboembolism: evidence from phase 3 trials. Blood124 (12): 1968–1975, 2014. doi:10.1182/blood-2014-04-571232

9. 9. Weitz JI, Lensing AWA, Prins MH, et al: Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 376:1211–1222, 2017. doi: 10.1056/NEJMoa1700518.

10. 10. Stevens SM, Woller SC, Kreuziger LB, et al: Antithrombotic therapy for VTE disease: Second update of the CHEST Guideline and Expert Panel Report [published correction appears in Chest 2022 Jul;162(1):269]. Chest 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055

Systemic thrombolytic therapy with alteplase (tissue plasminogen activator [tPA]) offers a noninvasive way to rapidly restore pulmonary blood flow, but long-term benefits do not clearly outweigh the risk of hemorrhage in some patients. Experts agree that systemic thrombolytic therapy should be given to patients with hemodynamic compromise if there are no contraindications, particularly when other means of rapidly reducing clot burden are not readily available. Although no prospective randomized trial of systemic thrombolytic therapy has shown improved survival in patients with intermediate-risk/submassive PE, some experts recommend thrombolytics, particularly when patients also have numerous or large clots; very severe RV dysfunction; marked tachycardia; significant hypoxemia; other concomitant findings such as residual clot in the leg, positive troponin values, and/or elevated BNP values; and there are no active contraindications to its administration. Others reserve thrombolytic therapy only for patients with high-risk (massive) PE.

Absolute contraindications to thrombolytics include

• Prior hemorrhagic stroke

• Ischemic stroke within 1 year

• Active external or internal bleeding from any source

• Intracranial injury or surgery within 2 months

• Intracranial tumor

• Certain surgeries within the previous weeks

Relative contraindications include

• Age > 75 years

• Recent surgery (≤ 10 days)

• Hemorrhagic diathesis (as in hepatic insufficiency)

• Pregnancy

• Recent punctures of large noncompressible veins (eg, subclavian vein)

• Recent femoral artery catheterization (eg, ≤ 10 days)

• Peptic ulcer disease or other conditions that increase the risk of bleeding

• Severe hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg)

• Head trauma from PE-induced syncope, even if brain CT is normal

Except for concurrent intracerebral hemorrhage, thrombolytic therapy is sometimes given to patients with high-risk (massive) PE who have "absolute contraindications" to such therapy if, without intervention, death is otherwise anticipated. In patients with relative contraindications, the decision to give systemic thrombolytics depends on individual patient factors.

In the United States, alteplase (tPA) is used for systemic thrombolysis. Streptokinase and urokinase are not used for acute PE.

In the United States, when systemic thrombolytics are given, heparin is usually stopped after the initial loading dose. However, in Europe, heparin is often continued, and there is no clear determination as to which method is preferred. The bleeding risk should be considered.

Bleeding, if it occurs, can be reversed with cryoprecipitate or fresh frozen plasma. Accessible vascular access sites that are bleeding can be compressed. The potential for bleeding after systemic thrombolysis has led to increased implementation of catheter-directed thrombolysis, because much lower doses of thrombolytic agents are used.

Catheter-directed PE therapy (thrombolytics, embolectomy) uses catheter placement in the pulmonary arteries for disruption, removal, and/or lysis of clot. Indications for its use are evolving in patients who are at high risk and those at intermediate high risk. In catheter-directed PE thrombolytic therapy, the pulmonary arteries are accessed via a typical pulmonary arteriography procedure, and thrombolytics are delivered directly to large proximal emboli via the catheter. The most widely studied technique uses high-frequency, low-power ultrasound. Ultrasound accelerates thrombolysis by disaggregating fibrin strands and increasing permeability of the clot to thrombolytics. One randomized controlled trial, the ULTIMA study, demonstrated that the use of catheter-directed thrombolytics in patients with proximal clot and evidence of RV strain leads to an improved RV/LV ratio at 24 hours compared with anticoagulation alone (2). However, there was no difference between the groups in RV function, RV/LV ratio at 90 days, or 90-day mortality (2).

Mechanical disruption, or removal of the thrombus via suction embolectomy without thrombolysis, is becoming more widely used. Mechanisms of clot removal include direct aspiration or fragmentation with aspiration. Devices for this purpose differ by size of catheter and method of embolectomy. If the use of thrombolysis is contraindicated, catheter-directed suction embolectomy may be considered and, depending on local resources and expertise, tried before surgical embolectomy. Anticoagulation is still required for patients undergoing mechanical thrombectomy. Data on the use of suction embolectomy devices are limited to patients at intermediate high risk or high risk who participated in single-arm studies and registries (3).

Surgical embolectomy is reserved for patients with PE who are hypotensive despite supportive measures (persistent systolic blood pressure ≤ 90 mm Hg after fluid therapy and oxygen or if vasopressor therapy is required) or on the verge of cardiac or respiratory arrest. Surgical embolectomy can be considered if use of thrombolysis is contraindicated, although catheter-directed suction embolectomy may be tried first. As with catheter-based thrombosis/clot extraction, the decision to proceed with embolectomy and the choice of technique depend on local resources and expertise. Surgical embolectomy as a management strategy for acute PE is decreasing in frequency as catheter-based percutaneous techniques become more widely available.

Extracorporeal membrane oxygenation (ECMO) is sometimes used in catastrophic acute pulmonary embolism when thrombolysis is contraindicated or failed. ECMO may serve as a bridge to surgical embolectomy or catheter-directed therapy, or it may buy time for improvement with anticoagulation alone.

1. 1. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830

2. 2. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129(4):479-486. doi:10.1161/CIRCULATIONAHA.113.005544

3. 3. Hountras P, Bull TM. Advanced therapies for pulmonary embolism. Curr Opin Pulm Med 2020;26(5):397-405. doi:10.1097/MCP.0000000000000714

1. 1. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121(3):877-905. doi:10.1378/chest.121.3.877

2. 2. Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30(5):1165-1171. doi:10.1016/s0735-1097(97)00319-7

Prevention of pulmonary embolism means prevention of deep venous thrombosis (DVT); the need depends on the patient’s risks, including

• Type and duration of any surgery

• Comorbid conditions, including cancer and hypercoagulable disorders

• Presence of a central venous catheter

• Prior history of DVT or PE

Patients who are bedbound and hospitalized and patients undergoing surgical, especially orthopedic, procedures benefit significantly from venous thromboembolism prophylaxis, and most of these patients can be identified before a thrombus forms (see table Risk Assessment for Thrombosis). Preventive measures include low-dose unfractionated heparin, low molecular weight heparin, warfarin, fondaparinux, direct oral anticoagulants (eg, rivaroxaban, apixaban), compression devices, and elastic compression stockings.

Choice of medication or device depends on various factors, including patient demographics, the perceived risk, contraindications (eg, bleeding risk), relative costs, and ease of use. The American College of Chest Physicians has published comprehensive evidence-based recommendations for prophylaxis of acute DVT, including the duration of prophylaxis, in surgical and nonsurgical patients and during pregnancy (1, 2). The need for prophylaxis has been studied in numerous patient populations.

The type of surgery as well as patient-specific factors determine the risk of DVT. Independent risk factors for surgical and nonsurgical patients include

• Age ≥ 60 years

• Prior DVT or PE

• Cancer

• Anesthesia ≥ 2 hours

• Bed rest ≥ 4 days

• Male sex

• Hospital stay ≥ 2 days

• Sepsis

• Pregnancy or the postpartum state

• Central venous access

• Body mass index (BMI) > 40

The Caprini score is commonly used for DVT risk stratification and determination of the need for DVT prophylaxis in nonorthopedic surgical patients (see table Risk Assessment for Thrombosis).

The need for DVT prophylaxis is based on the risk assessment score (see table Prophylaxis Based on Caprini Score). Appropriate preventive measures, ranging from early ambulation to use of heparin, depend on the total score (3).

Medication therapy to prevent DVT is usually delayed until after surgery to help avoid intraoperative bleeding. However, preoperative prophylaxis is also effective.

In general surgery patients, low dose unfractionated heparin is given for 7 to 10 days or until the patient is fully ambulatory. Patients who are immobilized and not undergoing surgery should also receive low dose unfractionated heparin until they are ambulatory.

Low molecular weight heparin dosing for DVT prophylaxis depends on the specific medication (enoxaparin, dalteparin, tinzaparin). Low molecular weight heparins are at least as effective as low dose unfractionated heparin for preventing DVT and PE.

Fondaparinux 2.5 mg subcutaneously once a day is as effective as low molecular weight heparin for patients who have undergone orthopedic surgery and for patients with heparin-induced thrombocytopenia or some other situations, such as after major orthopedic surgery (4). It is a selective factor Xa inhibitor.

Warfarin is usually effective and safe at a dose adjusted to maintain an INR of 2 to 3 in patients who have undergone total hip or knee replacement. Warfarin use is increasingly being supplanted by the use of direct oral anticoagulants.

The direct oral anticoagulants rivaroxaban and apixaban are factor Xa inhibitors. They can be used for prevention of acute DVT/PE in patients undergoing total knee or hip arthroplasty.

Inferior vena cava filters, intermittent pneumatic compression (also known as sequential compression devices [SCD]), and graded elastic compression stockings may be used alone or in combination with medications to prevent PE. Whether these devices are used alone or in combination depends on the specific indication.

An inferior vena cava filter (IVCF) may help prevent PE in patients with DVT in the leg or pelvic vasculature, but IVCF placement may risk long-term complications. Evidence raises questions regarding the efficacy of retrievable filters in patients receiving anticoagulation (5). A filter is most clearly indicated in patients who have

• Proven DVT and contraindications to anticoagulation

• Recurrent DVT (or emboli) despite adequate anticoagulation

• Possibly marginal cardiopulmonary function, causing concern for their ability to tolerate additional small emboli

Because venous collaterals can develop, providing a pathway for emboli to circumvent long-standing IVCFs, and because filters occasionally thrombose, patients with recurrent DVT or nonmodifiable risk factors for DVT may still require anticoagulation. An IVCF is placed in the inferior vena cava just below the renal veins via catheterization of an internal jugular or femoral vein. Most IVCFs are removable. Occasionally, a filter dislodges and may migrate up the venous bed, even to the heart or pulmonary vasculature. A filter can also become thrombosed, causing severe venous congestion (including acute phlegmasia cerulea dolens) in the leg, lower body ischemia, and acute kidney injury (6).

Intermittent pneumatic compression (IPC) with SCDs provides rhythmic external compression to the legs or to the legs and thighs. It is more effective for preventing calf than proximal DVT. It is insufficient as sole prophylaxis after hip or knee replacement but is often used in low-risk patients after other types of surgery or in medical patients who have a low-risk of DVT or who are at high risk of bleeding. IPC can theoretically trigger PE in patients who are immobilized and have developed occult DVT while not receiving DVT prophylaxis.

Graded elastic compression stockings are likely less effective than external pneumatic leg compression.

After surgical procedures with a high incidence of DVT/PE, low dose unfractionated heparin, low molecular weight heparin, or adjusted-dose warfarin is recommended.

After orthopedic surgery of the hip or knee, additional options include the direct oral anticoagulants rivaroxaban and apixaban. These medications are safe and effective and, unlike warfarin, they do not require laboratory tests to monitor the level of anticoagulation.

For total hip arthroplasty, patients should continue to take anticoagulants for 35 days postoperatively. In selected patients at very high risk of both DVT/PE and bleeding, temporary placement of an IVCF is an option for prophylaxis.

In patients undergoing elective neurosurgical procedures, the risk of DVT/PE is also high. Because of concern about intracranial bleeding, physical methods (SCDs and elastic stockings) have often been used in patients undergoing neurosurgery; however, low molecular weight heparin appears to be an acceptable alternative. Although no specific guidelines exist, the combination of SCDs and low molecular weight heparin may be more effective than either alone in patients who are at high risk.

In patients with spinal cord injury or multiple trauma, limited data support the combination of SCDs, elastic compression stockings, and low molecular weight heparin to prevent DVT/PE (7). For patients at very high risk, a temporary IVCF may be considered.

In acutely ill medical patients, low dose unfractionated heparin, low molecular weight heparin, or fondaparinux can be given. SCDs, elastic compression stockings, or both may be used when anticoagulants are contraindicated. For patients with ischemic stroke, low dose unfractionated heparin or low molecular weight heparin can be used; SCD, elastic compression stockings, or both may be beneficial.

1. 1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report [published correction appears in Chest 2016 Oct;150(4):988]. Chest 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

2. 2. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report [published correction appears in Chest 2022 Jul;162(1):269]. Chest 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055

3. 3. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [published correction appears in Chest 2012 May;141(5):1369]. Chest 2012;141(2 Suppl):e227S-e277S. doi:10.1378/chest.11-2297

4. 4. Tran AH, Lee G. Fondaparinux for prevention of venous thromboembolism in major orthopedic surgery. Ann Pharmacother 2003;37(11):1632-1643. doi:10.1345/aph.1C104

5. 5. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA 2015;313(16):1627-1635. doi:10.1001/jama.2015.3780

6. 6. Marron RM, Rali P, Hountras P, Bull TM. Inferior Vena Cava Filters: Past, Present, and Future. Chest 2020;158(6):2579-2589. doi:10.1016/j.chest.2020.08.002

7. 7. Aito S, Pieri A, D'Andrea M, Marcelli F, Cominelli E. Primary prevention of deep venous thrombosis and pulmonary embolism in acute spinal cord injured patients. Spinal Cord 2002;40(6):300-303. doi:10.1038/sj.sc.3101298