# Pulmonary Embolism - Diagnosis and Anticoagulation

## Epidemiology and Risk Factors

### Burden of Disease

Pulmonary embolism represents the third most common cardiovascular disease, with an annual incidence of 60-120 per 100,000 population. The 30-day mortality varies dramatically by severity classification: massive PE carries a mortality of 25-65%, submassive PE 3-15%, and low-risk PE less than 1%. The risk of recurrence following a first event is substantial, estimated at 5-10% within the first year after a provoked PE and 15-30% after an unprovoked PE without ongoing anticoagulation.

### Virchow's Triad

The pathophysiology of venous thromboembolism is classically described through Virchow's triad. Stasis encompasses immobilization, surgery, long-haul travel, paralysis, and obesity. Endothelial injury results from surgery, trauma, central venous catheters, and prior deep venous thrombosis. Hypercoagulability includes inherited thrombophilias (Factor V Leiden, prothrombin G20210A mutation, protein C and S deficiency, antithrombin deficiency, antiphospholipid syndrome) and acquired states (active malignancy, pregnancy, oral contraceptive or hormone replacement therapy use, myeloproliferative disorders, nephrotic syndrome, and COVID-19 infection).

## Diagnosis

### Clinical Probability Assessment

Accurate pre-test probability assessment is the foundation of the diagnostic algorithm for PE. The Wells Score for PE assigns points for clinical features: signs of DVT (3 points), PE as the most likely diagnosis (3), heart rate exceeding 100 (1.5), immobilization or surgery within the past 4 weeks (1.5), prior DVT or PE (1.5), hemoptysis (1), and active cancer (1). A score below 2 indicates low probability with a PE prevalence of 2-5%, a score of 2-6 indicates moderate probability with a prevalence of 15-20%, and a score exceeding 6 indicates high probability with a prevalence of 40-60%. The Revised Geneva Score offers an alternative that is more objective, eliminating the subjective criterion of PE as the most likely diagnosis. The YEARS algorithm provides a simplified approach using three items (signs of DVT, hemoptysis, PE as most likely diagnosis) with an adjusted D-dimer threshold: below 500 mcg/L if one or more YEARS items are present, and below 1000 mcg/L if no YEARS items are present. The PERC rule comprises eight criteria; if all are negative in a patient with low pretest probability, PE can be safely excluded without D-dimer testing. The criteria include age below 50, heart rate below 100, SpO2 above 94%, no hemoptysis, no estrogen use, no prior DVT or PE, no unilateral leg swelling, and no recent surgery or trauma.

### D-dimer

D-dimer testing offers high sensitivity exceeding 95% but low specificity of approximately 40-50%. Age-adjusted D-dimer cutoffs, calculated as age multiplied by 10 mcg/L for patients older than 50, were validated in the ADJUST-PE study and safely reduce CTPA utilization by approximately 12% without missing clinically significant PE. Pregnancy-adjusted cutoffs using trimester-specific thresholds or acceptance of a higher false-positive rate with conventional cutoffs are used in pregnant patients. D-dimer is elevated in numerous conditions beyond PE, including malignancy, infection, surgery, trauma, pregnancy, advanced age, hospitalization, disseminated intravascular coagulation, and aortic dissection.

### CTPA (CT Pulmonary Angiography)

CT pulmonary angiography serves as the gold standard for PE diagnosis, with a sensitivity of 95-98% and specificity of 95-97%. CTPA identifies the location and clot burden, distinguishing central, lobar, segmental, and subsegmental emboli. A right ventricle to left ventricle ratio exceeding 0.9 on CT suggests right ventricular dysfunction and informs risk stratification. The clinical significance of subsegmental PE (SSPE) remains debated, and current guidelines suggest that observation without anticoagulation may be appropriate in low-risk patients without proximal DVT and with adequate cardiopulmonary reserve.

### V/Q Scan

Ventilation-perfusion scanning serves as an alternative when CTPA is contraindicated due to contrast allergy, severe renal insufficiency, or pregnancy. The PIOPED II study established that a normal V/Q scan essentially excludes PE, while a high-probability V/Q scan in the setting of high clinical probability has a positive predictive value of approximately 96%. Non-diagnostic rates have been reduced with the adoption of SPECT V/Q imaging compared to traditional planar imaging.

### Echocardiography

Echocardiography is not diagnostic for PE in most cases, as it does not directly visualize the clot. However, it identifies right ventricular dysfunction through RV dilation, hypokinesis, McConnell's sign (RV free wall akinesis with preserved apical contractility), tricuspid regurgitation, and a D-shaped interventricular septum. Its principal utility is in hemodynamically unstable patients where transport to CT is unsafe. Bedside POCUS can rapidly detect RV dilation and dysfunction to guide immediate management decisions.

<image>A comprehensive diagnostic algorithm for suspected PE. Start with clinical probability assessment (Wells or YEARS). For low probability: PERC rule (if all negative, PE excluded; if any positive, D-dimer). For D-dimer: if negative (age-adjusted cutoff), PE excluded; if positive, CTPA. For moderate probability: D-dimer first; if positive, CTPA. For high probability: proceed directly to CTPA (skip D-dimer). Show CTPA outcomes: PE confirmed (risk stratify), PE negative (consider alternative diagnosis or lower extremity ultrasound if high clinical suspicion). For hemodynamically unstable: bedside echo first; if RV dysfunction, treat empirically or proceed to CTPA if stable enough. Include special populations: pregnancy (start with bilateral leg ultrasound, then V/Q SPECT or CTPA), renal insufficiency (V/Q scan). Use traffic light color coding for risk levels.</image>

## Risk Stratification

### Hemodynamic Classification

Risk stratification following PE diagnosis drives treatment intensity and disposition. Massive (high-risk) PE is defined by sustained systolic blood pressure below 90 mmHg for 15 minutes or more, requirement for vasopressors, or cardiac arrest, and carries a mortality of 25-65%. Submassive (intermediate-risk) PE describes normotensive patients with evidence of RV dysfunction on echocardiography or CT and/or elevated biomarkers including troponin and BNP. This category is further subdivided into intermediate-high risk (both RV dysfunction and elevated troponin) and intermediate-low risk (one but not both features). Low-risk PE describes normotensive patients without RV dysfunction and with normal biomarkers.

### Prognostic Tools

The Pulmonary Embolism Severity Index (PESI) incorporates age, male sex, cancer, heart failure, chronic lung disease, heart rate at or above 110, systolic blood pressure below 100, respiratory rate at or above 30, temperature below 36 degrees, altered mental status, and SpO2 below 90%. PESI Class I-II identifies low-risk patients with 30-day mortality below 2% who may be candidates for outpatient management. The simplified PESI (sPESI) uses six dichotomous variables, and a score of 0 identifies low-risk patients. The Hestia criteria comprise 11 criteria for assessing suitability for outpatient PE management; if all are negative, outpatient treatment is appropriate.

## Treatment

### Anticoagulation

| DOAC | Initial Dose | Maintenance Dose | Parenteral Lead-In | Key Trial | Extended Dose |
|------|-------------|------------------|-------------------|-----------|---------------|
| Rivaroxaban | 15 mg BID x 21 days | 20 mg daily | Not required | EINSTEIN-PE | 10 mg daily (EINSTEIN-CHOICE) |
| Apixaban | 10 mg BID x 7 days | 5 mg BID | Not required | AMPLIFY | 2.5 mg BID (AMPLIFY-EXT) |
| Edoxaban | 60 mg daily | 60 mg daily | >= 5 days LMWH/UFH | Hokusai-VTE | N/A |
| Dabigatran | 150 mg BID | 150 mg BID | >= 5 days LMWH/UFH | RE-COVER | N/A |

Initial anticoagulation should be started immediately when clinical probability is moderate to high, even before confirmatory imaging. Direct oral anticoagulants (DOACs) are the preferred first-line therapy for most patients. Rivaroxaban is administered at 15 mg twice daily for 21 days followed by 20 mg daily, without the need for initial parenteral anticoagulation, as validated in the EINSTEIN-PE trial. Apixaban is given at 10 mg twice daily for 7 days followed by 5 mg twice daily, also without initial parenteral therapy, as demonstrated in the AMPLIFY trial. Edoxaban at 60 mg daily and dabigatran at 150 mg twice daily both require at least 5 days of parenteral anticoagulation before initiation, as shown in the Hokusai-VTE and RE-COVER trials respectively. Low-molecular-weight heparin, including enoxaparin at 1 mg/kg subcutaneously twice daily or 1.5 mg/kg daily and dalteparin at 200 IU/kg daily, is an alternative. Unfractionated heparin, administered as an IV bolus of 80 U/kg followed by an infusion of 18 U/kg/hr targeting an aPTT of 1.5-2.5 times control, is preferred for massive PE due to its short half-life and reversibility, and for renal failure when creatinine clearance is below 30. Warfarin targeting an INR of 2.0-3.0 requires overlap with parenteral anticoagulation for at least 5 days and until the INR is 2.0 or greater for at least 24 hours, and is less preferred due to the monitoring burden and food and drug interactions.

### Duration of Anticoagulation

For PE provoked by a major transient risk factor such as surgery, trauma, or immobilization for 3 or more days, 3 months of anticoagulation is sufficient. For PE provoked by a minor transient risk factor such as oral contraceptives, travel, or minor surgery, 3-6 months is recommended. For a first unprovoked episode, a minimum of 3 months is given followed by reassessment for indefinite anticoagulation. Factors favoring indefinite therapy include male sex and a positive D-dimer after stopping anticoagulation as demonstrated in the PROLONG study. The HERDOO2 score may help identify women who can safely discontinue therapy (score of 1 or less), while men should generally continue indefinitely. For extended therapy, reduced-dose DOACs reduce bleeding risk while maintaining efficacy: rivaroxaban 10 mg daily (EINSTEIN-CHOICE) or apixaban 2.5 mg twice daily (AMPLIFY-EXT). Cancer-associated VTE should be treated with LMWH or DOACs, as validated in the CLOT, SELECT-D, Caravaggio, and Hokusai Cancer trials; DOACs should be used with caution in GI and GU malignancies due to increased mucosal bleeding risk. Antiphospholipid syndrome requires warfarin rather than DOACs, as the TRAPS trial demonstrated increased recurrence with rivaroxaban, particularly in triple-positive APS.

### Massive PE - Reperfusion Therapy

Systemic thrombolysis with alteplase 100 mg IV over 2 hours (or 0.6 mg/kg over 15 minutes for cardiac arrest) or weight-based tenecteplase is indicated for massive PE. The PEITHO trial evaluated tenecteplase in submassive PE and showed reduced hemodynamic decompensation (2.6% versus 5.6%) but increased major bleeding (6.3%) and intracranial hemorrhage (2%), establishing that routine thrombolysis is not recommended for submassive PE. Absolute contraindications include active internal bleeding, recent hemorrhagic stroke within 3 months, and intracranial neoplasm. Catheter-directed therapy (CDT) delivers lower-dose thrombolytics directly to the pulmonary arteries, with ultrasound-assisted devices (EKOS/EkoSonic) evaluated in the ULTIMA trial, which demonstrated improved RV/LV ratio at 24 hours compared to heparin alone. Surgical embolectomy is reserved for massive PE with thrombolysis failure or contraindication, requires cardiopulmonary bypass, and carries mortality of 20-30% at experienced centers.

<image>A risk stratification and treatment algorithm for acute PE. Start with confirmed PE on CTPA. First branch: hemodynamic status. Massive PE (SBP < 90, shock): immediate systemic thrombolysis (alteplase 100 mg over 2 hours) + IV heparin; if thrombolysis contraindicated: catheter-directed therapy or surgical embolectomy; ECMO as bridge. Submassive PE (normotensive): assess RV function (echo + CT RV/LV ratio) AND biomarkers (troponin, BNP). If intermediate-high risk: ICU monitoring, heparin, close surveillance for deterioration, consider catheter-directed therapy if worsening. If intermediate-low risk: ward admission, anticoagulation. Low-risk PE (sPESI 0, no RV dysfunction): consider outpatient management with DOAC (Hestia criteria). Show anticoagulation choices at bottom: DOAC vs. LMWH/warfarin vs. cancer-specific considerations. Use red, orange, yellow, green zones for risk levels.</image>

## Special Populations

### PE in Pregnancy

Both CTPA and V/Q scan are acceptable diagnostic modalities in pregnancy, with CTPA preferred for its ability to exclude alternative diagnoses and V/Q preferred by some clinicians for its lower fetal radiation dose. Treatment consists of LMWH (enoxaparin 1 mg/kg twice daily) throughout pregnancy, as DOACs and warfarin are both contraindicated. Peripartum management requires holding LMWH 24 hours before planned delivery, with restart 6-12 hours after vaginal delivery and 24 hours after cesarean section. The minimum treatment duration is 3 months and at least 6 weeks postpartum.

### Subsegmental PE

The clinical significance of subsegmental PE remains debated, as findings may represent in situ thrombus or imaging artifact. The ASH 2020 guideline suggests clinical surveillance without anticoagulation over anticoagulation in patients without proximal DVT, with low risk for recurrence, and with adequate cardiopulmonary reserve. Bilateral lower extremity ultrasound is recommended to exclude concurrent proximal DVT.

### Chronic Thromboembolic Disease

Approximately 2-4% of PE patients develop chronic thromboembolic pulmonary hypertension (CTEPH). Screening with echocardiography should be performed in patients with persistent dyspnea after 3-6 months of anticoagulation.

## IVC Filters

The indications for IVC filter placement are limited to an absolute contraindication to anticoagulation with acute proximal DVT or PE, and recurrent PE despite therapeutic anticoagulation. Retrievable filters should be removed when anticoagulation can be resumed, though retrieval rates remain disappointingly low in practice at approximately 30%. The PREPIC2 trial demonstrated no benefit of routine IVC filter placement as an adjunct to anticoagulation in severe PE, establishing that filters should not be used in addition to anticoagulation.

## Key Clinical Pearls

- Age-adjusted D-dimer (age x 10 mcg/L for patients > 50) safely reduces unnecessary CTPA imaging by ~12% without missing clinically significant PE (ADJUST-PE)
- Rivaroxaban and apixaban can be started without initial parenteral anticoagulation (lead-in dosing regimen), simplifying outpatient PE management
- Routine systemic thrombolysis for submassive PE is NOT recommended (PEITHO: reduced decompensation but increased ICH); reserve for massive PE with hemodynamic instability
- Cancer-associated VTE should be treated with DOACs (apixaban or edoxaban) or LMWH; caution with DOACs in GI/GU cancers due to mucosal bleeding risk
- For extended anticoagulation beyond initial treatment, reduced-dose DOACs (rivaroxaban 10 mg daily or apixaban 2.5 mg BID) provide continued protection with lower bleeding risk (EINSTEIN-CHOICE, AMPLIFY-EXT)

## References
1. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2020;41(4):543-603.
2. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med. 2014;370(15):1402-1411. (PEITHO)
3. Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020;382(17):1599-1607. (Caravaggio)
4. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med. 2017;376(13):1211-1222. (EINSTEIN-CHOICE)
5. Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124.