How should I work up the underlying cause of a pulmonary embolism in an adult patient?

Work-Up for Underlying Cause of Pulmonary Embolism

After confirming acute PE, systematically evaluate for provoked versus unprovoked etiology by assessing for major transient risk factors (surgery, trauma, immobilization within 3 months), persistent risk factors (active cancer, thrombophilia), and consider thrombophilia testing only in select cases of unprovoked PE in younger patients or those with recurrent events. 1

Initial Risk Factor Assessment

Immediately identify whether the PE is provoked or unprovoked, as this fundamentally determines anticoagulation duration and further work-up intensity. 1, 2

Major Transient (Provoked) Risk Factors

• Recent surgery or major trauma within the past 3 months—these are the strongest reversible risk factors 1, 2
• Prolonged immobilization (>3 days bed rest, long-distance travel >6 hours) 1, 2
• Recent lower limb trauma or orthopedic surgery 1
• Pregnancy or postpartum period (up to 6 weeks) 1, 2

Persistent Risk Factors Requiring Ongoing Evaluation

• Active malignancy—screen with age-appropriate cancer screening if not already done, as occult malignancy may present with PE 2, 3
• Prior documented DVT or PE—significantly increases recurrence risk 1, 4
• Estrogen exposure (oral contraceptives, hormone replacement therapy, patches, rings)—though considered a minor risk factor 1, 2

Clinical Examination for DVT Source

Perform focused lower extremity examination for unilateral leg swelling, calf tenderness, or pain on deep palpation, as approximately 70% of PEs originate from lower extremity DVT. 4

• Unilateral lower extremity edema is one of the highest-weighted variables in the Wells score (3 points) and strongly suggests DVT as the PE source 4
• Compression ultrasonography of lower extremities reveals proximal DVT in 30-50% of acute PE patients, even without clinical signs 4
• Detection of proximal DVT is sufficient to initiate anticoagulation without further PE imaging, as treatment is identical 4
• Note that most PE patients do not have clinically apparent DVT because the thrombus has already embolized 4

Thrombophilia Testing: When and What

Routine thrombophilia testing is NOT recommended for all PE patients—reserve it for unprovoked PE in patients <50 years old, recurrent VTE, thrombosis at unusual sites, or strong family history. 1

Testing Should Include (When Indicated):

• Factor V Leiden mutation—present in 15-20% of initial VTE episodes, increases risk 4-7 fold for heterozygotes 1
• Prothrombin G20210A mutation—second most common inherited thrombophilia 1
• Antithrombin, Protein C, and Protein S deficiencies—natural anticoagulant deficiencies 1
• Lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein-1 antibodies—for antiphospholipid syndrome 1
• Factor VIII levels—elevated levels increase VTE risk 1

Critical Timing Consideration:

• Do NOT test during acute thrombosis or while on anticoagulation, as results will be unreliable—wait until at least 2 weeks after completing anticoagulation 1

Malignancy Screening

In patients with unprovoked PE, perform age-appropriate cancer screening as occult malignancy is a major persistent risk factor. 2, 3

• Basic screening includes: complete blood count, comprehensive metabolic panel, chest X-ray 2
• Age-appropriate screening: colonoscopy (if due), mammography, PSA, pelvic examination 2
• Consider CT abdomen/pelvis if unexplained weight loss, anemia, or other constitutional symptoms 2
• Do not perform extensive cancer screening beyond standard age-appropriate measures unless clinical suspicion warrants it 2

Assessment for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Screen all PE patients for persistent dyspnea or functional limitation at 3-6 month follow-up, as CTEPH occurs in 2-4% of PE survivors and requires specialized treatment. 1, 2

Risk Factors for CTEPH:

• Large perfusion defects at diagnosis 1
• Recurrent PE 1
• Persistent right ventricular dysfunction 1
• Idiopathic PE 1

Follow-Up Protocol:

• Clinical assessment at 3-6 months post-PE for persistent dyspnea, exercise intolerance, or functional limitation 1
• If symptoms persist, obtain echocardiography to assess RV function and pulmonary pressures 1
• If CTEPH suspected, refer to specialized center for ventilation-perfusion scan and right heart catheterization 1

Documentation of Provoked vs. Unprovoked Status

Clearly document whether PE is provoked or unprovoked in the medical record, as this determines anticoagulation duration: 3 months for provoked, indefinite consideration for unprovoked. 1, 2

• Provoked PE: Identifiable major transient risk factor within 3 months—anticoagulate for 3 months 1, 2
• Unprovoked PE: No identifiable transient risk factor—consider indefinite anticoagulation given 10% annual recurrence risk after stopping therapy 1, 2
• Cancer-associated PE: Requires extended anticoagulation for duration of active malignancy 2

Common Pitfalls to Avoid

• Do not order extensive thrombophilia panels on all PE patients—this leads to overdiagnosis of clinically insignificant abnormalities and does not change management in most cases 1
• Do not test for thrombophilia during acute event or on anticoagulation—results will be falsely abnormal 1
• Do not assume normal D-dimer rules out recurrence—D-dimer is for initial diagnosis, not follow-up 1
• Do not forget to assess for CTEPH at follow-up—this treatable complication is often missed 1, 2