What is the recommended workup and management for a patient with suspected inherited thrombophilia?

Inherited Thrombophilia Workup

Testing for inherited thrombophilia should be reserved for highly selected patients with unprovoked venous thromboembolism (VTE) at young age (<50 years), recurrent VTE, thrombosis at unusual sites, or strong family history, as routine screening rarely changes management and most patients require the same anticoagulation duration regardless of results. 1

When to Consider Testing

Clinical Scenarios Warranting Evaluation

• Unprovoked VTE before age 50 with no identifiable acquired risk factors 1, 2
• Recurrent VTE episodes (two or more documented events) 3, 4
• Thrombosis at unusual sites including splanchnic veins (portal, mesenteric, hepatic), cerebral veins, or upper extremity 5, 1
• First-degree relatives of patients with severe thrombophilia (antithrombin, protein C/S deficiency) only in high-risk situations like pregnancy or contraceptive use 1
• Women with recurrent late-trimester fetal loss 5

When NOT to Test

• Asymptomatic individuals without personal VTE history, even with family history 5, 1
• Patients with clear provoked VTE (surgery, trauma, immobilization, active cancer) where all patients receive standard prophylaxis regardless 5
• During acute thrombosis or within first 3 months of anticoagulation, as results will be unreliable 1

Laboratory Workup Algorithm

First-Tier Testing (Preliminary Assessment)

• Complete blood count with peripheral smear and platelet count 1
• PT/INR and aPTT to assess baseline coagulation 1
• Fibrinogen level 1
• Liver function tests (especially for splanchnic thrombosis) 5, 1

Second-Tier Testing (Hereditary Thrombophilia Panel)

Genetic mutations (can be tested anytime, unaffected by anticoagulation):

• Factor V Leiden (R506Q) mutation - most common hereditary thrombophilia (5% prevalence, 5-7x VTE risk) 5, 1, 2
• Prothrombin G20210A gene mutation - second most common (2% prevalence, 2-3x VTE risk) 5, 1, 2

Natural anticoagulant levels (MUST be tested OFF anticoagulation or results invalid):

• Antithrombin activity (0.04% prevalence, 15-20x VTE risk) 5, 1
• Protein C activity (0.3% prevalence, 15-20x VTE risk) 5, 1
• Protein S activity (0.3% prevalence, 15-20x VTE risk) 5, 1

Critical timing consideration: Warfarin falsely lowers protein C and S levels; direct oral anticoagulants (DOACs) can overestimate antithrombin and protein C/S activities with risk of missing true deficiency. 6 Testing should be delayed until at least 2-4 weeks after stopping anticoagulation, or use DOAC removal devices to minimize false-negatives. 6

Third-Tier Testing (Acquired Thrombophilia)

• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) - must be positive on two occasions 12 weeks apart to confirm diagnosis 5, 1
• Paroxysmal nocturnal hemoglobinuria testing (flow cytometry) for splanchnic vein thrombosis 1

Additional Investigations

• Malignancy screening (CT imaging, tumor markers) for unexplained thrombosis, especially in older patients 1
• Homocysteine level in patients positive for Factor V Leiden 5

Management Based on Findings

Anticoagulation Duration by Thrombophilia Type

Severe thrombophilia (indefinite anticoagulation suggested):

• Antithrombin, protein C, or protein S deficiency 3, 4
• Homozygous Factor V Leiden or prothrombin mutation 3
• Combined thrombophilias (two or more defects) 5, 3
• Antiphospholipid antibodies 3

Moderate thrombophilia (6-12 months, consider indefinite):

• Heterozygous Factor V Leiden with idiopathic VTE 3
• Heterozygous prothrombin G20210A with idiopathic VTE 3

Standard treatment (3-6 months):

• First provoked VTE regardless of thrombophilia status 3
• First unprovoked VTE without identified thrombophilia 3

Target INR for Warfarin Therapy

• INR 2.0-3.0 (target 2.5) for all VTE treatment durations in thrombophilia patients 3

DOAC Considerations

DOACs show encouraging data in thrombophilia patients, but evidence is strongest for heterozygous Factor V Leiden and prothrombin mutations. 6 For severe natural anticoagulant deficiencies (antithrombin, protein C/S), warfarin remains preferred until more data emerge, given variable thrombosis risk within these conditions. 6

Critical Pitfalls to Avoid

• Do not withhold anticoagulation while awaiting thrombophilia results - treat VTE immediately based on clinical presentation 1, 2
• Do not test during acute thrombosis or on anticoagulation - results will be unreliable and may miss true deficiencies 1, 6
• Do not screen asymptomatic family members routinely - annual VTE risk even in carriers is low (0.1-1.7%) and does not justify prophylactic anticoagulation 1
• Do not assume single negative test excludes thrombophilia - multiple factors often coexist (46% of Budd-Chiari patients have ≥2 risk factors) 5
• Do not use thrombophilia results alone to determine treatment duration - clinical factors (provoked vs unprovoked, recurrence, bleeding risk) matter more than laboratory findings 1, 2
• Recognize that >50% of thrombophilia patients have additional acquired risk factors (surgery, pregnancy, hormones, immobility) contributing to their VTE 4

Family Counseling

When thrombophilia is identified, patients should understand: 5

• Genetic implications for first-degree relatives
• Relative risk varies dramatically by specific defect (2-3x for prothrombin mutation vs 15-20x for antithrombin deficiency) 1
• Absolute risk remains low in asymptomatic carriers without additional risk factors 1, 4
• Confidentiality and insurance discrimination concerns 5