Should a 28-year-old man with an unprovoked lower-extremity deep‑vein thrombosis, a family history of clotting disorders (factor V Leiden), and currently on Eliquis (apixaban) be referred to hematology or managed by primary care, and what laboratory tests should be ordered to evaluate for thrombophilia and bleeding disorders?

Hematology Referral and Thrombophilia Testing for Young Patient with Unprovoked DVT

A 28-year-old male with unprovoked DVT and family history of factor V Leiden should be referred to hematology for specialized evaluation and thrombophilia testing, as this presentation meets multiple criteria for inherited thrombophilia assessment and may warrant indefinite anticoagulation. 1

Rationale for Hematology Referral

Referral to hematology is strongly indicated based on the following high-risk features:

• Young age at presentation (28 years) with unprovoked thrombosis suggests underlying inherited thrombophilia 1, 2
• Positive family history of factor V Leiden indicates hereditary thrombotic disorder requiring specialized assessment 1, 3
• Unprovoked DVT carries 7.4 per 100 patient-years risk of recurrence, with decisions about indefinite anticoagulation requiring expert evaluation 1
• Complex decision-making regarding duration of anticoagulation (3-6 months vs. indefinite) benefits from hematology expertise, particularly given the competing risks of recurrence (5-7% case fatality) versus major bleeding (2-3% annually) 1, 4

Comprehensive Thrombophilia Testing Panel

The following laboratory tests should be ordered to evaluate for inherited and acquired thrombophilic conditions:

First-Tier Testing (Most Common Defects)

• Factor V Leiden mutation (R506Q) - most common inherited thrombophilia, present in 20% of idiopathic first VTE cases 1
• Prothrombin gene mutation (G20210A) - second most common genetic cause 1
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I) - most common acquired thrombophilia 2, 3
• Fasting homocysteine level - elevated levels contribute to thrombotic risk 1, 2

Second-Tier Testing (If First-Tier Negative)

• Antithrombin III activity - deficiency warrants indefinite anticoagulation 1, 3
• Protein C activity - deficiency indicates high-risk thrombophilia requiring extended treatment 1, 3
• Protein S activity (free and total) - deficiency suggests need for indefinite anticoagulation 1, 3

Important Testing Caveats

Timing of thrombophilia testing is critical to avoid false results:

• Do NOT test during acute thrombosis or while on anticoagulation - protein C, protein S, and antithrombin levels are artificially lowered by acute clot and warfarin/DOACs 3, 4
• Optimal timing: Test at least 2-4 weeks after completing initial anticoagulation course, or coordinate with hematology for testing strategy 4, 5
• Antiphospholipid antibodies require confirmation - positive results must be repeated at 12 weeks to confirm diagnosis 2, 3

Duration of Anticoagulation Based on Testing Results

The thrombophilia testing results will directly influence anticoagulation duration:

Indefinite Anticoagulation Indicated

• Homozygous factor V Leiden - very high recurrence risk 1
• Antithrombin III, protein C, or protein S deficiency - natural anticoagulant deficiencies warrant lifelong treatment 1, 6
• Antiphospholipid syndrome - requires indefinite anticoagulation at INR 2-3 1, 6
• Multiple thrombophilic defects (compound heterozygosity) - cumulative risk necessitates extended treatment 6

Standard 3-6 Month Course Acceptable

• Heterozygous factor V Leiden alone - does NOT increase recurrence risk sufficiently to mandate indefinite treatment 1
• Heterozygous prothrombin G20210A alone - prospective studies show no increased recurrence risk 1
• No thrombophilia identified - decision based on clinical factors (unprovoked nature, D-dimer levels post-treatment) 1, 6

Clinical Decision Algorithm

Follow this structured approach:

1. Continue current Eliquis for minimum 3 months from diagnosis 1

2. Refer to hematology immediately for:

   • Coordination of thrombophilia testing timing 4, 5
   • Assessment of family thrombotic history details 1, 3
   • Evaluation for extended anticoagulation candidacy 1, 4

3. At 3-month mark, hematology should assess:

   • Complete thrombophilia panel results 1
   • D-dimer level 3-4 weeks after stopping anticoagulation (if considering discontinuation) - elevated D-dimer predicts 2.6-fold increased recurrence 7, 6
   • Residual thrombosis on repeat ultrasound - persistent clot increases recurrence risk 6
   • Bleeding risk factors (age, renal function, prior bleeding) 7, 4

4. Final decision on 6-month vs. indefinite treatment based on:

   • Specific thrombophilia identified 1
   • Post-treatment D-dimer and imaging 7, 6
   • Individual bleeding risk assessment 1, 4

Why Primary Care Alone is Insufficient

Primary care management alone is inadequate for this complex case because:

• Specialized interpretation required - thrombophilia results require expert analysis in context of family history and recurrence risk stratification 1, 5
• Indefinite anticoagulation decisions carry significant morbidity/mortality implications requiring hematology expertise 1, 4
• Family counseling needs - positive genetic results have implications for relatives requiring specialized genetic counseling 1
• Emerging treatment options - hematologists can access novel anticoagulants with potentially lower bleeding risk for long-term management 4, 6