What is the approach to a thrombophilia workup?

Thrombophilia Workup Approach

Thrombophilia testing should be performed selectively and only when results will directly influence clinical management decisions, with testing avoided during acute thrombosis or the first 3 months of anticoagulation. 1, 2

When to Test (Clinical Indications)

Most patients should NOT undergo thrombophilia testing, as it rarely changes management and may cause harm. 2, 3 Testing should be reserved for highly specific situations:

Consider Testing Only In:

• Unprovoked VTE in patients where results may influence duration of anticoagulation - though even here, testing is controversial and often not recommended 2, 3
• Female relatives of patients with severe thrombophilia (antithrombin, protein C/S deficiency) who are considering estrogen-containing contraception or pregnancy - where results may guide contraceptive choices or pregnancy management 1, 2
• Recurrent pregnancy loss with clinical suspicion of antiphospholipid syndrome 1
• Thrombosis at unusual sites (splanchnic veins) where specific etiologies like paroxysmal nocturnal hemoglobinuria need exclusion 1

Do NOT Test In:

• Provoked VTE (surgery, trauma, immobilization, active cancer) - acquired risk factors explain the event and testing will not change management 2, 3
• Asymptomatic relatives without specific high-risk situations - systematic family screening is not recommended 1, 2
• During acute thrombosis or within 3 months of starting anticoagulation - results will be unreliable 1, 2

Timing of Testing

Critical timing considerations to ensure accurate results:

• Wait at least 3 months after completing anticoagulation before testing for protein C, protein S, or antithrombin, as anticoagulants (especially warfarin) falsely lower these levels 1, 2
• Genetic testing (Factor V Leiden, prothrombin G20210A mutation) can be performed at any time, including during anticoagulation, as DNA-based tests are unaffected 1
• Antiphospholipid antibody testing requires confirmation - positive results must be repeated at least 12 weeks apart to establish diagnosis 1
• Avoid testing during acute thrombosis, pregnancy, or acute illness, as these states alter protein levels 1, 2

Laboratory Workup Components

Initial Clinical Assessment

• Document personal history: age at first VTE, provoked vs unprovoked, recurrent events, unusual sites 1
• Document family history: first-degree relatives with VTE, especially if age <50 years or recurrent 1
• Identify acquired risk factors: active malignancy, recent surgery/trauma, pregnancy, estrogen use, prolonged immobilization, obesity 4, 1
• Physical examination findings: signs of post-thrombotic syndrome, underlying malignancy, or autoimmune disease 1

Basic Coagulation Studies

• Complete blood count with platelet count and blood smear 1
• Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen 1
• Mixing studies if aPTT is prolonged to distinguish factor deficiency from inhibitors (lupus anticoagulant) 1

Hereditary Thrombophilia Panel (When Indicated)

• Factor V Leiden mutation (R506Q) - most common hereditary thrombophilia, 5% population prevalence, 5-7x increased VTE risk 4, 1
• Prothrombin gene G20210A mutation - 2% population prevalence, 2-3x increased VTE risk 4, 1
• Protein C level - 0.3% prevalence, 15-20x increased VTE risk 4, 1
• Protein S level - 0.3% prevalence, 15-20x increased VTE risk 4, 1
• Antithrombin level - 0.04% prevalence, 15-20x increased VTE risk 4, 1

Acquired Thrombophilia Testing (When Indicated)

• Lupus anticoagulant - 1-5.6% prevalence, 3-10x increased VTE risk 4, 1
• Anticardiolipin antibodies (IgG and IgM) 1
• Anti-β2-glycoprotein I antibodies (IgG and IgM) 1
• Flow cytometry for paroxysmal nocturnal hemoglobinuria if splanchnic vein thrombosis 1

Additional Investigations Based on Clinical Context

• CT imaging and tumor markers if unexplained thrombosis suggests occult malignancy 1
• Liver function tests if splanchnic vein thrombosis present 1

Critical Pitfalls to Avoid

• Testing during anticoagulation produces unreliable results for protein C, protein S, and antithrombin - warfarin lowers these levels, heparin lowers antithrombin 1, 2
• A negative thrombophilia workup does not exclude thrombophilia - many genetic and acquired risk factors remain undiscovered, and multiple factors often interact 1, 3
• Testing rarely changes management - most patients with unprovoked VTE require extended anticoagulation regardless of thrombophilia status 2, 3
• Positive results may cause psychological harm and lead to unnecessary interventions in asymptomatic family members 2, 3
• The presence of one risk factor does not exclude others - thrombophilias can be multiple and compound risk 1

Management Implications

The key principle: test only if results will change management. 2, 3

• For most patients with unprovoked VTE, the decision for extended anticoagulation should be based on bleeding risk, not thrombophilia testing results 2, 3
• Asymptomatic carriers have low absolute VTE risk - annual incidence ranges from 0.1% (Factor V Leiden) to 1.7% (antithrombin deficiency), making prophylactic anticoagulation inappropriate 4
• High-risk thrombophilias (antithrombin, protein C/S deficiency, antiphospholipid syndrome) may warrant more aggressive management in specific situations like pregnancy or surgery 1
• Estrogen-containing contraception should be avoided in women with known thrombophilia, particularly Factor V Leiden or prothrombin mutation 1, 2