How is Factor V activity assessed and managed in a patient with suspected or known Factor V deficiency or Factor V Leiden thrombophilia?

Factor V Activity Assessment and Management

Assessment of Factor V Activity

For suspected Factor V Leiden thrombophilia, use either direct DNA-based genotyping or a Factor V Leiden-specific functional assay as the initial test, with DNA confirmation required to distinguish heterozygotes from homozygotes. 1

Testing Methodology

• DNA-based genotyping detects the R506Q mutation in the F5 gene and serves as the gold standard, providing definitive identification of heterozygous versus homozygous status 2
• Modified functional assay (based on dilute Russell Viper Venom Time) provides reliable differentiation between heterozygotes and homozygotes with minimal interference from anticoagulants 2
• Patients testing positive by functional assay must undergo DNA testing for confirmation and zygosity determination 1
• Patients on heparin therapy or with lupus anticoagulant should proceed directly to molecular testing if the modified functional assay is not used 1

Clinical Indications for Testing

Strong indications where testing should be performed 1:

• Age <50 with any venous thrombosis
• Venous thrombosis in unusual sites (hepatic, mesenteric, cerebral veins)
• Recurrent venous thrombosis at any age
• Venous thrombosis with strong family history of thrombotic disease
• Venous thrombosis in pregnant women or women taking oral contraceptives
• Myocardial infarction in female smokers under age 50

Consider testing in these situations 1:

• Venous thrombosis age >50 (except when active malignancy present)
• First-degree relatives of individuals known to have Factor V Leiden
• Women with recurrent pregnancy loss, unexplained severe preeclampsia, placental abruption, intrauterine growth retardation, or stillbirth

Comprehensive Thrombophilia Workup

When Factor V testing is indicated, obtain a complete thrombophilia panel including 2:

• Prothrombin G20210A mutation (critical as combination with Factor V Leiden significantly increases thrombotic risk)
• Plasma homocysteine levels
• Functional assays for protein C, protein S, and antithrombin III
• Lupus anticoagulant and anticardiolipin antibodies

What NOT to Test

Random screening of the general population is not recommended 1

• Do not perform routine screening in asymptomatic women before starting oral contraceptives 3
• Routine testing is not recommended for arterial thrombotic disorders except myocardial infarction in young female smokers 1

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Management Based on Factor V Status

Asymptomatic Carriers (No Prior VTE)

Avoid combined oral contraceptives in women with Factor V Leiden, as the combination increases thrombotic risk 30-fold compared to 4-fold with oral contraceptives alone 3

• Use alternative contraceptive methods in women with Factor V Leiden 3
• No routine long-term anticoagulation for asymptomatic heterozygotes 4
• Provide prophylactic anticoagulation during high-risk scenarios: surgery, trauma, prolonged immobilization 3

Pregnancy Management

For heterozygous Factor V Leiden without family history of VTE: clinical surveillance only throughout pregnancy 3

For Factor V Leiden with first-degree relative history of VTE 3:

• Consider prophylactic LMWH or UFH throughout antepartum period
• Postpartum: provide prophylactic- or intermediate-dose LMWH, or vitamin K antagonists (INR 2.0-3.0) for 6 weeks

After First VTE Event

Treat the first acute thrombosis according to standard VTE guidelines (therapeutic anticoagulation with LMWH bridged to warfarin or direct oral anticoagulants) 3

Duration of anticoagulation depends on zygosity and VTE characteristics 2:

• Heterozygous carriers with provoked VTE: standard 3-6 months anticoagulation (heterozygosity alone does not significantly increase recurrence risk)
• Heterozygous carriers with unprovoked VTE: consider extended anticoagulation based on individualized bleeding risk assessment
• Homozygous carriers: consider lifetime anticoagulation after any thrombotic event due to substantially elevated recurrence risk 2
• Compound heterozygotes (Factor V Leiden + prothrombin 20210A): high recurrence risk, consider extended anticoagulation 2

Long-Distance Travel Prophylaxis

For carriers during long-distance travel 3:

• Frequent ambulation and calf exercises
• Aisle seating
• Properly fitted below-knee graduated compression stockings (15-30 mmHg at ankle)

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Assessment of True Factor V Deficiency (Bleeding Disorder)

Initial Screening

• Mild prolongation of both prothrombin time (PT) and activated partial thromboplastin time (aPTT) suggests Factor V deficiency 5
• Confirm with specific Factor V activity and antigen assays 5

Distinguishing Factor V Deficiency from Factor V Leiden

Factor V activity and antigen levels differentiate these conditions 5:

• True heterozygous Factor V deficiency: both activity and antigen ~50% of normal
• Heterozygous Factor V Leiden: activity ~100%, antigen ~100% (normal levels, but functionally resistant to APC)
• Pseudohomozygous APC resistance (combined Factor V Leiden + true Factor V deficiency): activity ~50%, antigen ~100%

Management of Factor V Deficiency

• Homozygous and heterozygous true Factor V deficiency presents with bleeding, not thrombosis 5
• Combined Factor V and Factor VIII deficiencies require separate classification and management 5

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Key Clinical Pitfalls

• Do not withhold standard VTE prophylaxis during surgery or hospitalization based on unknown Factor V Leiden status 3
• Patients with combined heterozygous Factor V Leiden and heterozygous true Factor V deficiency can develop severe thrombosis despite reduced Factor V levels 5
• Half-normal Factor V activity does not protect against thrombosis in patients with heterozygous APC resistance 5
• Family screening should be selective, targeting first-degree relatives of symptomatic probands (annual VTE incidence 0.45-0.67% if carriers versus 0.10% if non-carriers) 6