Key Facts

Factor V Leiden is the most prevalent inherited thrombophilia, particularly in populations of European descent. It results from a single nucleotide polymorphism that causes resistance to APC, a key natural anticoagulant.

Epidemiology

• Heterozygous prevalence: 5% in Caucasians, rare in Asian and African populations
• Homozygous prevalence: 0.02% (1 in 5,000) in Caucasians
• Found in 20-25% of patients with first VTE
• Named after Leiden, the Netherlands, where it was discovered in 1994

Aetiology

• Single nucleotide polymorphism: G→A at position 1691 of factor V gene
• Results in Arg506Gln substitution at the APC cleavage site on factor Va
• Autosomal dominant inheritance with incomplete penetrance
• Most heterozygous carriers never develop VTE (lifetime risk ~10%)

Pathophysiology

• Activated protein C (APC) normally inactivates factor Va by cleavage at Arg506
• FVL mutation removes this cleavage site → factor Va persists → excessive thrombin generation
• Known as APC resistance
• The prothrombotic effect is primarily venous, as the arterial system relies less on the protein C pathway
• Risk is multiplicative with other thrombophilias and acquired risk factors

Heterozygous FVL

• Majority are asymptomatic (lifetime VTE risk ~10%)
• DVT – most common thrombotic event
• Pulmonary embolism
• Increased risk when combined with: COCP, pregnancy, surgery, immobility

Homozygous FVL

• Higher risk of VTE (annual risk ~1-3%)
• May present with VTE at younger age
• More likely to have recurrent VTE

Pregnancy-Related

• Possibly increased risk of: late pregnancy loss, pre-eclampsia, IUGR (evidence debated)

Red Flags

• VTE in young patient (<50) without provocation → screen for FVL
• Recurrent VTE → consider FVL and other thrombophilias
• Family history of VTE → offer screening

Bloods

• Genetic test (PCR) for Factor V Leiden (G1691A mutation): definitive test, unaffected by anticoagulation, pregnancy, or acute illness
• APC resistance assay: functional screening test (modified APTT-based) – abnormal result should be confirmed with genetic testing
• Full thrombophilia screen if clinically indicated (protein C, S, AT, prothrombin gene, antiphospholipid)

Special Tests

• Family screening: offer genetic testing to first-degree relatives if clinically relevant
• Consider testing the patient's partner if pregnancy planning (to assess homozygous offspring risk)

Imaging

• As indicated for the thrombotic event (Doppler USS, CTPA, etc.)

Non-pharmacological

• Counselling: explain risk, reassure that most carriers never develop VTE
• Avoid COCP/HRT: use progesterone-only contraception (POP, IUD, implant)
• Lifestyle: maintain hydration, avoid prolonged immobility, compression stockings for travel >4 hours
• Surgical prophylaxis: ensure appropriate thromboprophylaxis for any surgery

Pharmacological

Acute VTE treatment:

• Standard anticoagulation (same as general VTE population): apixaban 10mg BD for 7 days then 5mg BD, or rivaroxaban 15mg BD for 21 days then 20mg OD, or LMWH/warfarin
• FVL does NOT change acute treatment

Duration of anticoagulation:

• First provoked VTE: 3 months (standard)
• First unprovoked VTE (heterozygous FVL): consider extended anticoagulation if bleeding risk low
• Homozygous FVL with VTE: strong consideration for lifelong anticoagulation
• Recurrent unprovoked VTE: lifelong anticoagulation

Pregnancy (with FVL and prior VTE or obstetric complications):

• Prophylactic LMWH (enoxaparin 40mg SC OD) antenatally + 6 weeks post-partum
• Risk assessment individualised by obstetric medicine/haematology

Referral Criteria

• Confirmed FVL with VTE → haematology for counselling on anticoagulation duration
• FVL carrier planning pregnancy → specialist obstetric/haematology advice

• Heterozygous FVL: lifetime VTE risk ~10% (relative risk 3-8×)
• Homozygous FVL: lifetime VTE risk ~50-80% (relative risk 50-80×)
• Most carriers never develop VTE if they avoid additional risk factors
• Recurrence risk after first unprovoked VTE: ~5-10% per year without anticoagulation
• No increased risk of arterial thrombosis or overall mortality
• Combined FVL + COCP: ~35× increased VTE risk vs general population

Risk Multiplication with FVL

Management Summary by Scenario