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Factor V Leiden (FVL)

BASICS

  • Genetic point mutation in F5 gene at APC cleavage site (Arg506Glu).
  • Leads to reduced inactivation of factor Va by activated protein C → increased thrombin → hypercoagulability.
  • Most common inherited thrombophilia.
  • Affects cardiovascular, gastrointestinal, hemo/lymphatic, neurologic, pulmonary, reproductive systems.

EPIDEMIOLOGY

  • Prevalence: 5-8% heterozygosity in Caucasians; lower in Hispanic (~2%), African (~1%), and Asian (~0.45%) populations.
  • Small percentage (~5-10%) develop venous thromboembolism (VTE).
  • More common in Greece, Sweden, Lebanon; rare in Chinese/Japanese.

ETIOLOGY AND PATHOPHYSIOLOGY

  • Factor V amplifies thrombin production in clotting cascade.
  • APC inactivates factors V and VIII, limiting clot formation (negative feedback).
  • FVL mutation impairs APC cleavage → 20-fold slower degradation of factor Va → increased clot formation.

RISK FACTORS

  • VTE risk: ~7-fold increase heterozygotes; ~80-fold increase homozygotes.
  • Increased risk with:
  • Non-O blood type (A, B, AB): 2-4 fold.
  • Oral contraceptives (OCs): 35-fold heterozygotes, 100-fold homozygotes. Desogestrel OCs reduce risk by half.
  • Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs).
  • Testosterone therapy in men with thrombophilia.
  • Pregnancy/postpartum (7-16 fold increase).
  • Combined thrombophilias and ESRD → risk of calciphylaxis.
  • Accounts for ~30% of VTE cases combined with prothrombin mutation G20210A.

GENERAL PREVENTION

  • Asymptomatic FVL patients do not require prophylactic anticoagulation.

COMMONLY ASSOCIATED CONDITIONS

  • Venous thrombosis (DVT, PE, cerebral vein thrombosis, portal vein thrombosis).
  • Recurrent pregnancy loss and adverse pregnancy outcomes.

DIAGNOSIS

History

  • Assess provoked vs unprovoked VTE, family history of thrombosis or FVL mutation.
  • Symptoms of VTE or pregnancy complications.
  • No specific clinical features for FVL mutation in asymptomatic individuals.

Physical Exam

  • Signs of VTE (DVT, PE, cerebral thrombosis).
  • Test young patients (<50 years) with unusual site thrombosis or recurrent VTE.

Differential Diagnosis

  • Protein C, S deficiencies.
  • Antithrombin deficiency.
  • Other APC resistance causes (antiphospholipid antibodies).
  • Prothrombin mutation G20210A.
  • Elevated factor VIII levels.

Diagnostic Tests

  • Molecular genetic test for FVL mutation (DNA-based).
  • Functional assay for APC resistance (plasma coagulation assay).
  • Testing ideally performed off anticoagulation for accuracy.
  • Thrombophilia panel includes antithrombin III, protein C/S, antiphospholipid antibodies, homocysteine.
  • Testing recommended primarily when considering anticoagulation cessation after unprovoked VTE or for family screening before estrogen use or pregnancy.

TREATMENT

  • Indicated only after thrombotic event.
  • Initial VTE treatment same as for non-FVL patients.
  • Minimum anticoagulation duration: 3 months for first VTE.
  • Consider long-term anticoagulation if recurrent thrombosis occurs.

Medications

  • First-line:
  • LMWH (enoxaparin, fondaparinux, dalteparin, tinzaparin).
  • Direct oral anticoagulants (DOACs): apixaban, rivaroxaban, dabigatran (after parenteral therapy).
  • Second-line:
  • Heparin IV infusion for unstable patients.
  • Warfarin with INR target 2.0-3.0 (avoid in pregnancy and history of warfarin necrosis).

Contraindications & Precautions

  • Active bleeding contraindicates anticoagulation.
  • Monitor for bleeding, embolization, and thrombocytopenia.
  • Warfarin skin necrosis risk in deficiency states.
  • Dose adjustments in renal impairment and pregnancy.

ISSUES FOR REFERRAL

  • Recurrent thrombosis despite anticoagulation.
  • Difficulties in anticoagulation management.
  • Genetic counseling especially for homozygous patients and pregnancy planning.

SURGERY/OTHER PROCEDURES

  • Routine IVC filter not recommended except contraindications to anticoagulation.

ONGOING CARE

  • Warfarin requires regular INR monitoring (~monthly after stabilization).

PATIENT EDUCATION

  • Avoid NSAIDs while anticoagulated.
  • Family screening utility unclear; consider in pregnancy planning or before estrogen therapy.

PROGNOSIS

  • Most heterozygotes remain asymptomatic.
  • Homozygotes have ~50% lifetime thrombosis risk.
  • Recurrence risk post first thrombosis may be up to 5%.
  • Does not increase overall mortality.

COMPLICATIONS

  • Recurrent thrombosis.
  • Anticoagulant-related bleeding.

REFERENCES

  1. Dłuski D, Mierzyński R, Poniedziałek-Czajkowska E, et al. Adverse pregnancy outcomes and inherited thrombophilia. J Perinat Med. 2018;46(4):411-417.

CODES

  • ICD10: D68.51 Activated protein C resistance

CLINICAL PEARLS

  • Factor V Leiden is extremely rare in Asian and African populations.
  • Asymptomatic carriers do not require anticoagulation.
  • Pregnant homozygous women without prior VTE should receive postpartum prophylaxis with LMWH or vitamin K antagonists for 6 weeks. Antepartum prophylaxis if positive family history.