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Prothrombin 20210 (Mutation)

BASICS

  • Description: G20210A = gain-of-function mutation (adenine for guanine at 20210 position in F2/prothrombin gene). Causes increased prothrombin (factor II) levels, leading to prothrombotic state.
  • Inheritance: Autosomal dominant. Heterozygotes: 30% higher prothrombin, 3–4× risk of VTE. Homozygotes: higher risk.
  • Second most common inherited venous thrombophilia after factor V Leiden.

EPIDEMIOLOGY

  • Prevalence: 1–6% in Caucasians; ~2% overall
  • VTE patients: Prevalence 4.6–18%
  • Mean age of first thrombosis: 2nd decade
  • Gender: No difference

ETIOLOGY & PATHOPHYSIOLOGY

  • Gene: F2 (chromosome 11p) G20210A mutation (3′ UTR, noncoding region)
  • Mechanism: Increased prothrombin translation → elevated thrombin → enhanced fibrin formation → VTE risk
  • Mostly venous thrombosis: DVT/PE, mesenteric, cerebral veins. Not clearly linked to Budd-Chiari, portal, or hepatic vein thrombosis. Not a major arterial thrombotic risk factor.

Other prothrombin mutations: - Yukuhashi (G1787T) - C20209T (adjacent, more in African ancestry) - A19911G (may increase risk when present with G20210A)

RISK FACTORS

  • Family history of mutation or VTE
  • Co-inheritance with factor V Leiden (20× risk)
  • Virchow's triad: stasis, endothelial injury, thrombophilia
  • Additional risk factors: OCPs, pregnancy, surgery, cancer, immobility, air travel, obesity, smoking

PREGNANCY CONSIDERATIONS

  • Increased VTE risk during pregnancy/postpartum (start anticoagulation in 1st trimester for high risk)
  • C20209T may be linked to recurrent pregnancy loss (not well studied)

PREVENTION

  • No prophylactic anticoagulation for asymptomatic carriers
    • Exception: rare high-risk situations (e.g., strong family history, pregnancy with additional thrombophilia)
  • After first VTE: Consider indefinite anticoagulation if unprovoked or unusual location (mesenteric, cerebral)

ASSOCIATED CONDITIONS

  • Venous thromboembolism (DVT, PE, unusual sites)
  • Often seen with factor V Leiden

DIAGNOSIS

History

  • Personal/family history of VTE or known mutation

Physical Exam

  • DVT: Unilateral swollen, erythematous, tender limb
  • PE: Tachycardia, chest pain, hypotension
  • Mesenteric thrombosis: Tender abdomen

Differential Diagnosis

  • Factor V Leiden
  • Protein C/S deficiency
  • Antithrombin deficiency
  • Dysfibrinogenemia
  • Antiphospholipid syndrome
  • Homocystinuria
  • Other rare thrombophilias

Testing

  • Genetic test (PCR for G20210A)
    • Not recommended for general screening—consider for early/recurrent/unusual VTE or strong family history
  • Prothrombin levels are NOT diagnostic
  • Imaging as appropriate (US Doppler, CT, V/Q scan, MR/venography)

TREATMENT

General

  • Management of acute VTE is the same as non-mutant VTE
  • No need for routine anticoagulation in asymptomatic patients

Anticoagulation (VTE treatment):

  • First line (non-cancer): DOACs preferred
    • Apixaban: 10 mg BID ×7d, then 5 mg BID
    • Rivaroxaban: 15 mg BID ×21d, then 20 mg daily
    • Dabigatran: 150 mg BID (after 5–10 days parenteral anticoagulation)
    • Edoxaban: 60 mg daily (after 5–10 days parenteral anticoagulation)
  • Second line: Warfarin (INR 2–3, initial overlap with heparin/LMWH)
    • Enoxaparin (LMWH): 1 mg/kg SC BID if warfarin not feasible

Pregnancy

  • Anticoagulation as indicated (LMWH preferred)
  • Start in 1st trimester for high risk; stop at labor; resume postpartum

Indications for indefinite anticoagulation

  • Unprovoked VTE
  • VTE in unusual location
  • Multiple recurrences

Referral

  • Genetic counseling
  • Hematology if recurrent VTE or difficulty anticoagulating

Procedures

  • Hold anticoagulation before surgery
  • Vena cava filter: Only if anticoagulation contraindicated

ONGOING CARE

  • Monitor INR if on warfarin (goal 2–3)
  • Compression stockings for DVT prevention
  • DVT prophylaxis as indicated for hospitalized patients

DIET & PATIENT EDUCATION

  • Diet: No restrictions unless on warfarin (watch vitamin K, avoid grapefruit/St. John’s wort)
  • Educate about VTE symptoms, anticoagulant risks (bleeding), NSAID avoidance on warfarin

PROGNOSIS

  • Normal lifespan if VTE is well managed
  • Heterozygotes: Slightly increased recurrence risk, but length of anticoagulation not changed by mutation alone

COMPLICATIONS

  • Recurrent thrombosis
  • Bleeding on anticoagulation
  • Death possible from massive PE

ICD-10 CODE

  • D68.52 Prothrombin gene mutation

CLINICAL PEARLS

  • Prothrombin 20210 mutation: 2nd most common inherited VTE risk after factor V Leiden
  • No routine screening or anticoagulation for asymptomatic carriers
  • Management of VTE: Same as for other causes, but consider indefinite therapy for unprovoked or unusual-site VTE