Hereditary Thrombophilia

Indications for Testing

• Unprovoked venous thromboembolism (VTE) at <50 years of age

• Recurrent VTE, or thrombosis at unusual sites (cerebral veins, mesenteric veins, upper limb veins)

• First-degree relative with a confirmed hereditary thrombophilia

• Medicare rebate requires personal history of DVT/PE or a first-degree relative with a proven mutation (family history alone is insufficient)

• Typically test ≥2 weeks after cessation of anticoagulation to avoid false results (protein C and S can be suppressed by warfarin)

• Testing rarely alters acute management but may guide duration of anticoagulation or prophylaxis during high-risk periods

Types of Hereditary Thrombophilia

1. Factor V Leiden (FVL)

   • Most common inherited thrombophilia in Caucasian populations

   • Tested by activated protein C resistance (APCR) assay followed by specific FVL test if abnormal

   • Mutation makes factor V resistant to inactivation by protein C → increased clotting risk

2. Prothrombin Gene Mutation (G20210A)

   • Leads to increased prothrombin production → heightened coagulation

   • Associated with a modestly increased risk of VTE

3. Protein C or Protein S Deficiency

   • Deficiency reduces the inactivation of factors Va and VIIIa → promotes thrombosis

   • Levels can be falsely low in pregnancy, while on oral contraceptives, during acute thrombosis, or when on warfarin

4. Antithrombin III Deficiency

   • Decreased inhibition of thrombin and factor Xa → increased clot risk

   • Acquired deficiency may occur in acute thrombosis or during heparin therapy

   • Congenital antithrombin deficiency carries a high lifetime risk of VTE

5. MTHFR Mutation

   • Mutation may elevate homocysteine, contributing to vascular risk

   • No proven association with recurrent miscarriage

   • Not recommended for routine thrombophilia screening

   • Elevated homocysteine responds to vitamin supplementation (folate, B6, B12)

Management Considerations

• Risk Stratification

  • Combine genetic findings with personal/family history of thrombosis, obesity, immobility, hormone therapy, and other acquired factors (e.g. antiphospholipid syndrome)

  • High-risk thrombophilias (e.g. antithrombin deficiency, combined defects like FVL + PGM) may warrant lifelong anticoagulation after unprovoked VTE

• Anticoagulation

  • Acute management of VTE follows standard protocols (LMWH then transition to warfarin/DOAC unless contraindicated)

  • Duration of anticoagulation often prolonged if high-risk thrombophilia or strong family history

  • In pregnant patients with high-risk thrombophilia, LMWH prophylaxis is commonly used to prevent VTE

  • Factor V Leiden or prothrombin gene mutation carriers with no prior VTE usually do not need indefinite anticoagulation but require prophylaxis in high-risk situations (major surgery, prolonged immobilisation)

• Lifestyle & General Measures

  • Smoking cessation, weight control, adequate hydration, and active lifestyle can reduce VTE risk

  • Consider safer contraceptive options or use of progesterone-only methods if combined OCP is deemed high risk for VTE

  • Counsel about symptoms of DVT/PE and importance of seeking urgent care if suspected

Special Considerations

• Elevated Homocysteine

  • Associated with arterial and venous thrombosis risk

  • Correct deficiency of folate, vitamin B6, or B12 if found

• Pregnancy

  • Thromboprophylaxis with LMWH in selected patients (history of previous VTE, high-risk thrombophilia)

  • Avoid warfarin in pregnancy (teratogenic), monitor carefully for postpartum thrombosis risk

• Combined Oral Contraceptives or HRT

  • Relative contraindication in high-risk thrombophilias (especially antithrombin deficiency or double heterozygotes)

  • Detailed risk-benefit assessment if mild thrombophilia (heterozygous FVL) and no personal VTE history

• Surgery/Immobility

  • Short-term prophylaxis with LMWH or DOAC (where appropriate) to prevent perioperative thrombosis

Notes:

• Test only when results will influence clinical decisions (duration of anticoagulation, prophylaxis in pregnancy or surgery)

• Ensure testing is performed under stable conditions (off anticoagulants for ≥2 weeks unless bridging is impossible)

• Interpret in context of personal/family history and other risk factors

• Provide patient education on VTE risk, prophylactic measures, and early signs of DVT/PE

• Consider referral to haematology if results are uncertain, high-risk mutations are identified, or complex management is required