Makindo Medical Notes

Related Subjects: Thrombophilia testing |Antiphospholipid syndrome |Protein C Deficiency |Protein S Deficiency |Prothrombin 20210A mutation |Factor V Leiden Deficiency |Antithrombin III deficiency (AT3) |Cerebral Venous Sinus thrombosis |Budd-Chiari syndrome

🧠 Introduction

Clotting risk is often cumulative and additive. The Factor V Leiden (FVL) mutation is the most common inherited thrombophilia. It makes Factor V resistant to activated protein C (APC), tipping the balance towards thrombosis. FVL is strongly linked to venous thromboembolism (VTE), but its role in arterial stroke is less clear, though relevant in children & young adults.

🧬 Genetics & Epidemiology

• Point mutation (G1691A) → Arg506Gln substitution → APC resistance.
• Prevalence: 3–7% in Europeans; rare in Asian & African populations.
• Homozygotes: ~1 in 5,000; carry much higher risk.
• Inheritance: Autosomal dominant with incomplete penetrance.

⚙️ Pathophysiology

• Normal APC inactivates factors Va & VIIIa to limit clotting.
• FVL mutation → Factor V resistant to APC → excessive thrombin & fibrin generation.
• Leads to a pro-thrombotic state, mainly venous.

🩺 Clinical Features

• 🌡️ VTE presentations:
  • DVT → limb swelling, pain, erythema.
  • PE → dyspnoea, pleuritic chest pain, tachycardia.
  • CVST → headache, seizures, raised ICP.
  • Budd-Chiari syndrome → hepatomegaly, ascites, liver dysfunction.
• 📊 Risk in heterozygotes: 3–8× ↑ risk of first VTE.
• 📊 Risk in homozygotes: up to 80× ↑ risk; recurrent thrombosis common.
• 🧠 Arterial thrombosis: weak link; possibly ↑ risk of stroke/MI in young carriers.
• 🤰 Pregnancy complications: miscarriage, stillbirth, pre-eclampsia, IUGR, ↑ maternal VTE risk.

⚠️ Risk Factors & Triggers

• Acquired: surgery, trauma, immobility, obesity, OCP/HRT, pregnancy, cancer, smoking.
• Other thrombophilias: prothrombin G20210A mutation, protein C/S deficiency, antithrombin deficiency.

🧪 Diagnosis

• History of VTE, family history of early clotting.
• APC resistance assay → functional screen.
• PCR genetic testing → confirms G1691A mutation.
• Extended thrombophilia panel if unprovoked/recurrent events.

🔍 Differential Diagnosis

Other thrombophilias:

• 🧬 Prothrombin G20210A mutation (1–2%).
• ⬇️ Protein C/S deficiency (rare).
• ⬇️ Antithrombin III deficiency (very rare).
• 🧪 Antiphospholipid antibody syndrome (acquired).

🛡️ Management

Prevention

• 🏃 Lifestyle: exercise, mobility, weight control, stop smoking.
• 🚫 Avoid oestrogen OCP/HRT if possible.
• 💉 Prophylactic LMWH in high-risk settings (surgery, pregnancy, immobility).

Treatment of VTE

• Start with LMWH/heparin → transition to warfarin (INR 2–3) or DOACs (apixaban, rivaroxaban, dabigatran).
• 🕐 Duration: 3–6 months for provoked first VTE; indefinite for recurrent/unprovoked events or homozygotes.
• Regular monitoring for bleeding & recurrence.

Pregnancy

• Risk-stratified management.
• LMWH during pregnancy/postpartum if prior VTE or additional risks.
• Monitor fetal growth and placental function closely.

🧠 Arterial Thrombosis & Stroke

• Link with arterial disease remains weak; stronger in young, cryptogenic stroke cases.
• Routine screening for FVL in stroke not advised.
• Management = standard stroke prevention + addressing vascular risk factors.

👨‍👩‍👧 Genetic Counselling

• Family screening may be useful if strong VTE history.
• Educate carriers on DVT/PE warning signs & risk avoidance.

📈 Prognosis

Many carriers never clot. Risk is strongly influenced by coexisting factors (OCPs, surgery, pregnancy). With good risk management & anticoagulation where indicated, prognosis is favourable.

📚 References

• Connors JM. Thrombophilia Testing and Venous Thrombosis. NEJM. 2017.
• Dahlbäck B. Pathogenesis of thrombophilia. Blood. 2008.
• De Stefano V, et al. Inherited thrombophilia. Blood. 2016.
• Franchini M, Mannucci PM. Factor V Leiden. Clin Chem Lab Med. 2008.
• Martinelli I, et al. Prothrombin gene mutation & CVST risk. NEJM. 1998.