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

The Prothrombin G20210A mutation is the second most common inherited thrombophilia after Factor V Leiden. It causes elevated prothrombin (factor II) → ↑ thrombin generation → ↑ fibrin formation → a hypercoagulable state. This primarily predisposes to venous thromboembolism (VTE) such as DVT and PE, but is also linked to cerebral venous sinus thrombosis (CVST) and possibly young-onset arterial stroke.

🧬 Genetics & Epidemiology

• Single G→A substitution at nucleotide 20210 in the 3′-UTR of the prothrombin gene (chromosome 11).
• Prevalence: ~1–2% of Europeans; very rare in African/Asian populations.
• Homozygosity: extremely rare (~1 in 10,000) but carries higher risk.
• Inheritance: Autosomal dominant, incomplete penetrance.

⚙️ Pathophysiology

• Mutation stabilises mRNA → ↑ prothrombin synthesis.
• Excess prothrombin → ↑ thrombin generation.
• Fibrin-rich clot formation → predisposes to venous thrombosis.

🩺 Clinical Features

• 🌡️ VTE risk:
  • DVT – unilateral swelling, erythema, pain.
  • PE – sudden dyspnoea, pleuritic chest pain, tachycardia.
  • CVST – headache, seizures, focal deficits, papilloedema.
• 📊 Risk increase: heterozygotes ~2–3×; homozygotes substantially higher.
• 🧠 Arterial thrombosis: evidence weak, but relevant in young stroke with no risk factors.
• 🤰 Pregnancy: ↑ risk of miscarriage, stillbirth, pre-eclampsia, abruption + maternal VTE.
• 💊 Synergy: OCPs/HRT, obesity, immobility, cancer, or co-inheritance (e.g. Factor V Leiden) amplify risk.

⚠️ Risk Factors & Triggers

• Acquired: surgery, trauma, immobility, obesity, malignancy, pregnancy, smoking.
• Other thrombophilias: co-inheritance increases risk (e.g. FVL, protein C/S deficiency, antithrombin deficiency).

🧪 Diagnosis

• Careful clinical history – personal/family thrombotic events.
• Genetic test (PCR) – detects G20210A variant.
• Prothrombin activity – often mildly raised.
• Thrombophilia screen to check for co-existing conditions.

🔍 Differentials: Other Thrombophilias

• Factor V Leiden (~3–7%).
• Protein C deficiency (0.2–0.5%).
• Protein S deficiency (0.1–0.7%).
• Antithrombin deficiency (0.02%).
• Antiphospholipid antibody syndrome (acquired, variable prevalence).

🛡️ Management

Prevention

• 🏃 Lifestyle: weight control, exercise, avoid immobility, stop smoking.
• 🚫 Avoid oestrogen-containing OCP/HRT if possible.
• 🤰 Pregnancy: LMWH prophylaxis in high-risk women; close obstetric monitoring.

Treatment of Thrombosis

• 💉 Acute VTE: LMWH → warfarin (INR 2–3) or DOACs (apixaban, rivaroxaban, dabigatran).
• 🕐 Duration: 3–6 months if provoked; consider indefinite if recurrent/unprovoked or homozygote.
• Monitor bleeding risk + recurrence prevention.

🧠 Arterial Stroke Considerations

• Association mainly in young adults & children.
• Routine screening in stroke not recommended.
• Standard secondary prevention applies (antiplatelets, statins, risk factor control).

👨‍👩‍👧 Genetic Counselling

• Offer family discussion/testing if strong history of VTE.
• Educate on DVT/PE signs (leg swelling, chest pain, sudden breathlessness).
• Risk is context-dependent → many carriers remain asymptomatic lifelong.

📈 Prognosis

Most heterozygotes never clot. Risk depends on coexisting triggers. With tailored anticoagulation & lifestyle precautions, prognosis is favourable.

📚 References

• Rosendaal FR et al. Geographical distribution of 20210A variant. Thromb Haemost. 1998.
• Poort SR et al. Prothrombin mutation & VTE. Blood. 1996.
• Martinelli I et al. CVST risk in OCP users with mutation. NEJM. 1998.
• De Stefano V et al. Prothrombin G20210A & CVST. Stroke. 2006.
• NICE NG158: VTE disease: diagnosis, management & thrombophilia testing. 2020.