Thrombophilia (Prothrombotic) testing

🧠 Thrombophilia refers to an inherited or acquired tendency to develop venous thromboembolism (VTE). Testing should be carefully targeted - results often do not alter management and can cause anxiety or misinterpretation. 👉 Always assess for provoking factors (surgery, immobility, pregnancy, malignancy) before testing for heritable thrombophilia.

🧾 About

• 🩸 Thrombophilia = inherited or acquired predisposition to venous thrombosis (DVT/PE).
• 🔍 Screening is mainly for unprovoked VTE in younger patients or those with a strong family history.
• 🧬 Heritable thrombophilia rarely changes anticoagulation duration - most VTEs arise from a combination of genetic susceptibility + acquired risk.
• 👩‍⚕️ Consider only after completing initial anticoagulation; avoid testing during the acute phase or while on warfarin/heparin (affects results).

📌 Clinical Indications for Screening

• Age <40 with unexplained or recurrent VTE.
• Strong family history (first-degree relative <40 with VTE).
• Unprovoked VTE before age 50.
• Recurrent pregnancy loss or stillbirth → test for antiphospholipid antibodies.
• VTE at unusual sites (cerebral, portal, mesenteric, axillary veins).
• Unexplained arterial thrombosis in young adults → consider APS, myeloproliferative, or paroxysmal nocturnal haemoglobinuria (PNH).

🧪 Investigations

• 🧫 Lupus anticoagulant
• 🧫 Antiphospholipid antibodies: anticardiolipin, β2-glycoprotein I
• 🧬 Protein C / Protein S levels (vitamin K–dependent anticoagulants)
• 🧬 Antithrombin activity
• 🧬 Factor V Leiden mutation (APC resistance)
• 🧬 Prothrombin G20210A mutation
• 🧬 3′ prothrombin UTR variant
• 🧬 JAK2 mutation (for myeloproliferative thrombophilia)

🧬 Inherited Thrombophilic Conditions

📊 Frequency of Common Mutations

⚠️ Acquired & Inherited Prothrombotic States

• 🧬 Factor V Leiden (APC resistance)
• 🧬 Prothrombin G20210A mutation
• ⬇️ Protein C / Protein S deficiency (risk of warfarin skin necrosis)
• ⬇️ Antithrombin III deficiency (heparin resistance)
• 🤰 Pregnancy & OCP use (↑ oestrogen → ↑ clotting factors II, VII, VIII, X, fibrinogen)
• 🩸 Paroxysmal nocturnal haemoglobinuria (PNH) – intravascular haemolysis + thrombosis (often hepatic/mesenteric)
• 🩺 Myeloproliferative neoplasms (PV, ET, JAK2+)
• ⬆️ Hyperhomocysteinaemia → endothelial injury; treat with folate, B6, B12
• 💉 Heparin-induced thrombocytopenia (HIT) – paradoxical thrombosis with thrombocytopenia
• 🎗️ Malignancy – Trousseau’s syndrome, migratory thrombophlebitis, NBTE, DIC
• 🧪 Antiphospholipid syndrome (APS) – arterial + venous thrombosis + pregnancy morbidity

👩‍⚕️ Who to Screen?

🧪 Practical Test Notes

• 🧴 Sample requirements: 2× citrate (blue), 1× EDTA (purple), 1× clotted (gold).
• ⛔ Do not test Protein C, S, or ATIII during acute thrombosis or while on warfarin/heparin - results unreliable.
• Activated Protein C resistance ratio > 2.5 = normal.
• Genetic results (FVL, Prothrombin G20210A) reported as normal / heterozygote / homozygote.
• Lupus anticoagulant & anticardiolipin antibodies require confirmation ≥12 weeks apart to diagnose APS.

📖 Educational Summary

Thrombophilia is a common area of over-investigation. The teaching message is that genetic predisposition rarely acts alone - it amplifies risk when combined with factors like surgery, immobility, or pregnancy. Inherited forms (FVL, Prothrombin mutation) increase risk of first VTE but do not necessarily predict recurrence. Acquired forms (APS, cancer, HIT, myeloproliferative disease) are often more clinically significant. For exam purposes: “Factor V Leiden = most common; Antithrombin deficiency = most dangerous.” Always link results to clinical context rather than testing in isolation.

📚 References

• NICE NG158: Venous Thromboembolic Diseases (2020)
• British Committee for Standards in Haematology (BCSH): Thrombophilia Testing Guidelines, 2022
• BNF: Anticoagulation and Thrombophilia
• Davidson’s Principles and Practice of Medicine, 24th Ed – Haematology Section