Prothrombotic Hypercoagulable disorders

🧬 Introduction

• Clotting is a balance ⚖️ between antithrombotic and prothrombotic forces. A hypercoagulable state arises when this balance tips towards clot formation.
• Causes may be due to:
  • ⬇️ Intrinsic antithrombotic factors:
    • Antithrombin (III) deficiency
    • Protein C deficiency
    • Protein S deficiency
  • ⬆️ Intrinsic prothrombotic factors:
    • Factor V Leiden mutation (APC resistance)
    • Prothrombin G20210A mutation
    • Factor IX Padua (R338L mutation)
    • Other epidemiologic associations: high Factor VII, VIII, IX, XI, fibrinogen, von Willebrand factor
• Secondary (acquired) causes include antiphospholipid syndrome, malignancy, pregnancy, trauma, and immobility.

🧬 Causes of Thrombophilia

1️⃣ Factor V Leiden

• 📝 Description: APC resistance → ↑ thrombin generation
• 📊 Prevalence: ~5% Caucasians
• ⚠️ Risk: Moderate risk of venous thromboembolism (VTE)
• 🧪 Tests: Genetic test; APC resistance test
• 💊 Management: Anticoagulation if symptomatic or high-risk

2️⃣ Prothrombin G20210A

• 📝 Mutation → ↑ prothrombin levels
• 📊 Prevalence: ~2% of Caucasians
• ⚠️ Risk: Moderate VTE risk
• 🧪 Test: Genetic testing
• 💊 Anticoagulation if VTE or high-risk

3️⃣ Antithrombin Deficiency

• 📝 Loss of thrombin & Xa inhibition
• 📊 Rare (0.02–0.2%)
• ⚠️ High risk
• 🧪 Functional activity assay
• 💊 Anticoagulation; AT concentrate if severe

4️⃣ Protein C Deficiency

• 📝 Loss of natural anticoagulant
• 📊 Prevalence ~0.2%
• ⚠️ Risk: Moderate–high
• 🧪 Protein C activity assay
• 💊 Heparin → Warfarin/DOAC

5️⃣ Protein S Deficiency

• 📝 Loss of cofactor for Protein C
• 📊 Prevalence 0.03–0.13%
• ⚠️ Moderate–high risk
• 🧪 Antigen/activity assay
• 💊 Anticoagulation if symptomatic

6️⃣ Antiphospholipid Syndrome (APS)

• 📝 Autoantibodies against phospholipids
• 📊 Seen in ~5% of VTE patients
• ⚠️ High risk → venous + arterial thrombosis + pregnancy loss
• 🧪 Tests: Lupus anticoagulant, anticardiolipin, anti-β2GP1 antibodies
• 💊 Long-term warfarin (INR 2.5–3.5)

7️⃣ Hyperhomocysteinaemia

• 📝 Endothelial injury → thrombosis
• 📊 Prevalence 5–7% of general population
• ⚠️ Moderate risk
• 🧪 Plasma homocysteine
• 💊 B vitamins (folate, B6, B12); anticoagulation if VTE

8️⃣ Malignancy

• 📝 Tumour procoagulants & cytokines promote clotting
• 📊 Prevalence varies by cancer type
• ⚠️ High risk of thrombosis
• 🧪 Work-up: D-dimer, imaging, cancer screening
• 💊 LMWH or DOACs + treat underlying malignancy

🩺 Clinical Manifestations

• 💥 Deep vein thrombosis (DVT) – most common
• 💨 Pulmonary embolism (PE)
• 🔥 Superficial thrombophlebitis, splanchnic vein thrombosis
• 🧠 Cerebral venous sinus thrombosis
• 🤰 Recurrent pregnancy loss (APS)
• 🫀 Arterial thrombosis (mainly APS)

⚠️ Key Point: Primary inherited thrombophilias usually cause venous thrombosis, not arterial. But arterial occlusion can occur by paradoxical embolism through a patent foramen ovale.

⛔ Precipitants That Tip the Balance

• Pregnancy & puerperium
• OCP or HRT use
• Major surgery or trauma
• Immobilisation (e.g., long-haul flights, hospitalisation)
• Active cancer or chemo
• Chronic inflammatory disease (e.g., psoriasis, IBD)
• Myeloproliferative neoplasms

🔎 Who to Screen?

• Age < 40 with unprovoked VTE
• Recurrent DVT/PE
• Strong family history (first-degree relatives with unprovoked/recurrent VTE)
• Unusual sites (cerebral, mesenteric, portal vein thrombosis)

💡 Teaching pearl: Not every DVT/PE needs thrombophilia testing - most provoked events (surgery, trauma, OCP) do not. Screening should be selective, as results rarely change acute management but may affect duration of anticoagulation and family counselling.