Protein C Deficiency

🧬 Protein C Deficiency — NICE-Aligned Overview (UK)

Protein C deficiency is a rare inherited thrombophilia causing a hypercoagulable state 🩸. Protein C is a vitamin K–dependent anticoagulant that inactivates factors Va and VIIIa, limiting thrombin generation. Deficiency increases the risk of venous thromboembolism (VTE) — DVT, PE, and cerebral venous sinus thrombosis (CVST). Severe homozygous deficiency may cause neonatal purpura fulminans 🚨.

📊 Epidemiology

• Heterozygous deficiency: ~0.2–0.5% of population.
• Homozygous deficiency: rare (≈1 in 500,000 births).
• Inheritance: Autosomal dominant (heterozygous); recessive pattern in severe neonatal disease.

🧬 Genetics & Pathophysiology

Caused by mutations in the PROC gene (chromosome 2). Reduced protein C activity → impaired inactivation of Va & VIIIa → excess thrombin → thrombosis 🔥.

• Type I 📉: Low antigen + low activity (quantitative defect).
• Type II ⚠️: Normal antigen but low functional activity (qualitative defect).

🩺 Clinical Features

Heterozygous Protein C Deficiency

• 🩸 Recurrent VTE (often young adults).
• 🧠 CVST (headache, seizures, focal deficits).
• 🚺 Pregnancy-associated thrombosis risk.
• ⚠️ Warfarin-induced skin necrosis (early after initiation).

Homozygous Protein C Deficiency

• 👶 Neonatal purpura fulminans (DIC + skin necrosis).
• Severe early-life thrombosis.

⚠️ Thrombosis Triggers

• Pregnancy & postpartum 🤰
• Oestrogen-containing contraception 💊
• Surgery/trauma 🏥
• Immobilisation ✈️
• Obesity ⚖️
• Malignancy 🎗️

🔬 Diagnosis (NICE NG158 Aligned Principles)

⚠️ NICE (NG158 — VTE guideline) advises that routine thrombophilia testing is NOT recommended for most patients with VTE. Testing should only be considered if it will change management (e.g. young unprovoked VTE, strong family history, unusual sites).

• Protein C activity assay (functional test) 🧪
• Protein C antigen level (Type I vs II)
• Test when patient is:
  • Not in acute thrombosis
  • Off warfarin (warfarin lowers protein C)
  • Not vitamin K deficient
• Imaging as clinically indicated (Doppler US, CTPA, MRV)

🧠 Differential Diagnosis

• Protein S deficiency
• Antithrombin deficiency
• Factor V Leiden
• Prothrombin G20210A mutation
• Antiphospholipid syndrome

💊 Management (NICE NG158 — VTE)

1️⃣ Acute VTE

• First-line: DOAC (e.g., apixaban or rivaroxaban) unless contraindicated 💊.
• Alternative: LMWH → warfarin (with overlap).
• ⚠️ If starting warfarin, overlap with heparin ≥5 days to prevent skin necrosis.

2️⃣ Duration of Anticoagulation

• Provoked VTE → 3 months.
• Unprovoked VTE → assess recurrence vs bleeding risk.
• Recurrent VTE → consider long-term anticoagulation.

3️⃣ Pregnancy (NICE NG158 + RCOG guidance)

• LMWH is treatment of choice 🤰.
• Avoid DOACs in pregnancy.
• Consider prophylactic LMWH in high-risk women.

4️⃣ Severe Deficiency / Neonates

• Protein C concentrate or FFP 💉.
• Anticoagulation with heparin.
• Liver transplantation may be definitive in severe cases.

🧴 Warfarin-Induced Skin Necrosis

• Stop warfarin immediately ❌
• Give vitamin K
• Start therapeutic heparin
• Consider protein C replacement

🛡️ Prevention Advice

• Avoid oestrogen-containing contraception 🚫
• Maintain healthy weight ⚖️
• Early mobilisation after surgery
• Discuss thromboprophylaxis before major surgery

👨‍👩‍👧 Family Screening

• Consider if strong family history.
• Offer genetic counselling 🧬.

📈 Prognosis

• Heterozygous: normal life expectancy with appropriate management.
• Homozygous: life-threatening without early treatment.

📚 References

• NICE NG158 — Venous thromboembolic diseases (2020, updated).
• British Society for Haematology (BSH) Guideline on Thrombophilia Testing.
• RCOG Green-top Guideline — Thromboembolism in Pregnancy.