Protein S Deficiency

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

Protein S deficiency is a rare inherited or acquired thrombophilia. Protein S is a vitamin K–dependent glycoprotein that serves as a cofactor for activated protein C (APC), helping to inactivate factors Va and VIIIa. Deficiency → uncontrolled thrombin generation → venous thromboembolism (VTE) such as DVT, PE, and cerebral venous sinus thrombosis (CVST).

📊 Epidemiology

• Prevalence: 0.03–0.13% in the general population; 1–7% in patients with VTE.
• Inheritance: Autosomal dominant, variable penetrance.
• Affects all ethnic groups equally.

🧬 Genetics & Pathophysiology

Mutations in the PROS1 gene (chromosome 3q11.2). Protein S circulates in two forms:

• 🟢 Free Protein S: active form (cofactor for APC).
• ⚪ Bound Protein S: inactive, attached to C4b-binding protein.

• Type I: ↓ total + free antigen + ↓ activity.
• Type II: normal antigen, ↓ activity (dysfunctional protein).
• Type III: normal total antigen, ↓ free antigen + ↓ activity.

🩺 Clinical Features

• 🌡️ Venous Thromboembolism (VTE): Early-onset (<50), recurrent DVT/PE, provoked or spontaneous.
• 🧠 Cerebral Venous Sinus Thrombosis (CVST): Headache, papilloedema, seizures, focal deficits.
• ❤️ Arterial Thrombosis: Less common; stroke/MI in high-risk settings.
• 🤰 Pregnancy: Miscarriage, IUGR, pre-eclampsia, placental abruption, ↑ VTE risk.
• ⚠️ Warfarin-Induced Skin Necrosis: Rare complication when warfarin started without heparin bridging.

⚠️ Risk Factors & Triggers

• Hormones (OCPs, HRT).
• Pregnancy / postpartum.
• Surgery, trauma, immobilisation.
• Obesity, smoking, malignancy.
• Other thrombophilias (FVL, prothrombin G20210A).
• Antiphospholipid antibody syndrome.

🧪 Diagnosis

• Clinical history: VTE at young age, family history.
• Laboratory tests:
  • Total protein S antigen.
  • Free protein S antigen (active form).
  • Protein S activity assay (functional).
• Other coagulation work-up: Protein C, antithrombin III, Factor V Leiden, prothrombin mutation, APC resistance.
• Imaging: Doppler US (DVT), CTPA (PE), MRV (CVST).

⚠️ Levels fall in acute thrombosis, pregnancy, OCP use, warfarin, liver disease → test in steady state and off anticoagulation.

🔍 Differentials

• Protein C deficiency
• Antithrombin deficiency
• Factor V Leiden
• Prothrombin G20210A mutation
• Antiphospholipid syndrome
• DIC
• Lupus anticoagulant
• HIT

🛡️ Management

Preventive Measures

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

Treatment of Acute Thrombosis

• 💉 LMWH or unfractionated heparin → transition to warfarin or DOACs (rivaroxaban, apixaban) – specialist input recommended.
• ⚠️ Warfarin-induced skin necrosis: stop warfarin, give vitamin K, restart heparin, consider protein C concentrate.
• Duration: 3–6 months (provoked first VTE), longer if recurrent/unprovoked or high risk.

📅 Long-Term Anticoagulation

• Individualised: balance recurrence vs bleeding risk.
• Indefinite anticoagulation often needed in recurrent cases.
• Regular follow-up essential.

👨‍👩‍👧 Genetic Counselling

• Offer to affected families with strong thrombotic history.
• Educate on warning signs of VTE (leg swelling, chest pain, dyspnoea).
• Discuss risk during pregnancy and surgery.

📈 Prognosis

• Many live normal lives with risk-modifying measures.
• Recurrent VTE risk persists → vigilance needed.
• Pregnancy can be safe with prophylaxis and monitoring.

📚 References

• Dahlbäck B. Discovery of protein S function. ATVB. 2007.
• Patel JP et al. Protein S deficiency and pregnancy. Thromb Haemost. 2015.
• Miles JS et al. Importance of free protein S measurement. Br J Haematol. 1996.
• NICE Guideline NG158: VTE disease, 2020.
• James AH. Thrombophilia in pregnancy. Obstet Gynecol Surv. 2001.