Non-Thrombotic Manifestations of Protein C and S Deficiency

Introduction to Non-Thrombotic Complications

The American College of Cardiology and Chest guideline societies recommend that warfarin-induced skin necrosis, a non-thrombotic manifestation of protein C and S deficiency, be immediately treated with cessation of warfarin and heparin bridging, as it occurs in 3-8 days after initiating therapy 1, 2

Warfarin-induced skin necrosis is the most clinically significant non-thrombotic manifestation of protein C and S deficiency, requiring immediate cessation of warfarin with heparin bridging, and occurs due to extensive thrombosis of venules and capillaries within subcutaneous fat, creating necrotic lesions that appear 3-8 days after starting warfarin, with a pathophysiology involving a transient hypercoagulable state when warfarin is initiated 1, 2
The American College of Cardiology recommends starting warfarin at low doses (2 mg daily) with concurrent therapeutic heparin coverage, gradually increasing over 1-2 weeks, to prevent warfarin-induced skin necrosis in patients with protein C or S deficiency 1, 2
Painful, purple-to-black skin lesions that do not blanch with pressure are a common presentation of warfarin-induced skin necrosis, most commonly affecting areas with high subcutaneous fat, such as breasts, buttocks, and thighs 1, 2

Homozygous protein C deficiency in neonates causes severe, life-threatening purpura fulminans, presenting with widespread thrombosis from birth, extensive skin necrosis, and requiring immediate treatment with FFP 10-20 mL/kg every 12 hours or protein C concentrate, according to the American College of Cardiology and Chest guideline societies 1, 2

Patients with meningococcal sepsis develop acquired deficiency of protein C, protein S, and antithrombin III, contributing to purpura fulminans, dermal microvascular thrombosis, and hemorrhagic necrosis, with a direct correlation between declining protein C levels and clinical severity 5

Warfarin interferes with carboxylation of Gla proteins synthesized in bone, potentially leading to reduced bone density in children on warfarin for 1 year, and may induce vascular calcification by preventing activation of Gla proteins and growth arrest-specific gene 6 (Gas-6), according to Chest guideline society 2

The American College of Cardiology and Chest guideline societies recommend never starting warfarin without heparin coverage in patients with protein C or S deficiency, and to recognize that protein C and S deficiency can be acquired during acute illness, such as sepsis, DIC, or liver disease 1, 2, 5