What are the non-thrombotic manifestations of Complement (C) and S protein deficiency and how are they managed?

Non-Thrombotic Manifestations of Protein C and S Deficiency

The most clinically significant non-thrombotic manifestation of protein C and S deficiency is warfarin-induced skin necrosis, which occurs in 3-8 days after initiating therapy and requires immediate cessation of warfarin with heparin bridging. 1

Warfarin-Induced Skin Necrosis

This is the most important non-thrombotic complication you must recognize and prevent. The pathophysiology involves extensive thrombosis of venules and capillaries within subcutaneous fat, creating necrotic lesions that appear 3-8 days after starting warfarin. 1

Clinical Presentation

• Painful, purple-to-black skin lesions that do not blanch with pressure 1
• Most commonly affects areas with high subcutaneous fat (breasts, buttocks, thighs) 1
• Occurs because protein C has a shorter half-life (6-8 hours) than factors II, IX, and X, creating a transient hypercoagulable state when warfarin is initiated 1

Prevention Strategy

Always start warfarin at low doses (2 mg daily) with concurrent therapeutic heparin coverage, gradually increasing over 1-2 weeks. 1 This prevents the abrupt fall in protein C levels before reduction of procoagulant factors occurs. Never load warfarin in patients with known or suspected protein C or S deficiency. 1

Management if It Occurs

• Immediately discontinue warfarin 1
• Start therapeutic-dose heparin or LMWH 1
• If future anticoagulation is needed, restart warfarin at 2 mg daily under full heparin coverage, increasing slowly over weeks 1
• Several case reports confirm this approach prevents recurrence 1

Venous Limb Gangrene

This is a variant syndrome causing massive venous outflow obstruction of entire limbs. 1 It occurs particularly in:

• Cancer-associated DVT treated with warfarin 1
• Heparin-induced thrombocytopenia patients started on warfarin after heparin withdrawal 1

The mechanism is similar to skin necrosis but affects larger venous territories. Management requires the same cautious warfarin reintroduction protocol. 1

Purple Toe Syndrome

This rare complication appears 3-8 weeks after warfarin initiation (later than skin necrosis). 1 It results from cholesterol emboli rather than direct thrombosis, causing:

• Bilateral painful purple lesions on toes and sides of feet 1
• Lesions blanch with pressure (unlike skin necrosis) 1
• Non-hemorrhagic cutaneous complication 1

Neonatal Purpura Fulminans

Homozygous protein C deficiency in neonates causes severe, life-threatening purpura fulminans. 1 This presents with:

• Widespread thrombosis from birth 1
• Extensive skin necrosis 1
• Requires immediate treatment with FFP 10-20 mL/kg every 12 hours or protein C concentrate 2

The similarity between neonatal purpura fulminans and warfarin-induced skin necrosis strongly supports protein C depletion as the pathogenic mechanism. 1

Acquired Protein C/S Deficiency in Severe Infections

Patients with meningococcal sepsis develop acquired deficiency of protein C, protein S, and antithrombin III. 1 This contributes to:

• Purpura fulminans in 28 patients studied, with 50% mortality 3
• Dermal microvascular thrombosis and hemorrhagic necrosis 3
• Gangrene with deforming autoamputation in survivors 3

The magnitude of declining protein C levels directly correlates with clinical severity (P = 0.0053). 3 When protein C is low and platelets <50,000/mm³, risk of purpura fulminans with death or deformity significantly increases (P = 0.0001 and P = 0.0158 respectively). 3

Children under 4 years are particularly vulnerable due to immaturity of the protein C system. 3

Bone Effects (Pediatric Concern)

Warfarin interferes with carboxylation of Gla proteins synthesized in bone. 1 Two uncontrolled cohort studies show reduced bone density in children on warfarin for 1 year, though the role of underlying disorders remains unclear. 1

Vascular Calcification

By preventing activation of Gla proteins and growth arrest-specific gene 6 (Gas-6), warfarin may induce vascular calcification. 1 This represents a long-term non-thrombotic complication of therapy rather than the deficiency itself.

Critical Clinical Pitfalls

Never start warfarin without heparin coverage in patients with protein C or S deficiency. 1 The transient hypercoagulable state during the first week is when skin necrosis occurs.

Do not confuse warfarin-induced skin necrosis with purple toe syndrome—the former occurs at 3-8 days and doesn't blanch; the latter at 3-8 weeks and does blanch. 1 Treatment differs accordingly.

Recognize that protein C and S deficiency can be acquired during acute illness (sepsis, DIC, liver disease), not just inherited. 1, 3 Testing during acute thrombosis or severe infection will show low levels that don't represent true inherited deficiency. 4