What is the clinical significance and management of protein C deficiency?

Protein C Function and Clinical Significance

Primary Physiological Role

Protein C is the central anticoagulant protein in the hemostasis system that prevents excessive clot formation by inactivating activated factors V and VIII before thrombus formation occurs. 1, 2

• Protein C circulates as an inactive vitamin K-dependent zymogen that requires activation by the thrombin-thrombomodulin complex on endothelial cell surfaces 2, 3
• Once activated (APC), it forms an anticoagulant complex with protein S on cell membrane surfaces to selectively inactivate factors Va and VIIIa, thereby inhibiting the coagulation cascade 1, 4, 2
• This pathway allows anticoagulant activity to be expressed away from injury sites where procoagulant reactions occur, preventing systemic anticoagulation 2

Clinical Significance of Protein C Deficiency

Thrombotic Risk

Protein C deficiency is a significant independent risk factor for venous thromboembolism with an odds ratio of 11.1 for cerebral venous thrombosis. 5

• Heterozygous protein C deficiency is associated with recurrent thrombotic disease, though not all heterozygous individuals experience thrombotic complications 1, 4
• Homozygous protein C deficiency causes congenital purpura fulminans, a life-threatening condition with historical mortality rates of 5% and pulmonary embolism rates of 38% when treated with anticoagulation alone 5

Acquired Deficiencies

Multiple clinical conditions can cause acquired protein C deficiency 1:

• Warfarin therapy (protein C depletes rapidly, similar to factor VII) 1
• Liver disease 1, 4
• Disseminated intravascular coagulation (DIC) 1
• Acute thrombotic events (functional levels decrease due to consumption) 1

Management of Homozygous Protein C Deficiency

Acute Management of Purpura Fulminans

For acute episodes of congenital purpura fulminans, combination therapy with protein C replacement plus anticoagulation is superior to anticoagulation alone. 5, 6

• Protein C replacement can be administered as protein C concentrate or fresh-frozen plasma 5, 6
• Combined therapy reduces mortality, pulmonary embolism, bleeding, and skin necrosis to 0% compared to 5%, 38%, 14%, and 14% respectively with anticoagulation alone 5

Long-Term Management Options

Protein C replacement therapy is the preferred long-term treatment for homozygous protein C deficiency, offering superior effectiveness without the bleeding risks of high-intensity anticoagulation. 5, 6

Three management strategies exist, listed in order of preference:

1. Protein C replacement monotherapy (optimal but expensive) 5, 6

   • Requires IV or subcutaneous administration daily or multiple times weekly 5
   • Cost increases substantially as children grow due to weight-based dosing 5, 6

2. Combined protein C replacement with anticoagulation (when full replacement is cost-prohibitive) 5, 6

   • Reduces required anticoagulation intensity and associated bleeding risk 5, 6
   • More effective than anticoagulation alone 5, 6

3. Liver transplantation (curative option) 5, 6

   • All five transplanted children (ages 6 months to 8 years) survived with normal protein C levels and no major bleeding 5
   • Should be considered early before progressive organ damage occurs 5, 6
   • Carries upfront surgical risks and requires lifelong immunosuppression 5

Critical Management Pitfall

When anticoagulation with warfarin is necessary in protein C deficiency, start with very low doses (2 mg daily) under therapeutic coverage of parenteral anticoagulation, with gradual dose increases over 1+ weeks. 6, 7

• Warfarin causes rapid protein C depletion (faster than factors II, IX, and X), creating a transient hypercoagulable state in the first 3-8 days 7, 1
• This paradoxical effect can cause warfarin-induced skin necrosis, particularly in protein C-deficient patients 7, 1
• High loading doses of warfarin dramatically increase this risk 7

Laboratory Testing Considerations

When to Test

Targeted testing for protein C deficiency is recommended only when results will influence treatment decisions, particularly in patients with VTE and other risk factors. 5

• Indiscriminate testing in unselected VTE patients is not recommended 5
• Testing is most appropriate when evaluating thrombophilia in patients with recurrent VTE or family history of thrombosis 5

Sample Requirements

Proper specimen handling is critical 5:

• Collect blood in 3.2% trisodium citrate (1:10 ratio) 5
• Double-centrifuge to achieve platelet count <10 × 10⁹/L 5
• Test within 4 hours or freeze at -20°C (≤2 weeks) or -70°C (>2 weeks) 5
• Perform preliminary coagulation screening to detect factor deficiencies and anticoagulation that may interfere with testing 5

Diagnostic Confirmation

Diagnosis of protein C deficiency requires repeated abnormal determinations in the same patient or documentation of the same deficiency in family members, given the serious implications for the patient and kindred. 4