Description

• Protein C is a vitamin Kdependent anticoagulant protein synthesized in an inactive form by the liver.
• Activated protein C (APC) inhibits generation of thrombin by inactivating factors Va and VIIIa, using protein S as a cofactor.
• Deficiency in protein C activity therefore leads to a prothrombotic state.
• System(s) affected: cardiovascular, pulmonary, integumentary, hematologic, and immunologic

Epidemiology

Incidence
The estimated incidence is between 1 in 200 and 1 in 500 (1). Clinically substantial PCD is estimated to be 1 in 20,000. Severe PCD is rare, predicted in 1 in 4 million infants.

Prevalence

• 0.3% of the general population
• 3–5% of persons with VTE
• Mean age of first thrombosis is 45 years.
• There is no known gender predominance.

Etiology and Pathophysiology

• PCD can be inherited or acquired.
• Genetic mutations can lead to two types of PCD; however, the distinction between the two is clinically irrelevant.
  • Type I (most common) results in the reduction of protein C levels.
  • Type II results in a decreased functionality, despite having normal levels of protein C.
• Acquired PCD is more common and can occur in many disease states such as:
  • Liver disease
  • DIC
  • Severe infections (especially meningococcemia)
  • Autoantibody inhibitors directed toward protein C
  • Cancer and chemotherapy (i.e., L-asparaginase, 5-FU, methotrexate, and cyclophosphamide)
  • Initial use of vitamin K antagonists (warfarin)
  • Vitamin K deficiency (secondary to malnutrition or malabsorption of fat-soluble vitamins)
• Heterozygous PCD and mild deficiency can cause a wide range of symptom severity from asymptomatic to recurrent thromboses.
  • There is an increased risk of DVT, PE, and sequelae such as ischemic arterial stroke and pregnancy-associated thrombosis.

Genetics

• Autosomal dominant inheritance pattern with incomplete penetrance
• At least 270 genetic mutations have been described in the protein C (PROC) gene that can lead to a functional deficiency.
• Heterozygous patients often have mild or asymptomatic disease.
• Homozygous patients, or those with another coexisting genetic thrombophilia, often have more severe disease.
• Additionally, mutations in other genes (GCKR, EDEM2, BAZ1B, etc.) are associated with variability in the levels of protein C expression in the general population, although their clinical significance is currently unknown.
• Patients with PCD who start warfarin without concomitant heparin are at increased risk of developing warfarin-induced skin necrosis (WISN). This is thought to be due to the shorter half-life of protein C (5 to 8 hours) compared to other vitamin Kdependent clotting factors. However, not all patients who develop WISN have PCD.

Risk Factors

Acquired conditions such as heart failure, severe liver disease, DIC, vitamin K antagonists

General Prevention

Because PCD is usually a congenital disease, there are no preventive measures.

Commonly Associated Conditions

• VTE at any site, often spontaneous
• Arterial thrombosis is rare, and a causative relationship has not been clearly demonstrated.
• Homozygosity can be associated with catastrophic thrombotic complications at birth (e.g., purpura fulminans).
• Recurrent pregnancy losses