Protein C Deficiency
Protein C deficiency (PCD) is a rare heritable disorder or acquired risk factor resulting in a prothrombotic state. Symptoms range from an asymptomatic presentation to recurrent venous thromboembolism (VTE), life-threatening neonatal purpura fulminans, or severe disseminated intravascular coagulation (DIC).
- 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
The estimated incidence is between 1 in 200 to 1 in 500 (1). Clinically substantial PCD estimated to be 1 in 20,000. Severe PCD is rare, predicted in 1 in 4 million infants.
- 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
- 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.
- 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.
The prevention of warfarin necrosis has been achieved by avoiding loading doses of warfarin and the use of heparin bridging. Screening all patients for inherited or acquired forms of PCD prior to initiating warfarin is not cost-effective or prognostic because many patients with documented deficiency do not progress to WISN.
Acquired conditions such as heart failure, severe liver disease, DIC, vitamin K antagonists
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
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