Protein C Deficiency
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- Protein C is a vitamin K–dependent factor made by the liver that becomes activated when thrombin binds to the endothelial receptor thrombomodulin.
- Activated protein C, with protein S as a cofactor, inactivates factors Va and VIIIa.
- Patients with protein C deficiency have a thrombotic disorder that primarily affects the venous system, but can also affect the arterial system.
- System(s) affected: Cardiovascular; Hemic/Lymphatic/Immunologic; Pulmonary
- 0.3% of normal individuals
- 4–5% of persons with VT
- Predominant age: Mean age of first thrombosis is 45 years.
- Predominant sex: Male = Female
Patients heterozygous for protein C deficiency who start warfarin without concomitant heparin can develop warfarin-induced skin necrosis because the half-life of other vitamin K–dependent clotting factors, prothrombin, factor IX, and factor X is much longer than that of protein C (4–8 hours). These patients develop extremely low levels of protein C and subsequently increased thrombin generation, leading to necrosis of the skin over central areas of the body such as the breast, abdomen, buttocks, and genitalia (1)[A].
Since protein C deficiency is a congenital disease, there are no preventive measures.
- Polymorphisms in the promoter region of the protein C gene can affect antigen levels. At least 150 mutations have been described in the protein C gene that can lead to functional deficiency.
- Acquired protein C deficiency can occur with liver disease, ARDS, DIC, chemotherapy with L-asparaginase, 5-FU, methotrexate, and cyclophosphamide, as well as postoperative state and severe infections, especially meningococcemia. Also, rare patients can develop inhibitors to activated protein C. Neonates have lower levels of protein C than adults.
Commonly Associated Conditions
- Deep and superficial venous thrombosis, often spontaneous
- Up to 50% of homozygotes will have thrombosis.
- Homozygosity is associated with catastrophic thrombotic complications at birth (e.g., purpura fulminans)
- Sites of thrombosis can be unusual, including the mesentery and cerebral veins, especially when combined with other risk factors like oral contraceptives.
- Arterial thrombosis is rare.
- Skin necrosis can be seen in patients on warfarin.