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At a glance

Rare autosomal dominant or acquired (sepsis, disseminated intravascular coagulation) deficiency of protein C (vitamin K-dependent serine protease anticoagulant factor) that predisposes to thrombotic events.

Synonyms

Congenital Thrombotic Protein C Deficiency; Hereditary Thrombophilia; PC Deficiency; ProC Deficiency.

History

The addition of Protein C deficiency in the list of thrombotic diseases was suggested by J. H. Griffin in 1981.

Incidence

Inherited forms: 1:200 to 1:300 for heterozygotes; 1:200,000 for homozygotes.

Genetic inheritance

Autosomal dominant trait with variable expressivity.

Pathophysiology

This syndrome is due to mutations of the PROC gene mapped to locus 2q14.3. This gene encodes protein C, a vitamin K-dependent plasma glycoprotein, which is a key component of the anticoagulant system. Protein C is cleaved to its activated form, activated protein C, on endothelial cells by the thrombin-thrombomodulin complex and then acts as a serine protease to degrade the activated forms of coagulation factors V and VIII. Consequently, a deficiency in protein C results in defective control of the clotting mechanism with a widespread thrombotic tendency. Heterozygotes show an increased thrombotic tendency, whereas homozygotes present with severe thrombotic sequelae in the neonatal period. Most cases of protein C deficiency have had a quantitative defect in the protein C molecule. Protein C deficiency with a mutation that causes diminished synthesis of protein has been referred to as Type I and that with synthesis of a dysfunctional molecule as Type II. Acquired protein C deficiency is also observed in septic shock, hepatic disease, and Nephrotic Syndrome.

Diagnosis

Positive family history and a significant history of thrombosis or gangrene (skin, retinal, etc). Severe symptoms typically develop when the serum protein C level is below 20 to 25% of normal (4 μg/mL). Specific laboratory tests and assays are needed to exclude other causes of disseminated intravascular coagulation.

Clinical aspects

Heterozygotes for Protein C Deficiency (serum concentrations 40-60% of normal): Usually presents in adolescence with recurrent thrombophlebitis, deep venous thrombosis, and pulmonary thromboembolism. There is also an increased risk of thrombotic renal and cerebral disease and an increased risk of myocardial infarction.

Homozygotes manifest fatal thromboses in the neonatal period: Causes massive subcutaneous thrombosis (neonatal purpura fulminans) with cutaneous necrosis, gangrene, and widespread venous thrombosis, which usually starts in the first 24 hours of life. Severe bilateral vitreous hemorrhages, gangrene, and widespread venous thrombosis have been reported. Bilateral adrenal hemorrhage may lead to abdominal pain, hypotension, and hyponatremia. Hypertension and congestive cardiac failure commonly result from renal involvement. Treatment with heparin, antiplatelet drugs, or both is not effective. The only successful treatment is protein C replacement using protein C human concentrate, fresh-frozen plasma, or factor IX concentrate.

In case of ...

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