most common cause of hereditary predisposition to thrombosis

Defects in protein C are the most commonly occurring causes of the hereditary predisposition to thrombosis.

http://themedicalbiochemistrypage.org/protein-c.html

Introduction to Protein C

Protein C is one of the major anticoagulant proteins involved in the overall control of hemostasis. Like several other zymogens of the blood coagulation regulatory pathway, protein C is a vitamin K-dependent enzyme that is converted to its' active form (identified as activated protein C: APC) as a result of proteolysis. Proteolysis of protein C occurs via a complex of thrombin and thrombomodulin at the surface of the endothelium. There is a receptor for protein C/APC on the surface of endothelial cells that augments the formation of the activation complex. APC then binds to a co-factor called protein S, either on the surface of cells or to negatively charged phospholipid vesicles. Once activated the APC/protein S complex inactivates coagulation factors Va and VIIIa which in turn prevents further generation of thrombin. The protein C gene resides on chromosome 2q13–q14 spanning approximately 11 kb and consisting of 9 exons. Protein C is a multidomain protein and mutations affecting each of the functional domains have been described.

Clinical Features of Protein C Deficiency

Because protein C is a vitamin K-dependent hemostasis factor, biosynthesis of the active protein is inhibited by oral anticoagulants that function via inhibition of vitamin K-dependent carboxylation reactions (e.g. coumadin). There are both heterozygous and homozygous deficiencies in protein C. Defects in protein C are the most commonly occurring causes of the hereditary predisposition to thrombosis. Homozygous deficient infants develop purpura fulminans (hemorrhagic condition usually associated with infection or sepsis) shortly after birth. These complications can be treated by protein C supplementation. Heterozygous individuals are quite frequent in the general population with estimates of 0.3%. Many remain asymptomatic but up to 5% of familial thrombophilias are the result of protein C (or protein S) deficiency. It should be noted that because APC requires interaction with protein S for full activity, deficiencies in protein S are phenotypically similar to protein C deficiencies. In addition, some factor V mutants result in the inability of APC to bind to activated factor V (Va) resulting in similar phenotypes in factor V mutants. The clinical manifestations of heterozygous protein C, protein S and factor V mutants overlap and include venous thrombosis and pulmonary embolism.