Chapter 170

## Abstract

Abstract

1. Protein C is converted to an anticoagulant serine protease by a complex between thrombin and thrombomodulin (TM) on the surface of endothelial cells. An endothelial cell protein C/activated protein C receptor (EPCR) augments this process. Activated protein C (APC) binds to protein S on cell surfaces or on negatively charged phospholipid vesicles where the complex inactivates factor Va or factor VIIIa, thereby preventing further thrombin generation.

2. Protein C and protein S are vitamin K-dependent proteins. Therefore, their biosynthesis is inhibited by oral anticoagulants that function as vitamin K antagonists. Protein C levels decrease rapidly following initiation of oral anticoagulant therapy with a t½ ~ 24 h.

3. Homozygous protein C (MIM 176860) and protein S (MIM 176880) deficiency have been described. When the functional levels of these proteins are extremely low, infants develop purpura fulminans shortly after birth. In the case of protein C deficiency, the purpura can be successfully managed with protein C supplementation. Homozygous or compound heterozygous individuals with low, but detectable, levels of protein C may remain free of thrombosis at least until early adulthood.

4. Heterozygous protein C (MIM 176860) and protein S (MIM 176880) deficiency are each associated with approximately 5 percent of familial thrombophilias. Protein C deficiency appears to be relatively prevalent, affecting approximately 0.3 percent of the general population with the majority of these individuals asymptomatic. Patients with TM mutations (MIM 188040) and either arterial or venous thrombosis have been described, but the prevalence of these mutations in the general population and in thrombophilia remains uncertain. EPCR deficiencies have not been described.

5. A dimorphism in factor V (MIM 227400) resulting in replacement of Arg 506 with Gln is quite frequent in Caucasians (.5 percent), but much less common in other ethnic groups. Arg 506 is the first bond cleaved during factor Va inactivation and thus the substitution of Arg with Gln results in delayed factor Va inactivation, a situation known as APC resistance or factor V Leiden. Factor V can function as a cofactor for the inactivation of factor VIIIa. The Arg 506 to Gln substitution not only slows factor Va inactivation by APC, but it also appears to eliminate factor V cofactor activity in factor VIIIa inactivation.

6. Clinical manifestations of heterozygous protein C or protein S deficiency, and factor V Leiden include venous thrombosis and pulmonary embolism. Arterial thrombosis appears to be a less common complication of these defects in the protein C pathway. Studies have implicated TM mutations in venous thrombosis and in an increased risk of myocardial infarctions, but the epidemiology on TM defects in thrombotic disease is much less developed than for the other factors in the pathway.

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