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Protein C deficiency

INTRODUCTION

Inherited thrombophilia is a genetic tendency to venous thromboembolism. Factor V Leiden is the most common cause of the syndrome accounting for 40 to 50 percent of cases. The prothrombin gene mutation, deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases, while rare causes include the dysfibrinogenemias [1,2]. The total incidence of an inherited thrombophilia in subjects with a deep vein thrombosis ranges from 24 to 37 percent overall compared with about 10 percent in controls. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

This topic review will discuss the genetics, prevalence, clinical presentation, and diagnosis of protein C deficiency. Issues related to screening for and the general treatment of the inherited thrombophilias are discussed separately. (See "Evaluation of the patient with established venous thrombosis" and "Screening for inherited thrombophilia in asymptomatic populations" and "Management of inherited thrombophilia" and "Diagnosis and treatment of venous thromboembolism in infants and children".)

PHYSIOLOGY OF PROTEIN C

Protein C is a vitamin K-dependent protein synthesized in the liver. It has a molecular weight of about 62 kilodaltons and consists of two chains connected by a disulfide bridge. The gene for protein C is located on chromosome 2 (2q13-14) and appears to be closely related to the gene for factor IX [3,4].

Protein C circulates as a zymogen and exerts its anticoagulant function after activation to the serine protease, activated protein C (aPC) [5]. This process can be mediated by thrombin alone, but occurs more efficiently when thrombin is bound to endothelial thrombomodulin.

The primary effect of aPC is to inactivate coagulation factors Va and VIIIa, which are necessary for efficient thrombin generation and factor X activation [5]. The inhibitory effect of aPC is markedly enhanced by protein S, another vitamin K-dependent protein.
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