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Activated protein C resistance and factor V Leiden

INTRODUCTION

Factor V Leiden is the most common cause of inherited thrombophilia, 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 review will discuss the causes, prevalence, clinical presentation and diagnosis of activated protein C (APC) resistance and factor V Leiden. 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".)

PHYSIOLOGY

Factor V circulates in plasma as an inactive cofactor. Activation by thrombin results in the formation of factor Va, which then serves as a cofactor in the conversion of prothrombin to thrombin. (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

Factor Va is enzymatically inactivated by proteolytic cleavages in its heavy chain. The mechanism of factor Va inactivation is an ordered event. Factor Va is first cleaved at Arg506 and then at Arg306 and Arg679 by activated protein C. The peptide bond cleavage at Arg506 facilitates the exposure of cleavage sites at Arg306 and Arg679 [3].

In 1993, a group of individuals with unexplained venous thromboembolism were identified whose plasmas exhibited a poor response to activated protein C (APC) in an activated partial thromboplastin time (aPTT) assay. Recognized mechanisms for APC resistance, such as functional protein S deficiency or inhibitors of APC, were excluded. Other clinically affected relatives of the probands demonstrated APC resistance in the aPTT-based test, suggesting that the abnormality was inherited.
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