Congenital and acquired activated protein C resistance.
Resistance to the anticoagulant action of activated protein C, APC resistance, is a highly prevalent risk factor for venous thrombosis among individuals of Caucasian origin. In most cases, APC resistance is associated with a single missense mutation in the gene for coagulation factor V (FV (Leiden)), which predicts the replacement of Arg (506) with a Gln at one of the cleavage sites for APC in factor V. Factor V is a Janus-faced protein with dual functions, serving as an essential nonenzymatic cofactor in both pro- and anticoagulant pathways. Procoagulant factor Va, generated after proteolysis by thrombin or factor Xa, is a cofactor to factor Xa in the activation of prothrombin, whereas anticoagulant factor V, generated after proteolysis by APC, functions as a cofactor in the APC-mediated degradation of FVIIIa. The FV (Leiden) mutation affects the anticoagulant response to APC at two distinct levels of the coagulation pathway, as it impairs degradation of both activated factor V and activated factor VIII, the latter effect inasmuch as FVLeiden is a poor APC cofactor. Several other genetic traits, some of them quite common, are known to affect the anticoagulant response to APC, but none of them cause the same severe APC-resistance phenotype as FV (Leiden) and their importance as risk factors for thrombosis is unclear. A poor APC response may also result from acquired conditions, some of which are clearly involved in the pathogenesis of venous thrombosis. Venous thrombosis is a typical multifactorial disease, the pathogenesis of which involves multiple gene-gene and gene-environment interactions. In many patients with severe thrombophilia, APC resistance is found as a contributing risk factor.
Nicolaes
Gerry A F
GA
Department of Laboratory Medicine, Lund University, The Wallenberg Laboratory, University Hospital Malmö, Malmö, Sweden.
Dahlbäck
Björn
B
D020016:Activated Protein C Resistance / Q000151:congenital* / Q000175:diagnosis / Q000453:epidemiology / Q000628:therapy; D001779:Blood Coagulation Factors / Q000502:physiology; D006801:Humans; D010641:Phenotype; D012307:Risk Factors; D020246:Venous Thrombosis / Q000151:congenital / Q000175:diagnosis / Q000453:epidemiology / Q000628:therapy
D001779:Blood Coagulation Factors