Congenital and Acquired Activated Protein C Resistance

Gerry A. F. Nicolaes; Björn Dahlbäck

doi:10.1055/s-2003-38331

Seminars in Vascular Medicine, Table of Contents

Semin Vasc Med 2003; 03(1): 033-046
DOI: 10.1055/s-2003-38331

Congenital and Acquired Activated Protein C Resistance

Gerry A.F. Nicolaes^1,2 , Björn Dahlbäck¹

¹Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, The Wallenberg Laboratory, University Hospital Malmö, Malmö, Sweden and
²2(present address) Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Abstract

ABSTRACT

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 Arg⁵⁰⁶ 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.

KEYWORDS

Factor V - thrombophilia - APC resistance - activated protein C

Full Text

References

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