APC resistance: biological basis and acquired influences

Proteolytic inactivation of factors Va (FVa) and VIIIa (FVIIIa) by activated protein C (APC) and its cofactors protein S and factor V (FV) is a key process in the physiological down-regulation of blood coagulation. Functional abnormalities of this pathway, which manifest themselves in vitro as a poor anticoagulant response of plasma to added APC (APC resistance), are prevalent in the general population and are associated with an increased risk of venous thrombosis. APC resistance was originally discovered in thrombophilic families and later shown to be associated with the common FV Arg506Gln (FVLeiden) mutation, which abolishes one of the APC-cleavage sites in FV. Although FVLeiden is the major cause of hereditary APC resistance, it is becoming increasingly clear that several other genetic and acquired conditions contribute to APC resistance and thereby increase the risk of venous thrombosis. This paper reviews the multifactorial etiology of APC resistance and discusses its clinical implications.