Coagulation factor V and thrombophilia: Background and mechanisms

Abstract

Human coagulation factor V (FV) is an essential coagulation protein with functions in both the pro- and anticoagulant pathways. Failure to express and control FV functions can either lead to bleeding, or to thromboembolic disease. Both events may develop into a life-threatening condition. Since the first description of APC resistance, and in particular the description of the so-called factor V(Leiden) mutation, in which a prominent activated protein C cleavage site in FV has been abolished through a mutation in the FV gene, FV has been in the center of attention of thrombosis research. In this review we describe how the functions of FV are expressed and regulated and provide an extensive description of the role that FV plays in the etiology of thromboembolic disease.

Factor VLeiden

“…This idea is further supported by the very high thrombotic risk observed in patients who are compound heterozygotes for factor V-deficient and FV Leiden alleles (pseudohomozygotes). Despite bearing only one FV Leiden allele (heterozygous), the thrombotic risk in these patients is similar to that of FV Leiden homozygotes, consistent with the notion that a predominant thrombophilic effect of FV Leiden is related to the inability to generate the anticoagulant molecule FV ac [29].…”

“…Some evidence suggests that the risk of PE is not as great as the risk of DVT in FV Leiden individuals (termed the FV Leiden paradox) [25]. Studies have not consistently shown an increased risk for arterial thrombosis such as myocardial infarction or stroke, although FV Leiden may be more common in affected patients who are young and who have other risk factors such as smoking [26][27][28][29][30].…”

“…It is now clear that APC exerts anticoagulant effects beyond inactivating factor Va by cleaving at R306 and R506, generating inactive FV (FV ai ). In addition, APC also generates an anticoagulant molecule (FV ac ) by cleaving full-length factor V at R506; this FV ac acts as a cofactor with APC to degrade factor VIIIa [29,31]. Although the R506Q mutation in FV Leiden abrogates both these effects, a major cause of APC resistance and thrombophilia in these patients is believed to be the decreased generation of the FV ac anticoagulant [29].…”

“…In addition, APC also generates an anticoagulant molecule (FV ac ) by cleaving full-length factor V at R506; this FV ac acts as a cofactor with APC to degrade factor VIIIa [29,31]. Although the R506Q mutation in FV Leiden abrogates both these effects, a major cause of APC resistance and thrombophilia in these patients is believed to be the decreased generation of the FV ac anticoagulant [29]. This idea is further supported by the very high thrombotic risk observed in patients who are compound heterozygotes for factor V-deficient and FV Leiden alleles (pseudohomozygotes).…”

“…Of these, one of the more significant is FV R2 (H1299R) which is tightly linked to several other polymorphisms and collectively named the R2 haplotype [29]. FV R2 exhibits APC resistance entirely due to reduced APC cofactor activity and leads to an increased thrombotic risk when present in compound heterozygotes with FV Leiden [29,33].…”