Factor V Leiden: a disorder of factor V anticoagulant function.
OBJECTIVE
Activated protein C (APC) resistance, which is often associated with the factor V R506Q (FV Leiden) mutation, is a common risk factor for venous thrombosis. Study of the mechanism of APC resistance has revealed that coagulation FV stimulates the APC-catalysed inactivation of FVIIIa, and that this anticoagulant function of FV is impaired in FV Leiden. The present review covers the discovery, the physiological significance and the structural requirements of the APC-cofactor activity of FV.


RESULTS
Recent in vitro and in vivo experiments indicate that the anticoagulant activity of FV is physiologically relevant and that FV plays a major role in the maintenance of the haemostatic balance. Quantitative and functional defects of the APC-cofactor activity of FV lead to increased thrombin generation and are associated with a prothrombotic state. Although the structural requirements for the expression of the APC-cofactor activity of FV are now beginning to be unravelled, the underlying molecular mechanism remains elusive.


CONCLUSIONS
The APC-cofactor activity of FV and its impairment in FV Leiden can explain the different thrombosis risks associated with heterozygosity, homozygosity and pseudo-homozygosity for FV Leiden. Elucidation of the molecular mechanism of the anticoagulant function of factor V may provide novel targets for the design of antithrombotic drugs.
Castoldi
Elisabetta
E
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.
Rosing
Jan
J
D020016:Activated Protein C Resistance / Q000235:genetics / Q000378:metabolism; D001777:Blood Coagulation; D005165:Factor V / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D011486:Protein C / Q000502:physiology; D019851:Thrombophilia / Q000235:genetics / Q000503:physiopathology; D013927:Thrombosis / Q000235:genetics; D013997:Time Factors
D011486:Protein C; C095381:factor V Leiden; D005165:Factor V