Factor V and protein S as cofactors to activated protein C.
OBJECTIVE
Activated protein C (APC)-resistance, the most common risk factor for venous thrombosis described so far, is due to a single point mutation in the factor V gene. As a result, inactivation of factor-activated factor V by APC is impaired, which leads to a hypercoagulable state and a lifelong increased risk of thrombosis. The importance of protein S as an anticoagulant protein is illustrated by the association between protein S deficiency and venous thrombosis. The objective of this article is to examine the most recent advances on the role of factor V and protein S as cofactors to activated protein C.


METHODS
The material examined in the present review includes several personal papers in this field, and articles and abstracts published in journals covered by the Science Citation Index.


BACKGROUND
Factors V and VIII are homologous, high molecular weight glycoproteins with similar functional properties. Factors Va and VIIIa bind to negatively charged phospholipid and function as high affinity receptors/cofactors for factors Xa and IXa, respectively. Factors Va and VIIIa account for at least a 10(3) increase in the rate of activation of prothrombin and factor Xa, respectively. The potent anticoagulant activity of APC is mediated by the degradation of factors VIIIa and Va, resulting in inhibition of both Xase and prothrombinase activities. APC specifically degrades the membrane-bound activated forms of factors V and VIII, whereas the unactivated factors V and VIII are poor substrates for APC. Mature human protein S is a single chain glycoprotein composed of multiple domains, including a thrombin-sensitive region. Protein S acts as a cofactor to activated protein C. Thus function of protein S is lost upon thrombin cleavage, suggesting that the thrombin-sensitive region interacts with APC on the phospholid surface.


CONCLUSIONS
Recent data suggest that factor V and protein S work in synergy as phospholipid-bound cofactors to APC in the degradation of factor VIIIa and that factor VIIIa is preferred over factor Va as APC-substrate. Thus complicated multimolecular complexes, which are the result of protein-protein as well as protein-phospholipid interactions, appear to form the basis for efficient cleavage and inhibition of factors VIIIa and Va.
Dahlbäck
B
B
Department of Clinical Chemistry, University of Lund, University Hospital, Malmö, Sweden.
D001777:Blood Coagulation; D004198:Disease Susceptibility; D005165:Factor V / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D005167:Factor VII / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000502:physiology*; D018455:Protein S Deficiency / Q000150:complications; D013927:Thrombosis / Q000209:etiology / Q000235:genetics
D010743:Phospholipids; D011486:Protein C; D017293:Protein S; C095381:factor V Leiden; D005165:Factor V; D005167:Factor VII