PRIMARY STRUCTURE OF PROTHROMBIN

University Of Vermont &St Agric College, Burlington VT

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Abstract

Factor V is a central participant in the blood clotting process. In its activated form (factor Va), when bound to a membrane, it serves as a factor Xa receptor and an effector of catalytic activity in the activation of prothrombin to thrombin. Studies of the prothrombinase complex and its components have provided not only significant information with respect to this complex, but also insights into the overall mechanism by which blood clots. The participation of factor V in the prothrombinase complex function is a consequence of both positive and negative regulatory processes which influence both the receptor and effector functions of the molecule. The activation of the procofactor, factor V, to the cofactor, factor Va, can be elicited by a number of proteolytic mechanisms, with the most important being thrombin. The negative regulation of factor Va occurs as a consequence of proteolytic cleavage by activated protein C (APC), an anticoagulant enzyme activated paradoxically by thrombin. In recent times, defects in the protein C system involving defects in protein C, protein S, thrombomodulin, and factor Va have been associated with significant thromboembolic events. During the past decade, the primary structure of factor V, its posttranslational modifications, its cleavage during activation and inactivation, and its biosynthesis and catabolism have been described. The present application seeks to extend our knowledge of the functions of factor V and factor Va using extensions of the approaches that have proved valuable in the past. These include: (a) the evaluation of the structure and function of the protein using the proteolytic fragments derived from natural factor V, factor Va and factor Vai, (b) the development an utilization of recombinant cofactor V and factor Va fragments to develop an understanding of the activity and the regulation of this important molecule, (c) the development of practical immunologic and genetic measurements of factor V fragments which may be used to evaluate hypercoagulable states and provide predictive information regarding the nature of genetic alterations which influence factor V structure and function.