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. 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, elicited by proteolytic mechanisms, is essential to its procoagulant function. The negative regulation of factor Va, a consequence of proteolytic cleavage principally by activated protein C (APC), is also an essential function. The significance of factor V in human biology and medicine is assured by the pathology of parahemophilia, which results in hemorrhagic disease in humans and represents a lethal mutation in transgenic mice. Alterations in factor Va inactivation associated with either protein C or protein S disfunction and the relatively common mutation associated with factor V(Leiden) are associated with venous thrombosis. During the past decade, the primary structure of factor V, its posttranslational modifications, its cleavage during activation and inactivation, its biosynthesis and its catabolism have been described. The present application seeks to extend our knowledge of the functions of factor V and factor Va using the approaches that proved valuable in the past. These include: (a) the evaluation of the structure and function of the protein using intact and fragmented natural and recombinant proteins. Studies will include evaluation of catalytic and binding functions and include contributions to the elucidation of the crystal structure of factor Va and its complexes. (b) The second major aim is the elucidation of the structure/function/pathology relationships of a newly identified small molecule, which is associated with an acquired resistance to APC. """"""""APC resistance"""""""" is known to be caused by congenital alterations in factor V, by chemical modification and by antibodies, which interfere with the process of APC cleavage to the factor Va molecule. We recently discovered a small (molecular weight = 3500) carbohydrate polymer, which confers """"""""APC resistance"""""""" on the factor Va inactivation by APC. The level of this component is elevated in pathologies associated with thrombosis. The major aim of this project is to elucidate the structure/function relationships of this material with respect to factor V inactivation and to access its potential significance in the pathology of human thrombosis.
| Bravo, Maria Cristina; Orfeo, Thomas; Mann, Kenneth G et al. (2012) Modeling of human factor Va inactivation by activated protein C. BMC Syst Biol 6:45 |
| Rizoli, Sandro B; Scarpelini, Sandro; Callum, Jeannie et al. (2011) Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma 71:S427-34 |
| Brummel-Ziedins, K E; Whelihan, M F; Rivard, G E et al. (2011) Activated protein C inhibitor for correction of thrombin generation in hemophilia A blood and plasma1. J Thromb Haemost 9:2262-7 |
| Whelihan, M F; Orfeo, T; Gissel, M T et al. (2010) Coagulation procofactor activation by factor XIa. J Thromb Haemost 8:1532-9 |
| Mann, Kenneth G (2010) Taking the thrombin ""fork"". Arterioscler Thromb Vasc Biol 30:1293-9 |
| Mann, K G; Orfeo, T; Butenas, S et al. (2009) Blood coagulation dynamics in haemostasis. Hamostaseologie 29:7-16 |
| Undas, Anetta; Szuldrzynski, Konstanty; Brummel-Ziedins, Kathleen E et al. (2009) Systemic blood coagulation activation in acute coronary syndromes. Blood 113:2070-8 |
| Erdogan, Evrim; Bukys, Michael A; Orfeo, Thomas et al. (2007) Identification of an inactivating cleavage site for alpha-thrombin on the heavy chain of factor Va. Thromb Haemost 98:998-1006 |
| Undas, Anetta; Brzezinska-Kolarz, Beata; Orfeo, Tom et al. (2007) Blood coagulation at the site of microvascular injury in healthy and coumadin-treated subjects heterogenous for factor V Leiden mutation. Thromb Haemost 98:1024-30 |
| Mann, Kenneth G; Brummel-Ziedins, Kathleen; Orfeo, Thomas et al. (2006) Models of blood coagulation. Blood Cells Mol Dis 36:108-17 |
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