This application has as its long-term objective the understanding of the relationship between structure and function for the proteins involved in the blood coagulation process. In the present application, various specific aims are identified. The first of these involves examining the structures of the cofactor proteins, Factor V, and Factor VIII. This will be accomplished by primary sequence analysis of the two isolated proteins using microsequencing and microamino acid composition techniques which are applicable at the Mug level. The second specific aim deals with the relationship of the extent of vitamin K-dependent carboxylation of the human vitamin K-dependent proteins with the function of those proteins as enzymes and substrates in the blood clotting process. The studies anticipated here are involved in an attempt to correlate the efficacy of clinical anticoagulation with coumarin drugs to the extent and position of carboxylation in the various vitamin K-dependent proteins in plasma. This is especially relevant in view of recent observations that the vitamin K-antagonist coumarin drugs influence not only procoagulant vitamin K-dependent proteins but also an anticoagulant and profibrinolytic vitamin K-dependent protein (protein C). Hopefully, this study will provide a rational basis to understanding and monitoring vitamin K-antagonist therapy.
The third aim i s to conduct sequence studies to identify the substituted amino acids in a number of congenitally defective vitamin K-dependent proteins, particularly abnormal prothrombin. The studies are aimed at understanding the structure/function relationship of these proteins by making use of accidents of nature which permit the association of a single chemical modification which is associated with depressed function. Overall, the studies anticipated should provide fundamental insights into how the structures of the various proteins involved in the formation of blood clotting biocatalysts carry out their functions and may provide for the development of information and reagents that will be useful in influencing the processes of hemostasis and 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 |
| 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 |
| Rizoli, Sandro B; Scarpelini, Sandro; Callum, Jeannie et al. (2011) Clotting factor deficiency in early trauma-associated coagulopathy. J Trauma 71:S427-34 |
| 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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