Factor Va is a central cofactor in the blood clotting process. Studies of its participation with factor Xa and a membrane surface in the formation of the complex which converts prothrombin to thrombin have provided significant insights into the mechanisms by which blood clots. This mechanism is central to physiologic hemostasis, and lack of regulation results in thrombosis and the occlusive events associated with venous thrombosis, pulmonary embolism, stroke and myocardial infarction. This research program is aimed at understanding the fundamental molecular contributions of factor Va and factor VIIIa in the expressions of coagulant activity and the interactions of the various constituents within the enzymatic complexes by defining the peptide regions which are explicitly associated with various binding events. Because of recent breakthroughs which permit microchemical analysis of protein structure, the recent discovery of the total amino acid sequence of factor V by this laboratory and experience gained in the expression of the factor VIII molecule, we are in a position to provide detailed structural maps of sites of interaction in these important molecules. Insights into the structure of factor V will be explicitly evaluated and extended to structural studies on factor VIII. Peptide chemistry will be used to initially locate specific sties. Molecular biology will be used to verify and further explore sites of interaction. The full cycle of organic proof, from structural identification to resynthesis, will permit unequivical evaluation of research results. Studies of the type described in the present application will ultimately have specific applications in the development of better technology for the diagnosis and treatment of thrombotic and hemorrhagic diseases.
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| 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 |
| Mann, K G; Brummel-Ziedins, K; Undas, A et al. (2004) Does the genotype predict the phenotype? Evaluations of the hemostatic proteome. J Thromb Haemost 2:1727-34 |
| Beck, Daniel O; Bukys, Michael A; Singh, Lisam S et al. (2004) The contribution of amino acid region ASP695-TYR698 of factor V to procofactor activation and factor Va function. J Biol Chem 279:3084-95 |
| Mann, Kenneth G (2003) Thrombin: can't live without it; probably die from it. Chest 124:1S-3S |
| Mann, Kenneth G; Kalafatis, Michael (2003) Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 101:20-30 |
| Mann, Kenneth G; Butenas, Saulius; Brummel, Kathleen (2003) The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 23:17-25 |
| Mann, K G; Brummel, K; Butenas, S (2003) What is all that thrombin for? J Thromb Haemost 1:1504-14 |
| Singh, Lisam S; Bukys, Michael A; Beck, Daniel O et al. (2003) Amino acids Glu323, Tyr324, Glu330, and Val331 of factor Va heavy chain are essential for expression of cofactor activity. J Biol Chem 278:28335-45 |
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