This research program is aimed at understanding how thrombin is generated and how thrombin generation is regulated. Our approach to these questions comes via the convergence of four separate directions associated with 1) the physical properties of coagulation enzyme complexes, their constituents and how these complexes can assemble into efficient enzyme catalysts. 2) Studies in which multiple coagulation catalysts are mixed to attempt to duplicate the performance of the combined catalyst system such as that associated with the tissue factor pathway of thrombin expression. 3) To study this process in unadulterated minimally modified biological systems (whole blood) to evaluate the correctness of hypotheses derived from purified systems. 4) To attempt to create mathematical models which can be used to define, on a quantitative basis, the process of blood clotting and its regulation both to aid in experimental designs 1, 2, 3, and also to aid in the evaluation of the pharmacologic agents, hemostatic and thrombotic diseases.
The aim of the present investigation is to understand the nature of procoagulant and anticoagulant vitamin-K dependent complexes and their regulation during the process of thrombin generation. Studies will employ physical chemistry techniques including hydrodynamics and fluorescence spectroscopy, (the latter both in solution and on surfaces) to study complexes on synthetic membranes and cells. Reactions will be followed using both synthetic and natural substrates to monitor both presteady state and steady state kinetic events. Natural and recombinant inhibitors will be used to study the regulation of procoagulant and anticoagulant processes associated with thrombin generation. We will integrate the detailed information available through studies of individual reactions with that obtained from multi-reaction center systems. The relevance of these purified systems to events occurring in whole blood will be evaluated quantitatively by our system. Conversely, the processes noted to occur in the whole blood system will direct appropriate attention in the purified system analyses. We anticipate developing a quantitative evaluation of the biologically relevant chemistry associated with the complex reactions which occur simultaneously during a blood clotting event. These data have significance in interpreting normal physiology and in developing approaches to correct the coagulation pathology associated with thrombosis and hemophilia. The techniques we develop will provide tools for the evaluation of potential pharmacological intervention in hemostatic and thrombotic disease.
|Kusak, Piotr; Czarnecka, Danuta; Gissel, Matthew et al. (2016) Activated factor IX, factor XI and tissue factor identify patients with permanent atrial fibrillation treated with warfarin who are at risk of ischemic stroke. Arch Med Sci 12:1000-1007|
|Bouchard, Beth A; Chapin, John; Brummel-Ziedins, Kathleen E et al. (2015) Platelets and platelet-derived factor Va confer hemostatic competence in complete factor V deficiency. Blood 125:3647-50|
|Brummel-Ziedins, Kathleen E; Everse, Stephen J; Mann, Kenneth G et al. (2014) Modeling thrombin generation: plasma composition based approach. J Thromb Thrombolysis 37:32-44|
|Bouchard, Beth A; Gissel, Matthew T; Whelihan, Matthew F et al. (2014) Platelets do not express the oxidized or reduced forms of tissue factor. Biochim Biophys Acta 1840:1188-93|
|de Haan, Hugoline G; Bezemer, Irene D; Vossen, Carla Y et al. (2014) Genetic variants in Cell Adhesion Molecule 1 (CADM1): a validation study of a novel endothelial cell venous thrombosis risk factor. Thromb Res 134:1186-92|
|Undas, A; Brummel-Ziedins, K E; Mann, K G (2014) Anticoagulant effects of statins and their clinical implications. Thromb Haemost 111:392-400|
|Whelihan, Matthew F; Kiankhooy, Armin; Brummel-Ziedins, Kathleen E (2014) Thrombin generation and fibrin clot formation under hypothermic conditions: an in vitro evaluation of tissue factor initiated whole blood coagulation. J Crit Care 29:24-30|
|Krudysz-Amblo, Jolanta; Jennings 2nd, Mark E; Knight, Tyler et al. (2013) Disulfide reduction abolishes tissue factor cofactor function. Biochim Biophys Acta 1830:3489-96|
|Ayombil, F; Abdalla, S; Tracy, P B et al. (2013) Proteolysis of plasma-derived factor V following its endocytosis by megakaryocytes forms the platelet-derived factor V/Va pool. J Thromb Haemost 11:1532-9|
|Baker, Jason V; Brummel-Ziedins, Kathleen; Neuhaus, Jacqueline et al. (2013) HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation. J Am Heart Assoc 2:e000264|
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