Thrombin has multiple functions in blood coagulation and its regulation is central to maintaining the balance between excessive blood loss (hemorrhage) and inappropriate vascular occlusion (thrombosis). The goal of this application is to investigate how the process of thrombin formation relates to hemorrhagic and thromboembolic disorders. It has been established that major deficiencies in coagulation factors can lead to either bleeding (e.g. factor (f) VIII deficiency) or venous thrombosis (e.g. protein C (PC) deficiency). However, within these disease states the clinical manifestation between individuals is highly variable. For example, the inability to predict bleeding in hemophilia, despite knowledge of functional A/Ill levels, creates a therapeutic dilemma in the optimization of dosing regimens. We hypothesize that compensation by the ensemble of other coagulation proteins in individuals with specific factor deficiencies can """"""""normalize"""""""" an individual's thrombin generation process and that this effect represents a rationale for their unexpected phenotype. Thus, we expect that a systematic analysis of variations in the process of thrombin generation among individuals with specific pathologies will provide general criteria relevant to assessing any individual's propensity for hemorrhage or thrombosis. Our two approaches will be empirical and computational. We propose to use biologically relevant whole blood assays to develop empirical progress curves for the formation of thrombin, platelet activation, fVa and fibrin in two well-defined populations. These populations have been selected on the basis of having a specific genetic defect (A/Ill deficiency or PC deficiency), but varying phenotypes. Progress curves for individuals will be fitted using the classical four-parameter logistic model and the distribution of the estimated growth curve model parameters such as the inflection points will be statistically compared between phenotypes. We will also take a population averaged perspective approach by examining the average population growth curves for three subject groups consisting of healthy controls, hemophiliacs and those with familial thrombosis. Subgroups within the hemophiliac group (bleeders versus non bleeders) and PC deficiency group (with and without thrombosis) will also be evaluated. Our second approach will utilize our computational model of tissue factor initiated blood coagulation to further our understanding of the pathway to thrombin generation. In populations with defined clinical states we will evaluate the influence of each of the proteins (fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor) and complexes (flXa-fVllla and fXa-fVa) on thrombin generation profiles. This approach will add to our understanding of the compensatory influences of the coagulation proteins on phenotype. Relevance: We anticipate that this work will contribute to an integrated view of blood clotting behavior and will be instructive regarding an individual's risk of bleeding or clotting.
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