In the context of a given genotype and phenotype, the dynamics of blood clot assembly ultimately dictate: thrombosis; thrombolytic susceptibility of clots; stroke during cardiopulmonary bypass; restenosis after angioplasty; wound healing/inflammation; and pathogenesis of deep vein thrombosis or pulmonary embolism. During blood coagulation, activated platelets and neutrophils from homotypic and heterotypic aggregates through over ten receptor-mediated pathways while triggering thrombin formation and fibrin polymerization. Yet less is known quantitatively about the strengths and kinetics of platelet-platelet and platelet-neutrophil bonding that leads to aggregation or deposition under coagulating whole blood flow conditions or the biochemical reactivity of these aggregates. Furthermore, temporal resolution of events lasting only a few milliseconds is rarely achieved in most experiments. In vitro high speed imaging experiments will utilize human blood cells and proteins for kinetic studies of these interactions under controlled hemodynamic and coagulation conditions. Probability distributions and kinetic data from these experiments will be used to gain improved mechanistic understanding of human blood phenomena from receptor dynamics to vessel occlusion, in the hemodynamic setting. By defining the molecular dynamics of how blood clots are assembled under flow conditions as well as defining the flow regulation of various clotting scenarios, the risks of unregulated clotting, bleeding, and embolism will be more quantitatively understood for a given disease progression.
Specific aims are:
Aim 1 High speed imaging of platelet bonding dynamics that regulate thrombosis in clotting blood with emphasis on bond life dynamics.
Aim 2 High speed imaging of neutrophil bonding dynamics that enhance cellular deposition with emphasis on selectin mediated pathways, erythrocyte interactions and membrane tethering.
Aim 3 Quantifying mechanisms by which neutrophils act as procoagulant participants during clot assembly under defined flow conditions.
Aim 4 Develop a set of generalized computational tools for the study of heterotypically aggregating-reacting blood. Overall, these studies seek to provide fundamental insight into cell-cell interactions and coagulation biochemistry that occur under flow.
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