Cellular Procoagulant Activity Dictates Clot Structure and Stability as a Function of Distance From the Cell Surface

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Abstract
Background— Thrombin concentration modulates fibrin structure and fibrin structure modulates clot stability; however, the impact of localized, cell surface-driven in situ thrombin generation on fibrin structure and stability has not previously been evaluated. Methods and Results— Human fibroblasts were incubated with factors Xa, Va, prothrombin and fibrinogen, or plasma. Fibrin formation, structure, and lysis were examined using laser scanning confocal microscopy and transmission electron microscopy. In situ thrombin generation on the cell surface produced clots with a significantly denser fiber network in a 10-μm region proximal versus distal to (40 to 50 μm) the cell surface. This morphology was not altered by addition of integrin-blocking RGDS peptide and was not apparent in clots made by exogenous thrombin addition, suggesting that spatial morphology was dictated predominantly by localized thrombin generation on the fibroblast surface. The fibrin network lysed more rapidly distal versus proximal to th... Thrombin generation on the cell surface produced clots with a denser fiber network that was resistant to fibrinolysis in regions proximal versus distal to the cell surface. Our results suggest thrombin generation on the cell modulates the structure and function of the clot in three dimensions.