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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2247.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

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

Robert A. Campbell; Katherine A. Overmyer; C. Robert Bagnell; Alisa S. Wolberg

From the Department of Pathology and Laboratory Medicine (R.A.C., K.A.O., C.R.B., A.S.W.) the Center for Thrombosis and Hemostasis (A.S.W.), and the Carolina Cardiovascular Biology Center (A.S.W.), University of North Carolina, Chapel Hill.

Correspondence to Alisa S. Wolberg, PhD, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 815 Brinkhous Bullitt Building, CB #7525, Chapel Hill, NC 27599-7525. E-mail alisa_wolberg{at}med.unc.edu

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 the cell surface, suggesting that the structural heterogeneity of the clot affected its fibrinolytic stability.

Conclusions— In situ thrombin generation on the cell surface modulates the three-dimensional structure and stability of the clot. Thrombus formation in vivo may reflect the ability of the local cell population to support thrombin generation and, therefore, the three-dimensional structure and stability of the fibrin network.

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.

Key Words: coagulation • fibrin clot structure • thrombin generation • fibrinolysis

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