Thrombin generation, fibrin clot formation and hemostasis

Abstract

Hemostatic clot formation entails thrombin-mediated cleavage of fibrinogen to fibrin. Previous in vitro studies have shown that the thrombin concentration present during clot formation dictates the ultimate fibrin structure. In most prior studies of fibrin structure, clotting was initiated by adding thrombin to a solution of fibrinogen; however, clot formation in vivo occurs in an environment in which the concentration of free thrombin changes over the reaction course. These changes depend on local cellular properties and available concentrations of pro- and anti-coagulants. Recent studies suggest that abnormal thrombin generation patterns produce abnormally structured clots that are associated with an increased risk of bleeding or thrombosis. Further studies of fibrin formation during in situ thrombin generation are needed to understand fibrin clot formation in vivo.

Figure 1

The thrombin concentration present at the time of gelation dictates the fibrin clot structure. Scanning electron (A an B) and laser confocal (C and D) micrographs of fibrin clots formed by adding thrombin [2.5 nM (A and C), or 10 nM (B and D)] to purified fibrinogen (1 mg/mL) in 20 mM HEPES (pH 7.4), 150 mM NaCl. Scanning electron micrographs are at 76,030 × (micron bar is 200 nm). Laser confocal micrographs are at 63 X (micron bar is 10 μm).

Figure 2

Conceptual model of cellular tissue factor (TF)-initiated in situ thrombin generation. Please see text for details.