Sol Sherry Lecture in Thrombosis : research on clot stabilization provides clues for improving thrombolytic therapies.

This article is a summary of the Sol Sherry Lecture of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology, which was presented at the 71st Scientific Sessions of the American Heart Association in November 1998.1 It highlights the work from our laboratory, designed to dissect the intricate reactions and molecular control mechanisms that operate in the final stages of the coagulation cascade. This research brought forth the idea that, by selectively blocking the maturation and accretion of thrombi, we should be able to achieve a much safer and more efficient thrombolysis at lower dosages of clot dissolving agents than currently in use. Fibrin is the fundamental building block of the clot matrix. Network formation occurs in an orderly sequence, well separated in time into distinct phases during the course of coagulation of normal plasma. After the reaction of thrombin with fibrinogen, a protofibrillar lattice is formed, with fibrin units lined up in a half-staggered array, reminiscent of laying bricks without mortar (Figure 1, top panel). Lateral bundling into filaments and fibers with concomitant entanglements and branching generates a 3D gel, the appearance of which is a measure of “clotting time.” Then, under the influence of the activated fibrin stabilizing factor (factor XIIIa), covalent bonds are introduced into the structure that causes an irreversible, end-to-end fusion of the fibrin particles (Figure 1, middle panel). Finally, full maturation of the network is brought about by forming covalent bonds between the protofibrils and filaments (Figure 1, bottom panel). Clots displaying the features shown in the top panel of Figure 1 can be readily dissociated into monomeric fibrin in 5 mol/L urea2,3 and on removal of urea, the gel reforms. The equilibrium between the monomeric or low oligomeric forms of soluble fibrin and clotted fibrin can be described as: