Fibrinogen and fibrin polymerization: appraisal of the binding events that accompany fibrin generation and fibrin clot assembly.

M W Mosesson

Index: Blood Coag. Fibrinolysis 8 , 257-267, (1997)

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Abstract

Fibrinogen is a complex multifunctional protein comprised of three major domains (two outer D and one central E) which contains constitutive binding sites (e.g. Da, Db, gammaXL, D:D, gamma', thrombin substrate, platelet receptor) as well as binding sites that become exposed or expressed as a result of fibrinogen proteolysis by thrombin and/or that are exposed as a consequence of the polymerization process itself (tPA binding sites). Fibrin-dependent tPA-mediated activation of plasminogen is associated with exposure of polymerization-dependent epitopes (Aalpha148-160, gamma312-324) that are expressed in assembled fibrin and in crosslinked (polymerized) fibrinogen but not in unpolymerized fibrinogen or fibrin. Fibrin polymerization is initiated by thrombin cleavage of fibrinopeptide A from fibrinogen Aalpha chains, exposing two E domain E(A) sites. Cleavage of fibrinopeptide B from fibrinogen Bbeta chains exposes other E domain polymerization sites, termed E(B), that also interact with platelets, fibroblasts and endothelial cells. Fibrin generation is followed by an assembly process of intermolecular end-to-middle D to E associations to form linear and branched double-stranded fibrin fibrils, lateral fibril-fibril associations to form fibers and a branched fiber network. Binding sites in fibrinogen play their roles in fibrin assembly by self-association (gammaXL to gammaXL and D:D to D:D) or by complementary association with exposed sites in fibrin (Da to E(A) and Db to E[B]). Other binding sites in fibrinogen include thrombin substrate recognition sites in each E domain and a non-substrate high affinity thrombin binding site in the carboxy-terminal region of each gamma' chain, which also binds plasma factor XIII. Fibrin possesses low affinity thrombin binding sites in each E domain and retains the gamma' chain nonsubstrate thrombin-binding site.