Molecular mechanisms affecting fibrin structure and stability

Abstract

Fibrin structure and stability have been linked to many thrombotic diseases, including venous thromboembolism. Analysis of the molecular mechanisms that affect fibrin structure and stability became possible when the crystal structure of fibrinogen was solved. Biochemical studies of natural and recombinant variant fibrinogens have examined the interactions that mediate the conversion of soluble fibrinogen to the insoluble fibrin network. These studies identified intermolecular interactions that control fibrin structure, although some critical events remain ambiguous. Studies show that fibrin structure modulates the enzymatic lysis of the fibrin network, so the molecular mechanisms that control structure also control stability. Studies show that the mechanical stability of the fibrin clot depends on the properties of the fibrin monomer, leading investigators to explore the molecular basis of the monomer's mechanical properties. The work summarized here provides insights that might allow the development of pharmaceuticals and treatments to modulate fibrin structure and stability in vivo and thereby prevent or limit thrombotic disease.

Figure 1. Correlation of fibrinogen concentration, clot structure and thrombotic diseases

Epidemiologic studies have shown that fibrinogen concentration is a risk factor for thrombotic disease. Biochemical studies have shown fibrinogen concentration modulates clot structure, and clot structure modulates clot stability. Case control studies link fibrin clot structure and stability to thrombotic disease.

Figure 2. The structure of fibrinogen (A) and the fibrin protofibril (B)

A. Fibrinogen is a dimer with two copies each of three chains: Aα, shown in dark grey, Bβ, shown in light grey, and γ, shown in black. The schematic is based on the crystal structure with the addition of the two αC regions containing the αC connector and the αC domain. B. Fibrin monomers assemble into half-staggered, double-stranded protofibrils. Protofibril formation is mediated by interactions between knobs ‘A’ in the central E region and holes ‘a’ in the distal D regions; one set of ‘A:a’ interactions is circled. The structures and nomenclature are based on published recommendations.