Role of fibrin structure in thrombosis and vascular disease

Fibrin clot formation is a key event in the development of thrombotic disease and is the final step in a multifactor coagulation cascade. Fibrinogen is a large glycoprotein that forms the basis of a fibrin clot. Each fibrinogen molecule is comprised of two sets of Aα, Bβ, and γ polypeptide chains that form a protein containing two distal D regions connected to a central E region by a coiled-coil segment. Fibrin is produced upon cleavage of the fibrinopeptides by thrombin, which can then form double-stranded half staggered oligomers that lengthen into protofibrils. The protofibrils then aggregate and branch, yielding a three-dimensional clot network. Factor XIII, a transglutaminase, cross-links the fibrin stabilizing the clot protecting it from mechanical stress and proteolytic attack. The mechanical properties of the fibrin clot are essential for its function as it must prevent bleeding but still allow the penetration of cells. This viscoelastic property is generated at the level of each individual fiber up to the complete clot. Fibrinolysis is the mechanism of clot removal, and involves a cascade of interacting zymogens and enzymes that act in concert with clot formation to maintain blood flow. Clots vary significantly in structure between individuals due to both genetic and environmental factors and this has an effect on clot stability and susceptibility to lysis. There is increasing evidence that clot structure is a determinant for the development of disease and this review will discuss the determinants for clot structure and the association with thrombosis and vascular disease.