Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms

Abstract

Factor XIII and fibrinogen are unusual among clotting factors in that neither is a serine protease. Fibrin is the main protein constituent of the blood clot, which is stabilized by factor XIIIa through an amide or isopeptide bond that ligates adjacent fibrin monomers. Many of the structural and functional features of factor XIII and fibrin(ogen) have been elucidated by protein and gene analysis, site-directed mutagenesis, and x-ray crystallography. However, some of the molecular aspects involved in the complex processes of insoluble fibrin formation in vivo and in vitro remain unresolved. The findings of a relationship between fibrinogen, factor XIII, and cardiovascular or other thrombotic disorders have focused much attention on these 2 proteins. Of particular interest are associations between common variations in the genes of factor XIII and altered risk profiles for thrombosis. Although there is much debate regarding these observations, the implications for our understanding of clot formation and therapeutic intervention may be of major importance. In this review, we have summarized recent findings on the structure and function of factor XIII. This is followed by a review of the effects of genetic polymorphisms on protein structure/function and their relationship to disease. (Blood. 2002;100:743-754)

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

“…70 Imaging of thrombi has recently been accomplished through the specific detection of both αIIb-β3, which is expressed by activated platelets, and activated coagulation factor XIII (FXIIIa), a tissue transglutaminase that crosslinks fibrin and plasmin inhibitors to form stable thrombi. 7 Activated platelets were targeted with SPIO-RGD peptide conjugates in both ex vivo and in vivo thrombus models. 65 It is well established that RGD, a cyclic arginine-glycineaspartic acid peptide, specifically targets the αIIb-β3 integrin.…”

Genetic and Environmental Determinants of Fibrin Structure and Function

“…There are 4 glutamine residues potentially involved, and at least 15 lysine residues have been identified. 8 This number of potential cross-linking sites allows for a highly complex and intricate network to be formed between neighboring ␣C domains in the fibrin clot. These ␣ cross-links provide stability to the fibrin clot, 9,10 and they seem to form a protective barrier preventing plasmin-degrading fibrin.…”

“…Clinically, possession of the FXIIILeu34 allele has been found to be lower in some (but not all) studies of patients with MI and cerebral infarction. 8 Bearing in mind that fibrinogen concentrations are often increased in cardiovascular disease, it is possible that environmental factors alter fibrinogen concentrations and consequently the structure of the clot formed in the presence of the Leu34 allele to give a protective effect.…”

“…Changes fibrin structure/function 65 Macrovascular disease 50,67 Factor XIIIA Val34Leu Changes FXIII activation rate and fibrin structure/function 29,65,71,72 MI, Deep vein thrombosis (DVT) 8 Factor XIIIB His95Arg Unknown MI 73…”

Controlled assembly of peptide-functionalized gold nanoparticles for label-free detection of blood coagulation Factor XIII activity

“…[1][2][3] It belongs to the family of transglutaminases, and upon activation by thrombin and Ca 2+ catalyzes the formation of highly-organized intermolecular crosslinks between glutamine and lysine residues on fibrin molecules, forming stable blood clots that prevent excessive bleeding from damaged blood vessels. Pathological Factor XIII deficiency is associated with severe life-threatening bleeding, impaired wound healing, intracranial hemorrhage, recurrent pregnancy losses, and cardiovascular and gastrointestinal disorders.…”