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PubMed1984

Differential binding of plasminogen to crosslinked and noncrosslinked fibrins: its significance in hemostatic defect in factor XIII deficiency.

In spontaneous fibrinolysis of an alpha 2-plasmin inhibitor-deficient plasma clot or tissue-type plasminogen activator-induced fibrinolysis in a purified system without alpha 2-plasmin inhibitor, the lysis was faster when factor XIII-mediated crosslinking of fibrin to fibrin did not occur. During the initial period, the binding of plasminogen to fibrin steadily increased with incubation time. The initial level and subsequent increase of the binding, which may be critical for the subsequent development of fibrinolysis, were more remarkable when fibrin was not crosslinked. The amount of glu- or lys-plasminogen bound to noncrosslinked fibrin was around 4 or 1.5 times larger than the amount of the respective plasminogen bound to crosslinked fibrin. Plasmin was also found to be bound to noncrosslinked fibrin twice as much as the amount bound to crosslinked fibrin. Structural changes induced by crosslinking of fibrin alpha-chain may reduce either the affinity or the number of available complementary sites to lysine binding sites of plasmin(ogen), thereby decreasing the binding of plasmin(ogen) to fibrin. These results suggest that an increased affinity of noncrosslinked fibrin for plasmin(ogen) is contributory to the accelerated fibrinolysis observed in factor XIII deficiency, in addition to an absence of crosslinking of alpha 2-plasmin inhibitor to fibrin.

Enzyme Activation↗

PubMed1989

Congenital factor XIII deficiency with multiple benign breast tumours and successful pregnancy with substitutive therapy. A case report.

A 34-year-old woman with congenital factor XIII (FXIII) deficiency and multiple connective tissue tumours is reported. The subunit a of FXIII was totally absent in her plasma, platelets and histiocytes of breast fibroadenomas and considerably reduced in the monocytes (below 5%). The plasmatic level of subunit b was also reduced (25%). She had a bleeding tendency and habitual abortions. Fresh frozen plasma therapy permitted a successful pregnancy.

Adult↗

PubMed2003

Aspirin alters the cardioprotective effects of the factor XIII Val34Leu polymorphism.

BACKGROUND: The mechanism underlying decreased risk for myocardial infarction in carriers of the Leu34 polymorphism of the factor (F) XIII A-subunit is unclear. Given that acetylation of fibrinogen by aspirin can alter its clotting properties and the presence of fibrin stimulates thrombin-mediated activation of FXIII, we have tested the hypothesis that treatment with aspirin differentially modulates the influence of the FXIII Val34Leu polymorphism on its activation in vivo. METHODS AND RESULTS: The rates of the disappearance of FXIIIA chain and the appearance of its activated form (FXIIIAa) in sequential 30-second blood samples collected at the site of microvascular injury were compared in 14 healthy carriers of the Leu34 allele and 23 Val34 homozygotes both before and after a 7-day aspirin ingestion (75 mg/d), with the use of quantitative Western blotting. The presence of the Leu34 allele was associated with a significant increase in the maximum rate of FXIII activation by thrombin. Although the Leu34-positive and -negative subjects were similar with respect to aspirin-related impairment of thrombin generation, aspirin led to a more pronounced inhibition of the activation of FXIII in the Leu34 carriers as compared with the Val34 homozygotes. CONCLUSIONS: Inhibition of FXIII activation by aspirin is enhanced in the Leu34 carriers in vivo, suggesting that these subjects might benefit more than the Leu34-negative subjects from the reduction in risk for myocardial infarction with low-dose aspirin.

Adult↗

PubMed1995

Molecular and cellular basis of deficiency of the b subunit for factor XIII secondary to a Cys430-Phe mutation in the seventh Sushi domain.

We studied the defect responsible for deficiency of the b subunit for factor XIII in the first known case of this condition. The patient is a compound heterozygote of two genetic defects: deletion of A-4161 at the acceptor splice junction of intron A, resulting in a loss of the obligatory AG splicing sequence; and, replacement of G-11499 by T in exon VIII, resulting in an amino acid substitution of Cys430 by Phe. To determine how the latter mutation impaired b subunit synthesis, recombinant b subunit bearing the mutation was expressed in BHK cells. The mutant as well as wild-type b subunit was synthesized by the cells. However, the apparent molecular weight of the mutant was slightly higher than those of the wild-type and plasma b subunits under nonreducing conditions, probably because of destruction of a disulfide bond. The mutant b subunit was secreted from the cells much less effectively than the wild type and remained susceptible to endoglycosidase H, indicating that it was not transported from the endoplasmic reticulum to the Golgi apparatus where the processing of oligosaccharides occurs. Immunofluorescence study suggested that the mutant protein was retained in the endoplasmic reticulum. These studies demonstrate that a Cys430-Phe mutation does not prevent the de novo synthesis of the b subunit, but alters the conformation of the mutant protein sufficiently to impair its intracellular transport, resulting in its deficiency in this patient.

Animals↗

PubMed1989

Spontaneous intracerebral hematoma in a adolescent with factor XIII deficiency. Case report.

A case of a spontaneous cerebral hematoma in the left capsulo-nuclear area in an adolescent girl with congenital deficiency of coagulation Factor XIII is described.

Adolescent↗

PubMed1996

Immunohistochemical detection of factor XIIIa and factor XIIIs in synovial membranes of patients with rheumatoid arthritis or osteoarthritis.

In spite of differences in etiology, RA and OA lead to astonishingly similar synovitic alterations. Fibroblastic transformation of the synovial membrane and an increase in monocytes constitute a rare but highly characteristic feature of RA. Monocytes synthesize factor (F) XIII, implying that FXIII (a and s) in synovial tissue might help to differentiate between RA and OA. Biopsies were obtained at open surgery from 98 unselected patients with the clinical diagnosis of RA (n = 54) or OA (n = 44). In a three-stage (ABC) immunoperoxidase technique, polyclonal antisera against factor XIIIa and factor XIIIs were investigated. Compared to OA sections. RA synovium showed more FXIIIa-positive cells-monocytes, fibrocytes, fibroblasts and synovial lining cells. In the subsynovial layer, band-like structure of FXIIIa-stained cells was observed in 27.8% of the RA patients, but in only one OA specimen. Higher proportions of FXIIIa-positive monocytes, macrophages, histiocytes and fibroblasts, as well as positive Langhans giant cells and vascular wall regions (except endothelial cells), were observed in RA. OA specimens revealed more intense FXIIIa labeling of these cells with a lower percentage of stained cells. Overall, labeling with FXIIIs antibody resulted in less intense staining. In conclusion, distinction between synovitis caused by RA and synovitis due to OA is possible, as the former show higher numbers of FXIIIa-positive cells, including monocytes, fibroblasts, fibrocytes and synovial lining cells. Further more, RA tissue is stained less intensely than OA tissue. There is evidence for continuous excretion of FXIII in the synovial membrane by the above-mentioned cell systems.

Adolescent↗

PubMed2000

Cross-linking of wild-type and mutant alpha 2-antiplasmins to fibrin by activated factor XIII and by a tissue transglutaminase.

Human alpha(2)-antiplasmin (alpha(2)AP), the main inhibitor of plasmin-mediated fibrinolysis, is a substrate for plasma transglutaminase, also termed activated factor XIII (FXIIIa). Of 452 amino acids in alpha(2)AP, only Gln(2) is believed to be a fibrin-cross-linking (or FXIIIa-reactive) site. Kinetic efficiencies (k(cat)/K(m)((app))) of FXIIIa and the guinea pig liver tissue transglutaminase (tTG) and reactivities of Gln substrate sites were compared for recombinant wild-type alpha(2)AP (WT-alpha(2)AP) and Q2A mutant alpha(2)AP (Q2A-alpha(2)AP). [(14)C]Methylamine incorporation showed the k(cat)/K(m)((app)) of FXIIIa to be 3-fold greater than that of tTG for WT-alpha(2)AP. With FXIIIa or tTG catalysis, [(14)C]methylamine was incorporated into Q2A-alpha(2)AP, indicating that WT-alpha(2)AP has more than one Gln cross-linking site. To identify transglutaminase-reactive sites in WT-alpha(2)AP or Q2A-alpha(2)AP, each was labeled with 5-(biotinamido)pentylamine by FXIIIa or tTG catalysis. After each labeled alpha(2)AP was digested by trypsin, sequence and mass analyses of each labeled peptide showed that 4 of 35 Gln residues were labeled with the following reactivities: Gln(2) > Gln(21) > Gln(419) > Gln(447). Q(2)A-alpha(2)AP was also labeled at Gln(21) > Gln(419) > Gln(447), but became cross-linked to fibrin by FXIIIa or tTG at approximately one-tenth the rate for WT-alpha(2)AP. These results show that alpha(2)AP is a better substrate for FXIIIa than for this particular tTG, but that either enzyme involves the same Gln substrate sites in alpha(2)AP and yields the same order of reactivities.

Base Sequence↗

PubMed1994

Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII.

Mechanical stability in many biological materials is provided by the crosslinking of large structural proteins with gamma-glutamyl-epsilon-lysyl amide bonds. The three-dimensional structure of human recombinant factor XIII (EC 2.3.2.13 zymogen; protein-glutamine:amine gamma-glutamyltransferase a chain), a transglutaminase zymogen, has been solved at 2.8-A resolution by x-ray crystallography. This structure shows that each chain of the homodimeric protein is folded into four sequential domains. A catalytic triad reminiscent of that observed in cysteine proteases has been identified in the core domain. The amino-terminal activation peptide of each subunit crosses the dimer interface and partially occludes the opening of the catalytic cavity in the second subunit, preventing substrate binding to the zymogen. A proposal for the mechanism of activation by thrombin and calcium is made that details the structural events leading to active factor XIIIa'.

Catalysis↗

PubMed2005

A novel polymorphism in the factor XIII B-subunit (His95Arg): relationship to subunit dissociation and venous thrombosis.

BACKGROUND: Factor (F)XIII B-subunit, which plays a carrier role for zymogen FXIIIA, is highly polymorphic, but the molecular basis for these polymorphisms and their relationship to disease remains unknown. OBJECTIVES: To screen the FXIIIB gene coding region for common variation and analyze possible functional effects. METHODS AND RESULTS: We examined the FXIIIB gene by PCR-SSCP and identified three common single nucleotide polymorphisms: A8259G, C29470T and A30899G. A8259G results in substitution of His95Arg in the second Sushi domain. An FXIII tetramer ELISA was developed to analyze B-subunit dissociation from A-subunit (leading to access to the catalytic site of FXIII). Increased subunit dissociation, 0.51 vs. 0.45 (fraction of total tetramer), was found in plasma from subjects possessing the Arg-allele. However, when the variants were purified to homogeneity and binding was analyzed by steady-state kinetics, no difference was observed. The relationship between His95Arg and venous thrombosis was investigated in 214 patients and 291 controls from Leeds. His/Arg + Arg/Arg genotypes were more frequent in patients than controls (22.4% vs. 15.1%). His95Arg was also investigated in the Leiden Thrombophilia Study, in which a similar difference was observed for 471 patients vs. 472 controls (18.5% vs. 14.0%), for a pooled odds ratio (OR) of 1.5 (CI95 1.1-2.0). CONCLUSIONS: We have identified three FXIIIB polymorphisms, one of which codes for substitution of His95Arg. The Arg95 variant associates with a moderately increased risk for venous thrombosis, and with increased dissociation of the FXIII subunits in plasma, although in vitro steady-state binding between purified subunits was not affected.

Binding Sites↗

PubMed1994

Carboxyl-terminal truncation of recombinant factor XIII A-chains. Characterization of minimum structural requirement for transglutaminase activity.

A series of truncation mutants lacking 218, 229, 250, and 269 amino acid residues from the carboxyl terminus of blood coagulation factor XIII A-chains (FXIII A), designated as delta K513, delta A502, delta Y481, and delta K462, respectively, were expressed in Escherichia coli to define the minimum structure required for transglutaminase activity. delta K513 and delta A502 displayed a 3.8-4.7-fold reduction in the Kcat with no change in the Km for the glutamine substrate and a 2-fold increase in the Km of the primary amine substrate. There was no detectable transglutaminase activity for either thrombin-activated delta Y481 or delta K462. The rate of ammonia release of thrombin-activated delta K513 and delta A502 was reduced 6- and 4-fold, respectively, whereas ammonia release was not detected for the delta Y481 and delta 462 mutants. The Kact for calcium ions of the delta K513 mutant was similar to recombinant FXIIIa, whereas, it was increased by approximately 3-fold for the delta A502 mutant. The rate of fibrin gamma-chain dimer formation for the delta K513 and delta A502 mutants was reduced by approximately 19-fold. delta K462 did not bind to fibrin, while all of the other thrombin-cleaved mutants were bound. In conclusion, these results documented that the carboxyl-terminal calcium binding domain (Asp468-Glu495) was important for FXIIIa to adopt the correct conformation to ensure that efficient catalysis occurred.

Base Sequence↗

PubMed2000

Catalytic life of activated factor XIII in thrombi. Implications for fibrinolytic resistance and thrombus aging.

BACKGROUND: Because the increased fibrinolytic resistance of older thrombi may be caused by the continuous cross-linking action of fibrin-bound activated factor XIII (FXIIIa), we examined the persistence of FXIIIa catalytic activity in clots of various ages. METHODS AND RESULTS: The time-related changes in FXIIIa activity in clots was measured with (1) alpha(2)-antiplasmin (alpha(2)AP), a physiological glutamine substrate; (2) alpha(2)AP(13-24), a peptide; and (3) pentylamine, a nonspecific lysine substrate. The cross-linking of alpha(2)AP, alpha(2)AP(13-24), and pentylamine into fibrin by clot-bound FXIIIa declined rapidly with half-lives of 19, 21, and 26 minutes, respectively. Mutational studies showed that glutamine 14 (but not glutamine 3 or 16) and valine 17 of alpha(2)AP(13-24) were required for efficient cross-linking to fibrin. The loss of activity was not due primarily to FXIIIa proteolysis and was partially restored by reducing agents, suggesting that oxidation contributes to the loss of the enzyme's activity in clots. In vivo, the ability of thrombus-bound FXIIIa to cross-link an infused alpha(2)AP(13-24) peptide into existing pulmonary emboli also declined significantly over time. CONCLUSIONS: FXIIIa cross-links alpha(2)AP and an alpha(2)AP peptide, in a sequence-specific manner, into formed clots with a catalytic half-life of approximately 20 minutes. This indicates that FXIIIa activity is a hallmark of new thrombi and that the antifibrinolytic cross-linking effects of FXIIIa are achieved more rapidly in thrombi than previously believed.

Aging↗

PubMed1987