Characterization of the fibrin polymer structure that accelerates thrombin cleavage of plasma factor XIII

Greenberg, Charles S.; Achyuthan, Komandoor E.; Rajagopalan, Shrin; Pizzo, Salvatore V.

doi:10.1016/0003-9861(88)90176-2

Cited by 30 publications

(15 citation statements)

References 33 publications

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“…The activation of pFXIII is enhanced by polymerizing fibrin approximately one hundredfold [68,[79][80][81][82]. The binding to fibrin makes the orientation of both pFXIII and thrombin favorable for the proteolysis of FXIII-A at Arg37-Gly38 and accelerates the thrombin-induced cleavage of FXIII-A [80,83]. FXIII-B is required for this effect; in the case of cFXIII the presence of fibrin does not promote the removal of AP-FXIII [83,84].…”

Section: Tvnmentioning

confidence: 99%

Factor XIII: novel structural and functional aspects

Komáromi

Bagoly

Muszbek

2011

Journal of Thrombosis and Haemostasis

161

157

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Summary. Factor (F)XIII is a protransglutaminase that, in addition to maintaining hemostasis, has multiple plasmatic and intracellular functions. Its plasmatic form (pFXIII) is a tetramer of two potentially active A (FXIII-A) and two inhibitory/carrier B (FXIII-B) subunits, whereas its cellular form (cFXIII) is a dimer of FXIII-A. FXIII-A belongs to the family of transglutaminases (TGs), which show modest similarity in the primary structure, but a high degree of conservatism in their domain and sub-domain secondary structure. FXIII-A consists of an activation peptide, a bsandwich, a catalytic and two b-barrel domains. FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds. The structural elements of FXIII-A involved in the interaction with FXIII-B have not been elucidated; in FXIII-B the first sushi domain seems important for complex formation. In the circulation pFXIII is bound to the fibrinogen cÕ-chain through its B subunit. In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca 2+ FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen). cFXIII does not require proteolysis for intracellular activation. The three-dimensional structure of FXIIIa has not been resolved. Based on analogies with transglutaminase-2, a three-dimensional structure of FXIIIa was developed by molecular modeling, which shows good agreement with the drastic structural changes demonstrated by biochemical studies. The structural requirements for enzyme-substrate interaction and for transglutaminase activity are also reviewed.

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Section: Tvnmentioning

confidence: 99%

Factor XIII: novel structural and functional aspects

Komáromi

Bagoly

Muszbek

2011

Journal of Thrombosis and Haemostasis

161

157

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“…11,12 Polymeric fibrin acts as cofactor in thrombininduced activation of factor XIII. 13 The cleaved activation peptide does not dissociate from the parent molecule factor XIII, 14 but cleavage induces conformational changes that increase the catalytic activity. 15 Factor XIIIa introduces two reciprocal covalent bonds between the C-terminal g-chains of adjacent fibrin monomer units within the fibrin polymer.…”

Section: Fibrin Formation and Fibrin Dissolutionmentioning

confidence: 99%

Validation, Calibration, and Specificity of Quantitative D-Dimer Assays

Dempfle

2005

Seminars in Vascular Medicine

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Assays for D-dimer antigen are based on monoclonal antibodies reactive with epitopes found on fibrin fragment D-dimer but not on fibrinogen fragment D, other fibrinogen degradation products, or native fibrinogen. The antibodies react with conformational epitopes generated by factor XIII-induced linkage of the C-terminal appendages of the fibrin gamma-chains of adjacent D-domains within a fibrin polymer. For some monoclonal antibodies, degradation of the cross-linked fibrin compound by plasmin is an additional requirement for the generation of the epitope. In clinical plasma samples, D-dimer antigen assays detect an array of fibrin compounds of different molecular weights, including fibrin fragment D-dimer as well as higher-molecular-weight fibrin degradation products and fibrin X-oligomers. Most D-dimer antigen represents cross-linked soluble fibrin present in circulation rather than degradation products from particulate clots. Due to differences in epitope reactivity, harmonization of D-dimer antigen assays can only be achieved with standard preparations containing a similar variety of cross-linked fibrin compounds. Assay technologies include manual latex agglutination assays, automated latex-enhanced light-scattering immunoassays, enzyme-linked immunoassays, and others.

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“…After release of fibrinopeptides A from the parent fibrinogen molecule by thrombin or other thrombin-like proteases, the resulting fibrin monomers rapidly polymerize, forming fibrin complexes. These complexes serve as cofactors in thrombininduced factor XIII activation (2), as well as in tPA-induced plasminogen activation (3,4), making non-crosslinked and nonproteolyzed fibrin complexes a very transient species in vivo (5). Unlike D-dimer antigen assays, which react with a variety of different fibrin compounds containing covalently dimerized D-domains, including high molecular weight fibrin complexes Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score Carl-Erik Dempfle 1…”

Section: Introductionmentioning

confidence: 99%

Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score

Dempfle¹,

Wurst²,

Smolinski³

et al. 2004

Thromb Haemost

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The overt DIC score of the DIC subcommittee of the ISTH includes a fibrin-related marker (FRM) as indicator of intravascular fibrin formation. The type of marker to be used has not been specified, but D-dimer antigen, or fibrin degradation products are used by most investigators. Soluble fibrin complexes have been suggested as more specific indicators of acute intravascular fibrin formation. The aim of the present study was to compare the predictive value of the overt DIC score concerning clinical outcome in a surgical intensive care cohort, using either D-dimer antigen, or soluble fibrin antigen as FRM. The cutoff values for 2 and 3 score points for the FRM were assigned on the basis of the 25% and 75% quartiles of 1870 plasma samples obtained from 359 ICU patients during a period of 6 months. For 331 patients with complete diagnostic workup and day 1 blood samples, the Iatro SF as FRM component of the overt DIC score displayed the highest prognostic power concerning clinical outcome. The 28-day mortality of patients with overt DIC at day 1, using Iatro SF as FRM assay was 50.0%, whereas 28-day mortality of patients without overt DIC was 14.0% (p <0.0001). Using MDA D-dimer, and TINAquant D-dimer, 28-day mortality was between 35.5% and 39.3% in patients with overt DIC, and 15.5% to 15.6% in patients without overt DIC. Selection of the FRM as component of the DIC score has a small, but relevant impact on the prognostic performance of the overt DIC score. The present data on the distribution of values may provide a basis for the selection of appropriate cutoff points for assigning 2, and 3 points in the score.

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Characterization of the fibrin polymer structure that accelerates thrombin cleavage of plasma factor XIII

Cited by 30 publications

References 33 publications

Factor XIII: novel structural and functional aspects

Factor XIII: novel structural and functional aspects

Validation, Calibration, and Specificity of Quantitative D-Dimer Assays

Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score

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