Coming full circle with factor XIII

Lord, Susan T.

doi:10.1182/blood-2011-02-332627

Cited by 3 publications

(3 citation statements)

References 9 publications

(6 reference statements)

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“…Similarly, ultracentrifugation experiments with gA/g9 fibrinogen 9 may have been confounded by the presence of gel-like fibrin(ogen) dimers. 34,35 Thus, these conditions may have led to the conclusion that the zymogenbinding motif is contained within the g9 extension. More recent findings that FXIII-A 2 B 2 binds to a peptide derived from the fibrinogen aC domain (residues a371-425) suggested FXIII-A 2 B 2 binds to the fibrinogen aC region.…”

Section: Discussionmentioning

confidence: 99%

The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits

Byrnes

Wilson

Boutelle

et al. 2016

Blood

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Coagulation transglutaminase factor XIII (FXIII) exists in circulation as heterotetrameric proenzyme FXIII-AB Effectively all FXIII-AB circulates bound to fibrinogen, and excess FXIII-B circulates in plasma. The motifs that mediate interaction of FXIII-AB with fibrinogen have been elusive. We recently detected reduced binding of FXIII-AB to murine fibrinogen that has γ-chain residues 390-396 mutated to alanines (Fibγ). Here, we evaluated binding features using human components, including recombinant fibrinogen variants, FXIII-AB, and isolated FXIII-A and -B homodimers. FXIII-AB coprecipitated with wild-type (γA/γA), alternatively-spliced (γ'/γ'), and αC-truncated (Aα251) fibrinogens, whereas coprecipitation with human Fibγ was reduced by 75% (P <0001). Surface plasmon resonance showed γA/γA, γ'/γ', and Aα251 fibrinogens bound FXIII-AB with high affinity (nanomolar); however, Fibγ did not bind FXIII-AB These data indicate fibrinogen residues γ390-396 comprise the major binding motif for FXIII-AB Compared with γA/γA clots, FXIII-AB activation peptide release was 2.7-fold slower in Fibγ clots (P < .02). Conversely, activation of recombinant FXIII-A (lacking FXIII-B) was similar in γA/γA and Fibγ clots, suggesting fibrinogen residues γ390-396 accelerate FXIII-AB activation in a FXIII-B-dependent mechanism. Recombinant FXIII-B bound γA/γA, γ'/γ', and Aα251 with similar affinities as FXIII-AB, but did not bind or coprecipitate with Fibγ FXIII-B also coprecipitated with fibrinogen from FXIII-A-deficient mouse and human plasmas. Collectively, these data indicate that FXIII-AB binds fibrinogen residues γ390-396 via the B subunits, and that excess plasma FXIII-B is not free, but rather circulates bound to fibrinogen. These findings provide insight into assembly of the fibrinogen/FXIII-AB complex in both physiologic and therapeutic situations.

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Section: Discussionmentioning

confidence: 99%

The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits

Byrnes

Wilson

Boutelle

et al. 2016

Blood

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“…Albeit that Yang et al [54] and Gielen et al [55] demonstrated the presence of a perpetual relationship between postoperative plasma fibrinogen level and the postoperative rate of bleeding, infusion of fibrinogen concentrate or cryoprecipitate did not reduce bleeding in these studies. As FXIII circulates in complex with fibrinogen (parts of it with high-affinity binding [56]) one might speculate that decreased fibrinogen concentrations are also a marker for a parallel decrease in FXIII. Our results, however, strongly suggest that this is not the case, at least not in the postoperative setting.…”

Section: Discussionmentioning

confidence: 99%

Factor XIII Deficiency and Thrombocytopenia Are Frequent Modulators of Postoperative Clot Firmness in a Surgical Intensive Care Unit

Rappard¹,

Hinnen²,

Lussmann³

et al. 2017

Transfus Med Hemother

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Objective: Fibrinogen and factor XIII (FXIII) have been shown to critically influence clot firmness in the intraoperative setting and thus likely influence intraoperative bleeding. We were interested to identify potential modulators of postoperative clot firmness in a tertiary care hospital surgical intensive care unit setting, independent of their clinical course during surgery. Methods: 272 day-shift consecutive patients were evaluated for whole blood clot firmness evaluated by the ROTEM® EXTEM thrombelastometric assay and various potential modulators of clot firmness upon arrival at the surgical intensive care unit (SICU). Results: Maximum clot firmness on the SICU was found to be independently influenced by the amount of colloids given during surgery as well as by platelet count, fibrinogen concentration, and FXIII activity at the time of SICU admission. In patients with lowest clot firmness, FXIII activity was the most important independent modulator of clot firmness; in patients with the highest clot firmness, platelet count and fibrinogen concentration were the most important modulators of clot firmness. Deficiencies (i.e., results below normal range) of these modulators of clot firmness were most prevalent for FXIII (activity < 70%: 45% of cases), which was significantly more frequent than thrombocytopenia (<150 × 10⁹/l: 32%) or fibrinogen deficiency (<1.5 g/l: 6%). Conclusions: Postoperative clot firmness as evaluated by whole blood thrombelastometry (ROTEM EXTEM assay) is independently and frequently modulated though FXIII activity and the platelet count, while fibrinogen concentration is also an independent but much less frequent modulator. Different modulators show different influences, depending on the clot firmness being present. Colloids infused during surgery also independently modulate postoperative clot firmness. Based on our data, strategies can be developed to improving postoperative care of patients with bleedings or at risk for bleeding.

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“…Both the γ′‐splice form of the fibrinogen γ‐chain and the αC‐chain of fibrinogen have been suggested to contain the binding site . This topic has recently been reviewed in detail .…”

Section: Fxiiimentioning

confidence: 99%

Tissue-regenerating functions of coagulation factor XIII

Soendergaard

Kvist

Seidelin

et al. 2013

Journal of Thrombosis and Haemostasis

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To cite this article: Soendergaard C, Kvist PH, Seidelin JB, Nielsen OH. Tissue-regenerating functions of coagulation factor XIII. J Thromb Haemost 2013; 11: 806-16. Summary. The protransglutaminase factor XIII (FXIII) has recently attracted attention within the field of tissue regeneration, as it has been found that FXIII significantly influences wound healing by exerting a multitude of functions. It supports hemostasis by enhancing platelet adhesion to damaged endothelium, and by its cross-linking activity it stabilizes the formed fibrin clot. Furthermore, FXIII limits bacterial dissemination from the wound and incorporates macromolecules of importance for cellular infiltration, supporting cell migration and survival. FXIIImediated complex formation of the vascular endothelial growth factor receptor 2 and a V b 3 integrin is important for angiogenesis, supporting the formation of granulation tissue. Chronic inflammatory conditions involving bleeding and activation of the coagulation cascade have been shown to lead to reduced FXIII levels in plasma. Of particular importance for this review is the fact that patients suffering from inflammatory bowel disease (IBD) have reduced FXIII antigen levels and activity. Furthermore, these patients show impaired mucosal healing, which supports the inflammatory state of the disease. This review summarizes the role of FXIII in the healing of wounds, and briefly summarizes the previous use of FXIII in clinical settings. Moreover, it addresses the potential role for FXIII as a therapeutic agent in the healing of persistent wounds during chronic conditions, with an emphasis on IBD.

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Coming full circle with factor XIII

Cited by 3 publications

References 9 publications

The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits

The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits

Factor XIII Deficiency and Thrombocytopenia Are Frequent Modulators of Postoperative Clot Firmness in a Surgical Intensive Care Unit

Tissue-regenerating functions of coagulation factor XIII

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