Inhibitors of blood coagulation factor XIII

Schmitz, Thomas; Bäuml, Charlotte A.; Imhof, Diana

doi:10.1016/j.ab.2020.113708

Cited by 19 publications

(19 citation statements)

References 134 publications

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“…Until we have a complete understanding of the mechanism involved it may be difficult to predict which common anti-coagulant therapy, if any, is most appropriate. Given the apparent role of FXIII and VWF in the defective coagulation, experimental therapies targeting these factors such as the FXIII inhibitor tridegin 45 and rADAMTS13 46, 47 , are potentially worth pursuing. The apparent fibrinolytic resistance in COVID-19 patients may also impact on the efficacy of rt-PA thrombolysis to treat hyperacute ischaemic stroke or massive pulmonary embolism complicating SARS-CoV-2 infection and, again, experimental avenues might need to be explored to overcome this.…”

Section: Discussionmentioning

confidence: 99%

Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy

Circo

2020

Preprint

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Background: Early clinical reports have suggested that the prevalence of thrombotic complications in the pathogenesis of COVID-19 may be as high as 30% in intensive care unit (ICU)-admitted patients and could be a major factor contributing to mortality. However, mechanisms underlying COVID-19-associated thrombo-coagulopathy, and its impact on patient morbidity and mortality, are still poorly understood. Methods: We performed a comprehensive analysis of coagulation and thromboinflammatory factors in plasma from COVID-19 patients with varying degrees of disease severity. Furthermore, we assessed the functional impact of these factors on clot formation and clot lysis. Results: Across all COVID-19 disease severities (mild, moderate and severe) we observed a significant increase (6-fold) in the concentration of ultra-large von Willebrand factor (UL-VWF) multimers compared to healthy controls. This is likely the result of an interleukin (IL)-6 driven imbalance of VWF and the regulatory protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Upregulation of this key pro-coagulant pathway may also be influenced by the observed increase (~6-fold) in plasma α-defensins, a consequence of increased numbers of neutrophils and neutrophil activation. Markers of endothelial, platelet and leukocyte activation were accompanied by increased plasma concentrations of Factor XIII (FXIII) and plasminogen activator inhibitor (PAI)-1. In patients with high FXIII we observed alteration of the fibrin network structure in in vitro assays of clot formation, which coupled with increased PAI-1, prolonged the time to clot lysis by the t-PA/plasmin fibrinolytic pathway by 52% across all COVID-19 patients (n=23). Conclusions: We show that an imbalance in the VWF/ADAMTS13 axis causing increased VWF reactivity may contribute to the formation of platelet-rich thrombi in the pulmonary vasculature of COVID-19 patients. Through immune and inflammatory responses, COVID-19 also alters the balance of factors involved in fibrin generation and fibrinolysis which accounts for the persistent fibrin deposition previously observed in post-mortem lung tissue.

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Section: Discussionmentioning

confidence: 99%

Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy

Circo

2020

Preprint

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“…Notably, the coagulation factor XIII in human blood is also a kind of TGase. With the enzyme, fibrin stabilizing molecules were formed by the cross-linking reaction between fibrin molecules, leading to blood coagulation ( Schmitz et al, 2020 ). Therefore, TGase has a unique effect in catalyzing cross-linking of protein molecules.…”

Section: Transglutaminase-catalytic Process and Gel Formation Mechanismmentioning

confidence: 99%

Transglutaminase-Catalyzed Bottom-Up Synthesis of Polymer Hydrogel

Lai

Bao

Zhu

et al. 2022

Front. Bioeng. Biotechnol.

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Enzyme catalysis has attracted increasing attention for application in the synthesis of polymer hydrogel due to the eco-friendly process and the devisable catalytic reaction. Moreover, bottom-up approaches combining enzyme catalysts and molecular self-assembly have been explored for synthesizing hydrogel with complex architectures. An enzyme widely distributed in nature, transglutaminase (TGase) has been confirmed to catalyze the formation of isopeptide bonds between proteins, which can effectively improve the gelation of proteins. In this mini-review, TGase-catalyzed synthesis of polymer hydrogels, including fibrin hydrogels, polyethylene glycol hydrogels, soy protein hydrogels, collagen hydrogels, gelatin hydrogels and hyaluronan hydrogels, has been reviewed in detail. The catalytic process and gel formation mechanism by TGase have also been considered. Furthermore, future perspectives and challenges in the preparation of polymer hydrogels by TGase are also highlighted.

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“…Besides MAb 309, the antibodies MAb 9C11 and MAb 10G10 were also found to affect the thrombin-mediated FXIII activation pathway [17]. Although these antibodies block FXIII activation through blockade of the thrombin binding site or induce conformational changes in FXIII molecular structure which leads to the inhibition of FXIII activation, due to the competitive mechanism of binding kinetics, an excess amount of thrombin causes a displacement of the antibodies, which limits the usage of this kind of antibodies for pharmacological purposes [18]. The inhibition of fibrin crosslinking via amine-containing competitive inhibitors which act as alternative substrates for the FXIIIa-catalyzed reaction is another approach to address FXIII activity [19].…”

Section: Introductionmentioning

confidence: 99%

Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII

Hamedani

Biswas

Rudan

et al. 2021

JCM

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Coagulation factor XIII (FXIII) is a protransglutaminase which plays an important role in clot stabilization and composition by cross-linking the α- and γ-chains of fibrin and increasing the resistance of the clot to mechanical and proteolytic challenges. In this study, we selected six DNA aptamers specific for activated FXIII (FXIIIa) and investigated the functional characterization of FXIIIa after aptamer binding. One of these aptamers, named FA12, efficiently captures FXIIIa even in the presence of zymogenic FXIII subunits. Furthermore, this aptamer inhibits the incorporation of FXIII and α2-antiplasmin (α2AP) into fibrin(ogen) with IC50-values of 38 nM and 17 nM, respectively. In addition to FA12, also another aptamer, FA2, demonstrated significant effects in plasma-based thromboelastometry (rotational thromboelastometry analysis, ROTEM)-analysis where spiking of the aptamers into plasma decreased clot stiffness and elasticity (p < 0.0001). The structure–function correlations determined by combining modeling/docking strategies with quantitative in vitro assays revealed spatial overlap of the FA12 binding site with the binding sites of two FXIII substrates, fibrinogen and α2AP, while FA2 binding sites only overlap those of fibrinogen. Taken together, these features especially render the aptamer FA12 as an interesting candidate molecule for the development of FXIIIa-targeting therapeutic strategies and diagnostic assays.

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Inhibitors of blood coagulation factor XIII

Cited by 19 publications

References 134 publications

Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy

Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy

Transglutaminase-Catalyzed Bottom-Up Synthesis of Polymer Hydrogel

Functional and Structural Characterization of Nucleic Acid Ligands That Bind to Activated Coagulation Factor XIII

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