Newly-Recognized Roles of Factor XIII in Thrombosis

Byrnes, James R.; Wolberg, Alisa S.

doi:10.1055/s-0036-1571343

Cited by 70 publications

(72 citation statements)

References 109 publications

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“…37 Moreover, in vivo studies with factor XIII-deficient mice suggested that this mechanism can modulate thrombus size via cross-linking of fibrin's α-chains. 38,39 Collectively, these findings suggest that platelet-driven, fibrin-mediated clot contraction can play an important role in preventing blood loss, reducing the volume of the clot, and restoring blood flow past otherwise obstructive thrombi. 7,40 Dysfibrinogenemias Dysfibrinogenemia is a collective name for qualitative defects of fibrinogen that affect its functionality, almost invariably the ability to form fibrin clots, as this is usually the mode of discovery, and they can have thrombotic or bleeding consequences or be asymptomatic.…”

Section: Blood Clot Contractionmentioning

confidence: 94%

What Is the Biological and Clinical Relevance of Fibrin?

Litvinov

Weisel

2016

Semin Thromb Hemost

107

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As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery.

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Section: Blood Clot Contractionmentioning

confidence: 94%

What Is the Biological and Clinical Relevance of Fibrin?

Litvinov

Weisel

2016

Semin Thromb Hemost

107

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“…8 Findings on the role of this polymorphism in thrombosis risk have been inconsistent; however, both independent studies and meta-analyses suggest the 34Leu variant offers modest but significant protection against venous thrombosis. [9][10][11][12][13][14] Discovery that the effects of the Val34Leu polymorphism are mediated by gene-environment interactions between FXIII-A genotype and plasma fibrinogen concentration has resolved some of the discord. 15 For example, in the Leiden Thrombophilia Study, although Leu homozygosity showed weak protection against venous thrombosis in men, 16 reanalysis adjusting for fibrinogen concentration strengthened the association for both men and women, especially in individuals older than 45 years.…”

Section: Introductionmentioning

confidence: 99%

The factor XIII‐A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

Kattula

Bagoly

Tóth

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Factor XIII (FXIII) promotes fibrin crosslinking and red blood cell (RBC) retention in clots. The FXIII‐A polymorphism, Val34Leu, is associated with protection against venous thrombosis. This effect is hypothesized to result from fibrinogen concentration‐dependent changes in fibrin structure. Effects of the FXIII‐A Val34Leu polymorphism in whole blood clots have not been investigated. Aim Characterize effects of FXIII‐A Val34Leu polymorphism and fibrinogen on whole blood clots. Methods We isolated platelet‐poor plasmas from human donors (FXIIIVal/Val, FXIIIVal/Leu, FXIIILeu/Leu), reconstituted plasmas with platelets and RBCs, and triggered clotting. We assessed contributions of gender, age, clotting times, thrombin generation, FXIII activity, FXIII‐A Val34Leu polymorphism, and fibrinogen to clot mass. We also reconstituted FXIII‐depleted plasma with platelets, RBCs, and purified FXIIIVal/Val or FXIIILeu/Leu, varied fibrinogen, and characterized effects on clot mass. Results Clot mass was associated with age, fibrinogen, prothrombin time, and thrombin generation. Clots reconstituted with plasmas from individuals with FXIII‐AVal/Val and FXIII‐AVal/Leu did not differ in mass from clots with FXIII‐ALeu/Leu. However, clots containing a 34Val allele demonstrated a fibrinogen concentration‐dependent increase in mass, whereas clots with homozygous 34Leu did not. In plasmas with high fibrinogen, mass was higher for clots with 34Val alleles compared with clots with homozygous 34Leu. In clots reconstituted with purified FXIII, increasing fibrinogen enhanced clot mass in the presence of 34Val, but decreased mass in the presence of 34Leu. Conclusions FXIII 34Leu mitigates the effect of elevated fibrinogen on whole blood clot mass. The Val34Leu polymorphism may protect against venous thrombosis by reducing clot mass.

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“…Fibrin clot structure is dependent upon fibrinogen levels, rates of fibrinopeptide cleavage, and FXIII activity [6, 43–46]. Clot architecture could be further controlled by designing FXIII AP sequences that are easier or more difficult to be cleaved by thrombin [27, 41].…”

Section: Introductionmentioning

confidence: 99%

Screening cleavage of Factor XIII V34X Activation Peptides by thrombin mutants: A strategy for controlling fibrin architecture

Jadhav

Goldsberry

Zink

et al. 2017

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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In blood coagulation, thrombin converts fibrinogen into fibrin monomers that polymerize into a clot network. Thrombin also activates Factor XIII by cleaving the R37-G38 peptide bond of the Activation Peptide (AP) segment. The resultant transglutaminase introduces covalent crosslinks into the fibrin clot. A strategy to modify clot architecture would be to design FXIII AP sequences that are easier or more difficult to be thrombin-cleaved thus controlling initiation of crosslinking. To aid in this design process, FXIII V34X (28–41) activation peptides were kinetically ranked for cleavage by wild-type thrombin and several anticoagulant mutants. Thrombin-catalyzed hydrolysis of aromatic FXIII F34, W34, and Y34 APs was compared with V34 and L34. Cardioprotective FXIII L34 remained the variant most readily cleaved by wild-type thrombin. The potent anticoagulant thrombins W215A and W215A/E217A (missing a key substrate platform for binding fibrinogen) were best able to hydrolyze FXIII F34 and W34 APs. Thrombin I174A and L99A could effectively accommodate FXIII W34 and Y34 APs yielding kinetic parameters comparable to FXIII AP L34 with wild-type thrombin. None of the aromatic FXIII V34X APs could be hydrolyzed by thrombin Y60aA. FXIII F34 and W34 are promising candidates for FXIII – anticoagulant thrombin systems that could permit FXIII-catalyzed crosslinking in the presence of reduced fibrin formation. By contrast, FXIII Y34 with thrombin (Y60aA or W215A/E217A) could help assure that both fibrin clot formation and protein crosslinking are hindered. Regulating the activation of FXIII is predicted to be a strategy for helping to control fibrin clot architecture and its neighboring environments.

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Newly-Recognized Roles of Factor XIII in Thrombosis

Cited by 70 publications

References 109 publications

What Is the Biological and Clinical Relevance of Fibrin?

What Is the Biological and Clinical Relevance of Fibrin?

The factor XIII‐A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

Screening cleavage of Factor XIII V34X Activation Peptides by thrombin mutants: A strategy for controlling fibrin architecture

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