Tissue transglutaminase 2 revealed as an unexpected stabilizer of blood clots

For decades, the final stabilization of a blood clot has been credited to a single enzyme: Factor XIIIa, the plasma transglutaminase that welds fibrin strands into a rigid, resilient mesh. Now a study published in Cell Death Discovery challenges that long-standing exclusivity. Researchers led by Mauro Piacentini of the University of Rome Tor Vergata, Nicola J. Mutch of the University of Aberdeen and Martin Griffin of Aston University, together with colleagues in Italy, China and the United Kingdom, present evidence that transglutaminase 2, or TG2, a ubiquitous enzyme abundantly present in erythrocytes, also contributes to clot stabilization. The finding adds a previously unrecognized player to the hemostatic machinery and could reshape how scientists think about bleeding, thrombosis and the pharmacology of anticoagulation.

The chemistry at the heart of the discovery is well established. During clot formation, fibrin and associated proteins are cross-linked via Nε-(γ-glutamyl)lysine bonds, covalent bridges between glutamine and lysine residues that provide clot rigidity and reduce the rate of fibrinolysis, the enzymatic dismantling of the clot. This cross-linking also incorporates fibrinolytic inhibitors into the clot matrix, further protecting it from premature dissolution. To date, this function has been attributed exclusively to Factor XIIIa, also known as plasma transglutaminase, one of eight transglutaminases identified in mammals. The new report demonstrates that TG2, a second member of the family, contributes to the same stabilizing chemistry in vivo.

The experimental logic behind the claim is straightforward but compelling. The researchers isolated whole thrombi from TG2-deficient mice and from wild-type controls and observed clear differences between the two groups, indicating that the absence of TG2 alters the structural integrity of the clots that form in living animals. In parallel experiments with human thrombi, the team found that clots were more stable in the presence of active TG2 than when TG2 activity was specifically inhibited. That pharmacological loss-of-function result is particularly significant, because it shows that the effect is not merely a developmental compensation in genetically modified mice but a direct, acute dependence on the enzyme’s catalytic activity.

TG2 is no stranger to cell biologists. It is a ubiquitous enzyme, expressed in many tissues and cell types, and it is abundantly present in erythrocytes, the red blood cells that are themselves structural components of any thrombus. Red cells constitute a large fraction of clot volume, and their membranes and cytoskeletal proteins are potential substrates for transglutaminase-mediated cross-linking. The new findings suggest that TG2 released or active within the erythrocyte-rich environment of a thrombus can forge the same Nε-(γ-glutamyl)lysine bonds that Factor XIIIa creates, effectively providing a second, redundant cross-linking engine embedded within the clot itself.

The implications for fibrinolysis deserve particular attention. The resistance of a mature clot to plasmin-mediated degradation depends not only on the rigidity of the fibrin mesh but also on the incorporation of fibrinolytic inhibitors such as alpha-2-antiplasmin into the clot structure. If TG2 contributes to this incorporation, then inhibiting TG2 could, in principle, render clots more susceptible to lysis, a property that might be exploited therapeutically in settings where pathological clot persistence is the problem, such as ischemic stroke or myocardial infarction. Conversely, situations in which excessive clot fragility or premature fibrinolysis causes bleeding might benefit from strategies that support TG2-dependent cross-linking.

The study also reframes the evolutionary and physiological logic of hemostasis. Factor XIIIa circulates in plasma as the zymogen Factor XIII and is activated by thrombin during the coagulation cascade, a highly regulated, feed-forward system. TG2, by contrast, is not a classical coagulation factor; it is a multifunctional enzyme implicated in cell death programs, extracellular matrix assembly and signal transduction. Its presence in erythrocytes means that every thrombus, by virtue of the red cells it traps, carries its own reservoir of cross-linking potential. The authors therefore propose TG2 as an additional factor involved in blood coagulation, a formal elevation of the enzyme into the coagulation hierarchy that textbooks will need to accommodate.

Methodologically, the work spans genetically defined animal models and human material. The mouse experiments compared whole thrombi isolated from TG2-deficient and wild-type animals, an approach that captures the net effect of the enzyme in a physiological setting rather than in simplified reconstituted systems. The human experiments used specific inhibition of TG2 activity, a strategy that isolates the enzyme’s catalytic contribution from its possible non-catalytic scaffolding roles. The convergence of genetic and pharmacological evidence on the same conclusion, that clots lacking TG2 activity are measurably less stable, strengthens the causal interpretation and rules out the most obvious alternative explanations, such as differences in clot formation independent of stabilization.

The clinical horizon is speculative but real. Drugs that inhibit TG2 are under development for other indications, including fibrosis and cancer, and the new findings raise the question of whether such agents could affect hemostasis in patients. The observation that human thrombi are less stable when TG2 is inhibited suggests a potential bleeding liability that would need to be evaluated in clinical trials. On the other side of the ledger, the enzyme’s role in stabilizing clots and incorporating fibrinolytic inhibitors suggests that TG2 activity could be a determinant of thrombus persistence, and modulating it might one day complement existing fibrinolytic therapies. Any such applications would require careful dose-finding and safety work, but the study provides the mechanistic foundation for that translational conversation.

There are also broader lessons for the coagulation field. The cross-linking of fibrin via Nε-(γ-glutamyl)lysine bonds has been studied almost exclusively through the lens of Factor XIIIa since its function was established, and the assumption of exclusivity has shaped experimental design, drug discovery and diagnostic thinking. The demonstration that a second transglutaminase contributes to the same process in both mouse and human clots is a reminder that biological systems often maintain redundancy in critical hemodynamic mechanisms, and that a single-enzyme paradigm can obscure parallel pathways. The authors’ finding that TG2 is abundantly present in erythrocytes, cells that are present in every clot but usually treated as passive structural filler, is a vivid example of how a familiar cell type can harbor an unexpected biochemical function.

The study, published open access in Cell Death Discovery on 17 October 2026, was led by Mauro Piacentini, Nicola J. Mutch, Eleonora Candi, Zhuo Wang, Martin Griffin and Gerry Melino, with contributions from Alessandro Mauriello, Manuel Scimeca, Mara Mancini, Valerio Da Ros, Francesco Barilla and Yufang Shi. The work was supported in part by the Italian NextGenerationEU programme through the Heal Italia project, by the Italian Association for Cancer Research and by the Italian Ministry of Health. The authors declare no competing interests. As the field digests the result, the central message is clear: the blood clotting cascade has at least two transglutaminase contributors, not one, and the second has been hiding in plain sight inside our red blood cells all along.

Subject of Research: Role of transglutaminase 2 in blood clot stabilization and coagulation

Article Title: Transglutaminase 2 contributes to the blood clotting cascade

Article References: Piacentini, M., Mutch, N. J., Mauriello, A., Scimeca, M., Mancini, M., Da Ros, V., Barilla’, F., Shi, Y., Candi, E., Wang, Z., Griffin, M., & Melino, G. (2026). Transglutaminase 2 contributes to the blood clotting cascade. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03388-1

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03388-1

Keywords: transglutaminase 2, blood clotting, coagulation, fibrin, Factor XIIIa, hemostasis, fibrinolysis, clot stability, erythrocytes, thrombus, Cell Death Discovery, enzyme cross-linking