New insights into trauma: TG2 and fibrin cross-linking Free

In this issue of Blood, Boateng et al¹ identify tissue transglutaminase (TG2) as the key driver of fibrin β-chain cross-linking in trauma patients—a novel enzymatic activity distinct from canonical factor XIII (FXIII)–mediated α-α/γ-γ cross-linking. Using an innovative cross-linking mass spectrometry methodology, the authors discover unique β-α cross-links in the fibrin clots of trauma patients, specifically catalyzed by TG2. Crucially, TG2 drives β-chain incorporation into high molecular weight complexes independent of thrombin. This finding exposes a previously unrecognized pathological pathway that reframes the understanding of trauma-induced coagulopathy (TIC). Thus, this study leverages innovative proteomic technologies to illuminate the fibrin modification landscape, revealing TG2-driven β-chain cross-linking as a key pathophysiological driver of TIC.

As a central mechanism in the coagulation system, fibrin cross-linking has long been conceptualized within a FXIII-centric paradigm.^2,3 Boateng et al fundamentally redefine this established framework by identifying TG2 as a pathology (ie, trauma)-induced plasma transglutaminase. This paradigm shift integrates tissue-derived enzymes into the coagulation regulatory network, establishing TG2 as a molecular nexus bridging “tissue injury” and “coagulation dysfunction.”

During traumatic stress, TG2 is normally compartmentalized within tissues and translocated into plasma, where it specifically catalyzes β-α chain cross-links of fibrinogen. This generates a structurally distinct β-α modification network, thereby adding TG2 to the fibrin cross-linking beyond FXIII. Thus, TG2's unique β-chain–targeting specificity provides a mechanistic basis for previously enigmatic coagulation imbalances in trauma-induced coagulopathy (TIC).

TG2 activity is precisely regulated by calcium, GTP, redox status, and mechanical tension. It catalyzes transamidation reactions in extracellular matrix (ECM) proteins including fibrinogen, collagen, and fibronectin.⁴ Chronic TG2 hyperactivation promotes fibrosis and hypertension via dual cross-linking and signaling functions.⁵ In parallel, Boateng et al¹ demonstrated acute TG2-mediated fibrinogen β-chain cross-linking in trauma. Thus, TG2 serves as a shared node between fibrosis (“tissue hardening” via collagen cross-linking) and hemostasis (“clot reinforcement” via fibrin cross-linking), suggesting that precise modulation of TG2 activity may bridge therapeutic strategies for these seemingly divergent pathologies.

The researchers documented significantly elevated plasma TG2 levels in trauma patients compared to healthy controls, with concentrations showing a positive correlation with injury severity (New Injury Severity Score). This correlation suggests plasma TG2 and its catalytically generated β-α cross-links hold promise as novel diagnostic biomarkers. Current transfusion protocols require reassessment to evaluate whether plasma components exacerbate TG2-mediated pathological cross-linking, which if true, should facilitate the development of precision-guided transfusion strategies for TIC. Foremost in translational potential is TG2-directed intervention. Thus, exploring synergy between TG2 inhibitors and antifibrinolytics is the first step in exploring if TG2-directed interventions may overcome the current clinical challenges in TIC management.

The covalent cross-linking of fibrin γ- and α-chains catalyzed by FXIII constitutes a critical determinant of clot stability and function.^6,7 However, the absence of overt bleeding diathesis and impaired wound healing in certain FXIII-deficient patients raises a pivotal question: does effective hemostasis merely require a threshold of 10% plasma FXIII activity,^8,9 or do FXIII-independent compensatory mechanisms come into play?. The Boateng et al study suggests that TG2-mediated cross-linking may provide a physiological bypass, offsetting FXIII loss through alternative fibrin modification pathways. Consequently, quantifying plasma TG2 levels and activity in FXIII-deficient individuals may hold the diagnostic and therapeutic relevance for elucidating this phenotypic heterogeneity.

This discovery leads to multiple important unanswered questions requiring deeper investigation. Although erythrocyte-derived TG2 plays documented roles in stabilizing key proteins within mature red blood cells,¹⁰ its contribution as a plasma TG2 source after experiencing trauma, remains undetermined. Competing hypotheses posit alternative origins: erythrocyte membrane rupture, tissue barrier compromise or active cellular secretion under stress conditions may serve as primary contributors to trauma-induced plasma TG2 elevation. Furthermore, upstream regulatory signals controlling TG2 activation including hypoxia and/or oxidative stress need to be determined. Critically, the functional duality of β-α cross-linking remains unresolved: does it serve as a compensatory hemostatic mechanism or a driver of pathological thrombosis? As such, expanded multicenter clinical cohorts, functional validation and deep mechanistic studies of elevated TG2-mediated β-α cross-linking in progression of thrombi formation, hemorrhage volume and organ failure are imperative to address these knowledge gaps and may promote the current new discovery to the foundational framework for precision-targeted coagulation remodeling therapies.

In conclusion, Boateng et al’s research has made seminal contributions to thrombosis and hemostasis. By establishing TG2 as the principal mediator of pathologic fibrin β-chain cross-linking and fundamentally challenging canonical thrombin cascade paradigms, they have added a new component to the coagulation system. This work redefines coagulation networks through the lens of erythrocyte- and tissue-derived enzymes, fostering interdisciplinary collaboration across hematology, traumatology, and proteomics. Future research should prioritize 2 critical frontiers: mechanistic exploration through advanced trauma models to decipher upstream signaling networks governing TG2 release and activation, and translational validation via multicenter clinical studies assessing TG2's therapeutic potential and prognostic utility. Concerted efforts across basic and clinical research are needed to transform this paradigm-shifting discovery into life-saving clinical applications for trauma patients (see figure).

Conflict-of-interest disclosure: The authors declare no competing financial interests.