Background Tranexamic acid (TXA) is a synthetic lysine analog that inhibits fibrinolysis by blocking lysine-binding sites on plasminogen and plasmin. Although early therapeutic TXA reduces bleeding mortality in major trials, prophylactic benefit appears context- and timing-dependent. TXA is generally not associated with increased thromboembolism, yet its net effect on thrombus formation remains uncertain. Because plasmin(ogen) also acts on leukocytes, endothelium and platelets via cell-surface receptors, TXA may exert cell-dependent effects beyond antifibrinolysis. Objectives To determine how cellular elements modulate TXA’s impact on thrombus formation. Methods We studied TXA in an in vivo murine venous thrombosis model without endothelial injury (IVC stenosis). Plasma VWF: Ag and MCP-1 were measured by ELISA. Thrombin generation was assessed in whole blood and plasma-based systems to evaluate cell dependence. Leukocyte-associated plasminogen activation was quantified using plasmin generation assays in fibrin. Primary hemostasis was assessed by tail bleeding. Results TXA reduced the odds of venous thrombus formation by 90% but did not alter thrombus mass once clots formed. VWF: Ag remained unchanged, whereas the stenosis-induced rise in MCP-1 was largely suppressed by TXA. TXA decreased thrombin generation in whole blood but not in platelet-rich plasma, indicating a cellular requirement. Consistently, TXA markedly inhibited leukocyte surface–mediated plasminogen activation within fibrin clots. Tail bleeding was unaffected. Conclusion TXA was not prothrombotic in venous stasis; it reduced thrombus initiation without impairing primary hemostasis. We show for the first time that TXA modulates thrombin generation in a cellular environment, consistent with inhibition of leukocyte-associated plasmin activity.
Virág et al. (2026) studied this question.