Fibrinolysis and tranexamic acid: mechanistic principles
Abstract
Traumatic injury results in an activation of the coagulation cascade and formation of a fibrin clot. Via the exposure of lysine residues fibrin acts as a co-factor for plasmin formation and subsequent fibrinolysis, thereby orchestrating its own degradation. Tranexamic acid (TXA), a lysine analogue, competes with lysine residues on the fibrin clot, preventing co-localization and interaction of plasminogen and its main endogenous activator tissue-type plasminogen activator (t-PA), resulting in inhibited fibrinolysis. Hence, TXA has been harnessed for its blood-sparing effects in conditions associated with blood loss. TXA was first tested in a large randomized controlled trial (RCT) in bleeding trauma patients in the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) study almost a decade ago, which demonstrated improved survival in patients administered TXA within 3 h after bleeding onset. Paradoxically, later administration was associated with an increased risk of death due to bleeding. A possible explanation for this observation was provided by an animal study on traumatic brain injury (TBI) that was linked to the potentiation of urokinase (u-PA)-mediated plasminogen activation by TXA; an initial peak of t-PA levels in cerebrospinal fluid occurred early after TBI, but rapidly declined and was followed by a peak of u-PA. As u-PA-mediated plasminogen activation is enhanced by TXA, due to a conformational change in the plasminogen molecule. TXA…
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