Tranexamic acid: less bleeding and less thrombosis?

The early administration of tranexamic acid (TXA) to bleeding trauma patients reduces all-cause mortality without increasing the risk of vascular occlusive events. Indeed, the risk of arterial thrombosis appears to be reduced with TXA. In this commentary we hypothesize that TXA has an antithrombotic effect and explore potential mechanisms. These include inhibition of the inflammatory effects of plasmin, effects on platelets and effects on factors V and VIII. If proven, these antithrombotic effects would have major implications for the systemic use of TXA in surgical patients, where TXA has been clearly shown to reduce bleeding.


Introduction
Th e antifi brinolytic agent tranexamic acid (TXA) has been shown to reduce bleeding in elective surgery. A recent systematic review of randomised controlled trials shows that TXA reduces the probability of receiving a blood transfusion by nearly 40% [1]. Th ere was also a non-signifi cant reduction in the risk of myocardial infarction (MI) with TXA (relative risk (RR) = 0.68, 95% confi dence interval (CI) 0.43 to 1.09; P = 0.11).
Th e CRASH-2 (Clinical Randomisation of an Antifi brinolytic in Signifi cant Haemorrhage 2) trial of TXA in bleeding trauma patients was motivated by the evidence that TXA reduces surgical bleeding and the knowledge that the haemostatic responses to trauma and surgery share common features. Th e results showed a signifi cant reduction in death due to bleeding and allcause mortality with TXA [2]. Th e reduction was largest for those treated soon after injury [2]. TXA treatment within 3 hours of injury reduced the risk of death due to bleeding by nearly 30%. Moreover, there were fewer vascular occlusive deaths with TXA (RR = 0.69, 95% CI 0.44 to 1.07; P = 0.096) and a signifi cant reduction in fatal and non-fatal MI (RR = 0.64, 95% CI 0.42 to 0.97; P = 0.035). We hypothesize that TXA may have an antithrombotic eff ect and explore the possible mechanisms.
Th e reduction in MI could be due to the anti-infl ammatory eff ects of TXA. Trauma and surgery are known to generate a systemic infl ammatory response, characterized by systemic activation of fi brinolysis, coagulation, comple ment, platelets, and oxidative pathways [3,4]. Th is infl am mation is associated with increased risk of thrombosis. While a causal role for chronic infl ammation in atherosclerotic disease is well established, evidence that acute infl ammation may promote vascular events is accumulating, with increases in risk after infection [5] and surgery [6].
TXA has anti-infl ammatory eff ects. It is a synthetic derivative of the amino acid lysine that blocks the lysine binding sites of plasminogen and plasmin, inhibiting their eff ects, including their fi brinolytic and infl ammatory eff ects. Plasminogen binds not only to fi brin, causing fi brinolysis, but also to receptors on cells involved in the infl ammation process, such as monocytes, macrophages, neutrophils, endothelial cells and platelets. Plasminogen receptors include the annexin A2-S100A10 heterotetramer, α-enolase, histone H2B and the transmembrane plasminogen receptor Plg-R(KT). Th e binding of plasmino gen to these receptors initiates infl ammatory processes. For example, the binding to annexin A2 increases the expression and release of a major chemokine called monocyte-macrophage chemo-attractant protein (MCP-1) [7]. Th e binding to α-enolase is involved in monocyte recruitment in infl ammatory lung disease [8]. Plg-R(KT) is a plasminogen receptor that is co-localized on the monocyte surface with the urokinase receptor (uPAR) and interacts directly with tissue plasminogen activator [9]. Plg-R(KT) is believed to play a role in plasminogendependent regulation of macrophage migration, invasion, and recruitment in the infl ammatory response. In summary, after binding to its receptors, plasminogen has a range of potent pro-infl ammatory eff ects, which may be inhibited by TXA.
Once activated, plasmin can stimulate lipid mediator release, increase the biosynthesis of leucotrienes,

Abstract
The early administration of tranexamic acid (TXA) to bleeding trauma patients reduces all-cause mortality without increasing the risk of vascular occlusive events. Indeed, the risk of arterial thrombosis appears to be reduced with TXA. In this commentary we hypothesize that TXA has an antithrombotic eff ect and explore potential mechanisms. These include inhibition of the infl ammatory eff ects of plasmin, eff ects on platelets and eff ects on factors V and VIII. If proven, these antithrombotic eff ects would have major implications for the systemic use of TXA in surgical patients, where TXA has been clearly shown to reduce bleeding. pro mote cytokine release and induce the expression of some infl ammatory genes. Plasmin also causes degradation of extra cellular matrix components, thus facilitating chemo taxis and infl ammatory cell migration across adhesive substrates. Plasmin also activates infl ammatory signalling networks, leading to phosphorylation and activation of the p38 mitogen-activated protein kinase (MAPK) and JAK/STAT signalling pathways [10]. By blocking the bind ing sites of plasminogen and plasmin, TXA could inhibit these infl ammatory eff ects. A ran domised controlled trial of TXA in patients undergoing cardio pulmonary bypass showed that perioperative TXA reduced the infl am ma tory response and vasoplegic shock [4].
TXA may also reduce thrombotic events via eff ects on platelets and coagulation proteins. Th ere is some evidence that plasmin can cause platelet activation. Th is was clinically noted in the early trials of thrombolysis in myocardial infarction where fi brinolytic (plasmin) activators were used initially without anti-platelet agents. Reocclusion occurred in approximately 20% of cases after stopping fi brinolytic agents [11]. However, the use of anti-platelet drugs prevented re-occlusion. Plasmin may mediate platelet aggregation through proteolytic cleavage of a thrombin receptor, protease-activated receptor 4 (PAR4) [12]. Other anti-platelet mechanisms have been suggested. Plasmin is believed to cause platelet aggregation by stimulating platelet degranulation and release of both dense granules, with ADP, and alpha granules, with fi brinogen and von Willebrand factor, which lead to the activation, recruitment, and aggregation of platelets. Plasmin also stimulates the arachidonic acid cascade, which leads to activation of prostacyclin biosynthesis and, hence, platelet activation. Finally, plasmin may cause platelet aggregation by complement activation [13].
Plasmin also has a role in coagulation. At high concentrations, plasmin has procoagulant eff ects. Plasmin proteolyses coagulation factors but has a unique biphasic eff ect on factors V and VIII: proteolytic breakdown is preceded by a brief burst of activation [14,15]. Incubation of factor V or VIII with plasmin results in a rapid increase in procoagulant activity, factor VIII levels increase twofold within 3 minutes and then are undetectable within 45 minutes [16]. Th is brief activation may generate enough thrombin to produce a signifi cant procoagulant eff ect. Another procoagulant eff ect of plasmin is that it causes proteolytic breakdown of a physiological anticoagulant, tissue factor protein inhibitor, a major inhibitor of tissue factor-mediated coagulation [17], and these changes are abolished by antifi brinolytic agents [18].

Conclusion
Plasminogen and plasmin have a wide range of potential pro-thrombotic eff ects. Th e reduction in MI observed with TXA in the CRASH-2 trial is compatible with a signifi cant antithrombotic eff ect of TXA. Th is eff ect may be mediated via its impact on infl ammation, platelet eff ects or coagulation factors. However, the data are limited and more in vitro and clinical studies are required.
If TXA reduces the need for blood transfusion and reduces the risk of thrombosis, this would have major implications for surgical patients. Every year, world-wide, between 500,000 and 900,000 patients experience perioperative cardiac death, non-fatal MI or non-fatal cardiac arrest [19]. If the eff ect of TXA on the risk of arterial thrombotic events seen in trauma also applies in surgery, TXA might prevent hundreds of thousands of cardiac events. Because thrombotic events are uncommon, small trials lack power and a meta-analysis of small trials would be vulnerable to publication bias. For this reason a large pragmatic trial of TXA administration in surgical patients is needed. Th e possibility that TXA could reduce surgical morbidity and mortality through a reduction in perioperative bleeding and postoperative thrombosis justifi es the eff ort involved.