Reliable evidence that TXA reduces blood transfusion in surgical patients has been available for many years. Several systematic reviews of randomized trials in patients undergoing elective or emergency/urgent surgery treated with TXA identified a reduction in blood transfusion by 30 % without serious adverse effects but with no significant reduction in mortality. Although the effect on thromboembolic events remains uncertain, the use of TXA in cardiac surgery did not increase the risk of myocardial infarction (MI), stroke, deep venous thrombosis, pulmonary embolus, or renal dysfunction [3, 6, 7] (Table 5.1).

Since the hemostatic responses to surgery and trauma are similar, the effects of TXA on death, vascular occlusive events, and the receipt of blood transfusion on adult trauma patients with significant hemorrhage or at risk of significant hemorrhage were evaluated by a large multicenter, placebo-controlled trial, the CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2). Tranexamic acid was administrated within eight hours from injury, with a loading dose of 1 g over 10 min followed by infusion of 1 g over 8 h. The trial included 20,211 patients, and treatment with TXA was associated with a reduction in all-cause mortality with no apparent increase in vascular occlusive events, in the number of patients receiving blood products, and in the amount of blood transfused within the two groups (1.7 % vs. 2.0 %, 50.4 % vs. 51.3 %, 6.06 vs. 6.29, respectively). The relative risk (RR) of death with TXA was 0.91 (95 % confidence interval [95 % CI] 0.85–0.97, p = 0.0035) [4].

Although the reduction of fibrinolysis is a plausible mechanism, no measure on fibrinolytic activity has been performed in the trial. Alternative plausible hypotheses that may explain the effects take into account the reduction of the pro-inflammatory effects of plasmin, hemostasis improvement, or other mechanisms [5].

A further analysis of the CRASH-2 results showed that TXA treatment within three hours of injury reduced the risk of death due to bleeding by nearly 30 % (p < 0.0001), and the effect was even greater if the time of administration was less than 1 h from injury (5.3 % vs. 7.7 %; RR 0.68, 95 % CI 0.57–0.82; p < 0.0001). Moreover, there were fewer vascular occlusive deaths with TXA and a significant reduction in fatal and nonfatal MI. Treatment given more than 3 h after injury, on the other hand, significantly increased the risk of death due to bleeding (4.4 % vs. 3.1 %). The hypothesized mechanisms are antithrombotic or anti-inflammatory effects together with the effect on myocardial oxygen demand and oxygen supply, secondary to the reduction of bleeding [5, 8–10].