CE: Madhur; ACO/200886; Total nos of Pages: 4; ACO 200886 SPECIAL COMMENTARY CURRENT OPINION Should antifibrinolytics be given in all patients with trauma? Marcel Levi Purpose of review Hemorrhage is the second most important cause of death in patients with trauma, contributing to approximately 30% of trauma-related mortality. Pharmacological prohemostatic agents may be useful adjunctive treatment options in patients with severe blood loss. Recent findings Tranexamic acid was evaluated in a large international randomized controlled study in patients with trauma and severe blood loss. The drug was shown to reduce death due to bleeding, provided the treatment was given within 3 h after injury. Tranexamic acid treatment did not result in serious adverse events nor thrombotic complications. Summary In view of this efficacy and safety of this relatively cheap and simple drug, it may be recommended to put tranexamic acid in the first (maybe even prehospital) line of management of patients with severe traumatic hemorrhage. Keywords antifibrinolytics, hemorrhage, prohemostatic drugs, tranexamic acid, trauma INTRODUCTION physiological anticoagulation. This strategy may be Bleeding is a frequently occurring clinical problem. useful in the prevention and treatment of bleeding A substantial number of hospital admissions in in patients with coagulation defects but also in medical wards is related to bleeding and peri- patients with an a priori normal coagulation system, operative bleeding is one of the most frequent com- who experience severe (postoperative) bleeding or plications of surgery [1&&]. Bleeding is of particular are to undergo procedures known to be associated importance in trauma and is the second most with major blood loss [5]. important cause of death in trauma patients, The safety of prohemostatic therapy also deserves contributing to approximately 30% of trauma- some consideration. Interfering in the balance related mortality [2]. Trauma-related coagulopathy between coagulant and anticoagulant mechanisms proceeds via a myriad of mechanisms, including loss can indeed result in undesirable adverse effects. of factors and platelets due to massive bleeding, The best illustration may be the higher risk of bleed- acidosis and hypothermia further compromising ing in patients receiving anticoagulant therapy. the coagulation system, dysregulation of mediatory Conversely, prohemostatic agents may, at least pathways, such as the activated protein C system theoretically, predispose for thrombotic compli- and fibrinolysis, and systemic activation of throm- cations. The occurrence of such complications are bin generation [3&]. fortunately relatively rare. Obviously, the expected Management of bleeding consists of local benefit of the application of prohemostatic agents control measures to retain adequate circulation, and proper transfusion procedures [4]. In addition Department of Medicine, Academic Medical Center, University of to these strategies, prohemostatic treatment may, Amsterdam, Amsterdam, The Netherlands in some cases, support the treatment of (severe) Correspondence to Marcel Levi, MD, Academic Medical Center, bleeding. Pharmacological agents that are capable University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The of promoting hemostasis or fibrin formation, or Netherlands. Tel: +31 20 5662109; e-mail: mailto:[email protected] can block fibrinolytic activity, may interfere in Curr Opin Anesthesiol 2012, 25:000–000 the balance between activation of coagulation and DOI:10.1097/ACO.0b013e3283532b29 0952-7907 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-anesthesiology.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE: Madhur; ACO/200886; Total nos of Pages: 4; ACO 200886 Special commentary their fibrinolysis-inhibiting capacity. Indeed, tran- KEY POINTS examic acid (Cyklokapron, Pfizer, New York, NY, Bleeding is of particular importance in trauma and is USA) is at least 10 times more potent than e-amino- the second most important cause of death in trauma caproic acid (Amicar, Xanodyne Pharmaceuticals patients, contributing to approximately 30% of trauma- Inc., Newport, KY, USA). Tranexamic acid was shown related mortality. to be effective in reducing blood loss, transfusion requirement, and prevention of re-exploration due Prohemostatic strategies, including antifibrinolytic agents, may support the treatment of severe bleeding in to ongoing hemorrhage in a variety of clinical set- trauma patients. tings, including cardiac surgery, major orthopaedic surgery, and gynaecological conditions [11–13]. Randomized controlled trials showed a reduction of A recently conducted large randomized trial mortality in patients with major trauma and with, or at with tranexamic acid in 20 211 patients (admitted risk of, severe hemorrhage that received the antifibrinolytic agent tranexamic acid. to 274 hospitals in 40 different countries) with major trauma and with, or at risk of, severe hemor- Tranexamic acid is remarkably well tolerated in rhage showed a reduction of mortality in patients patients with trauma and is not associated with who received tranexamic acid compared with thrombotic complications or other adverse events. placebo [9&&]. Patients were treated within 8 h of It has been calculated that universal use of tranexamic injury with either tranexamic acid (1 g over 10 min acid may result in the aversion of death in more than followed by another gram over 8 h) (n ¼ 10.096), or 70 000 trauma patients each year worldwide. placebo (n ¼ 10.115). All-cause mortality at 4 weeks after admission was 14.5% in the tranexamic acid group as compared with 16% in the placebo group [relative risk (RR) 0.91, 95% confidence interval (CI) in distinct clinical situations should be balanced 0.85–0.97, P ¼ 0.0035]. The risk of death due to with the risk of thrombosis in that particular patient haemorrhage was reduced from 5.7% in controls population. to 4.9% in the tranexamic acid-treated patients Prohemostatic treatment can interfere with (RR 0.85%, 95% CI 0.76–0.96, P ¼ 0.0077). Interest- the coagulation system or promote primary hemo- ingly, there were no detectable differences in the rate stasis [1&&,6–8]. One of the best studied prohemo- of transfusion and the need for surgical (re)explora- static interventions is antifibrinolytic treatment. tion between the two groups. Tranexamic acid was Recently, the use of the antifibrinolytic agent remarkably well tolerated in this study. In the tran- tranexamic acid was shown to reduce mortality examic acid group, 168 patients (1.7%) had occlusive in trauma patients with excessive blood loss in a vascular events compared with 201 patients (2.0%) large international controlled multicenter trial [9&&]. in the placebo group. There were also no differences We will briefly report on the findings in this trial and in deaths due to vascular complications between the subsequently try to answer the question whether two groups. all patients with trauma should be treated with In an additional analysis, the authors found tranexamic acid. strong evidence that early administration of tran- examic acid was relatively more favourable in com- parison with administration at a later time after ANTIFIBRINOLYTIC TREATMENT IN trauma [14&]. Early (<1 h) treatment with tran- TRAUMA examic acid reduced the rate of death due to bleeding Agents that exert antifibrinolytic activity are to 5.3% compared with 7.7% in the placebo group aprotinin and the group of lysine analogues [10]. (RR 0.68, 95% CI 0.57–0.82, P < 0.0001), whereas Lysine analogues, that is, e-aminocaproic acid and this RR decreased when the drug was given 1–3 h tranexamic acid are potent inhibitors of fibrinolysis after trauma to 0.79 (95% CI 0.64–0.97, P ¼ 0.03) [10]. The antifibrinolytic action of lysine analogues and was 1.44 (95% CI 1.12–1.84, P ¼ 0.004) when is based on the competitive binding of these tranexamic acid was given later than 3 h. There was agents to the lysine-binding sites of a fibrin clot, no evidence that the effect of tranexamic acid thereby competing with the binding of plasmino- on death due to bleeding was influenced by other gen. Impaired plasminogen binding to fibrin delays factors, including Glasgow Coma Score, type of the conversion of plasminogen to plasmin and injury, or SBP. Another analysis concerned the subsequent plasmin-mediated fibrinolysis, which subgroup of patients with traumatic brain injury. then proceeds at an inefficient and slow rate. In a nested case–control study, the authors studied Subtle molecular variations between different lysine 270 patients who also had traumatic brain injury in analogues may have important consequences for addition to their extracranial bleeding due to trauma 2 www.co-anesthesiology.com Volume 25 Number 00 Month 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE: Madhur; ACO/200886; Total nos of Pages: 4; ACO 200886 Antifibrinolytics in patients with trauma Levi [15]. Mean intracranial hemorrhage growth at 24– to show time-related transfusion rates or (excessive) 48 h after admission was 5.9 ml (SD 26.8) in the transfusion-free survival rates, information which tranexamic acid group as compared with 8.1 ml is probably not available. Another (not unlikely) (SD 29.2) in the placebo group. There were new focal possibility is that transfusion protocols are not very cerebral ischemic lesions in 5% of patients treated well tailored to the bleeding