Critical Care Update

David J. Dries, MSE, MD, and Colleen T. Morton, MBBCh, MS

00 Article titlePart 2 Coagulation: Tranexamic Acid in Trauma: Who Needs It Napolitano LM, Cohen MJ, Cotton BA, et al. Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg. 2013;74:1575-1586. Pusateri AE, Weiskopf RB, Bebarta V, et al. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock. 2013;39:121-126. Valle EJ, Allen CJ, Van Haren RM, et al. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76:1373-1378. CRASH-2 Trial Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23-32. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147:113-119. Morrison JJ, Ross, JD, Dubose JJ, et al. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury. Findings from the MATTERs II Study. JAMA Surg. 2013;148:218-225. The disturbance of coagulation occurs in nearly all patients after significant injury. Impaired clotting after injury was thought to be caused by iatrogenic causes including hypothermia, acidosis, and hemodilution during resuscitation. Later work revealed that many severely injured patients developed coagulation abnormalities even before resuscitation was initiated. This acquired coagulopathy of trauma is associated with tissue hypoperfusion independent of iatrogenic causes. Coagulopathy after trauma is associated with increased blood product requirements, increased morbidity, and increased mortality. The importance of hyperfibrinolysis after trauma was highlighted in recent studies using thromboelastography after severe injury. The incidence of hyperfibrinolysis, or accelerated clot breakdown, ranges from 2% to 34% in reported studies and varies based on the instrument measuring fibrinolysis, how soon after injury the sample is drawn, the threshold selected, and the severity of injury. In some of these studies, hyperfibrinolysis has been identified as 246

an independent predictor of need for massive transfusion and mortality. Specific predictors of hyperfibrinolysis include shock on arrival to hospital, admission hypothermia, and increased base deficit. Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and is an antifibrinolytic agent acting by binding to plasminogen and blocking the interaction of plasminogen with fibrin, thereby preventing dissolution of the fibrin clot. TXA has been available for more than 20 years and has been used in cardiac surgery and to reduce bleeding episodes during tooth extraction in hemophilia patients. The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 trial brought TXA to the forefront of the trauma literature. In this massive multinational randomized placebo-controlled study, early administration of TXA reduced 28-day hospital mortality, vascular events, and transfusions in adult trauma patients. Over 20,000 subjects were enrolled. All-cause 28-day mortality in this massive trial was 14.5% in TXA-treated patients and 16% in placebo patients. Because TXA is an antifibrinolytic agent whose primary mechanism of action is reduction in clot lysis, the potential for increased thromboembolic events was evaluated. Secondary outcomes were vascular occlusive events such as myocardial infarction, stroke, pulmonary embolism (PE), and deep venous thrombosis (DVT). There was no difference in the rate of vascular occlusive events between groups and no difference in venous thrombotic events. Based on the results of the CRASH-2 trial, TXA has been added to the World Health Organization’s list of essential medications. Cochrane systematic reviews suggest that TXA may decrease the need for blood transfusion in patients undergoing operative procedures without increased risk of DVT, PE, myocardial infarction, or stroke. When the CRASH-2 data were examined for the impact of TXA on death caused by bleeding rather than all-cause 28day mortality, early TXA treatment (⬍ 1 hour from injury) was associated with the greatest reduction (32% reduction) in deaths caused by bleeding. Treatment given between 1 and 3 hours after injury was also associated with a reduced risk of death caused by bleeding. In contrast, TXA given after 3 hours after injury was associated with an increased risk of death caused by bleeding. Reasons for this are unclear. In a study from the same investigators involving intracranial hemorrhage, TXA administration was associated with a nonsignificant reduction in hemorrhage growth and fewer deaths. The majority of observed deaths in this study were caused by traumatic brain injury (TBI), not bleeding. Two military trials have examined the use of TXA in trauma emergency resuscitation. Trauma patients were identified from UK and US trauma registries. The TXA group had a lower unadjusted mortality than the groups who did not Air Medical Journal 33:6

receive TXA. This benefit was greatest in multiple trauma patients in whom TXA use was associated with a survival advantage and less coagulopathy. Thrombotic events were significantly increased in the TXA group for both PE and DVT. However, after correcting for severity of injury, there was no association of TXA use with increased risk of DVT or PE. A second military trial, the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs)-II trial, examined the combined use of TXA and cryoprecipitate. TXA and cryoprecipitate were independently associated with reduced mortality. Military resuscitation guidelines advocate the early use of TXA for any patient requiring blood products in the treatment of combat-related hemorrhage and particularly for patients judged likely to require massive transfusion. A number of important gaps in our knowledge regarding the use of TXA in trauma remain. First, complications and efficacy of TXA have not critically been studied in the context of damage control resuscitation. Most of the available data come from broad international trials and military experience. There are relatively little data regarding the use of TXA in modern civilian trauma practice. A recent single-center civilian trial suggests that TXA may not be helpful in the highacuity patient group with a large transfusion volume. We need a better definition of which types of injury could benefit from TXA. TBI is an obvious group to study. There may be other patient groups in whom TXA use should be emphasized. Although it is attractive to give TXA in the prehospital setting, there are little data on efficacy. Finally, when is TXA most effective? Timing considerations have been described. The role of TXA administration with and without specific blood products needs further investigation. It remains unclear how TXA reduced mortality in injury. In the CRASH-2 trial, there was no statistical difference in red blood cell transfusion between groups. TXA, as an antifibrinolytic agent, inhibits plasmin, which is known to induce proinflammatory effects by activation of monocytes, neutrophils, platelets, endothelial cells, and complement releasing lipid mediators and cytokines by the induction of proinflammatory genes. Thus, it is possible that improved survival in TXAtreated patients may be caused by the attenuated inflammatory response rather than the reversal of fibrinolysis. At present, a recommended approach for the use of TXA use in trauma includes targeted administration in trauma patients with severe hemorrhagic shock (systolic blood pressure ⱕ 75 mm Hg) with known predictors of fibrinolysis (such as TBI) or known fibrinolysis by thromboelastography. Only administer TXA if less than 3 hours after injury. Finally, the recommended dosing is 1 g intravenously over 10 minutes followed by 1 g intravenously administered over 8 hours.

Prothrombin Complex Concentrates for the Patient Taking Warfarin Baumann Kreuziger LM, Keenan JC, Morton CT, Dries DJ. Management of the bleeding patient November-December 2014

receiving new oral anticoagulants: a role for prothrombin complex concentrates. Biomed Res Int. 2014;014:583794. Voils SA, Baird B. Systematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: does it matter? Thromb Res. 2012;130:833-840. Holland L, Warkentin TE, Refaai M, et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49:11711177. Sarode R, Milling T, Refaai M, et al. Randomized phase IIIb study comparing the safety and efficacy of four-factor prothrombin complex concentrate with plasma in subjects receiving vitamin K antagonists with major bleeding. Am J Hematol. 2012;87:S146. Although much attention has been focused on the new oral anticoagulants (see Coagulation Part I Air Med J. 2014;33:129-132), the majority of patients seen for the foreseeable future receiving chronic oral anticoagulant therapy will be receiving warfarin. Warfarin creates a deficiency of factors II, VII, IX, and X through the inhibition of vitamin K–dependent carboxylation of clotting proteins. The replacement of functional coagulation factors can reverse the anticoagulant effect of warfarin. As we have reviewed, prothrombin complex concentrates (PCCs) are plasmaderived products containing factors II, VII, IX, and X. Three-factor PCCs contain a minimal amount of factor VII. Kcentra (CLS Behring, King of Prussia, PA) is 1 of the 4-factor PCCs containing all of the vitamin K–dependent proteins as well as protein C and protein S. Kcentra contains small amounts of heparin, which is insufficient to cause anticoagulation but contraindicates the use of this product in patients with a history of heparin-induced thrombocytopenia. PCCs provide replacement of functional vitamin K–dependent proteins to directly reverse the anticoagulant effects of warfarin. Reversal of the anticoagulant effect of warfarin is multifaceted. The administration of vitamin K allows restoration of functional coagulation proteins but requires up to 24 hours for a complete clinical effect. The vitamin K–dependent coagulation proteins can be replaced through the administration of plasma or PCCs. Because of the smaller infusion volume and rapid nature of reversal, PCC infusion is preferred over plasma infusion in patients taking warfarin with uncontrolled bleeding and significant international normalized ratio (INR) elevation. Studies comparing 3-factor PCCs with plasma show decreased time to INR correction with PCC administration without a difference in clinical outcomes. Combining a 247

Figure 1. The protocol for reversing warfarin when the INR is ⬎ 2. *Aspirin, clopidogrel, prasugrel, ticagrelor, and aspirin/dipyridamole.

3-factor PCC with either plasma or recombinant factor VIIa has been suggested to replace all of the vitamin K–dependent proteins in warfarin-associated hemorrhage. Studies using this approach in patients with intracranial hemorrhage showed a decreased time to INR reversal with a PCC in combination with plasma and/or recombinant factor VIIa but did not report a difference in neurologic outcomes. Alternatively, all of the vitamin K–dependent factors could be provided through an infusion of a 4-factor PCC. A recent systematic review evaluated the use of 3-factor versus nonactivated 4factor PCCs (eg, Kcentra) for the reversal of warfarin-induced anticoagulation. Of 18 included studies from recent literature, none were prospective randomized trials, and none directly compared 3- and 4-factor PCCs. However, 92% (12/13) of the 4-factor PCCs studies reported an INR less than or equal to 1.5 one hour after PCC administration compared with only 66% of studies (6/9) using 3-factor PCCs. Based on the mechanism of action, a 4-factor PCC should reverse the effect of warfarin and decrease bleeding in patients taking warfarin more effectively than a 3-factor PCC because the factor VII–tissue factor complex is an essential step in coagulation initiation and 3-factor PCCs have very little factor VII. In a randomized trial of patients with acute major hemorrhage, a 4-factor PCC was compared with plasma for the correction of warfarin-induced coagulopathy. In addition, all patients received 5 to 10 mg of intravenous vitamin K. The 4-factor PCC was noninferior to plasma for achieving effective hemostasis (72% vs. 65%) and superior to plasma at correcting the INR less than or equal to 1.3 at 30 minutes (62% vs. 10%). Thromboembolic events, an important consideration, were 248

similar between the groups. Fluid overload and cardiac events occurred in 4.9% of the 4-factor PCC group and 12.8% of the plasma recipients. The 4-factor PCC (Kcentra) was Food and Drug Administration approved in April 2013 on the basis of this trial. Our protocol to manage warfarin-associated hemorrhage reflects this development (Figs. 1 and 2). The initial care of the bleeding patient receiving warfarin therapy is the same for any bleeding patient—local intervention for source control, if possible, and supportive care. The transfusion of packed red blood cells and a transfusion protocol featuring a balance of packed red blood cells, plasma, and platelets may be used depending on the severity and etiology of hemorrhage. The effects of antiplatelet agents are reversed by the transfusion of 2 aphaeresis units of platelet concentrates if needed. Kcentra is licensed for the management of warfarin-associated hemorrhage in patients with an INR greater than 2.0. Thus, in patients taking warfarin with life-threatening bleeding and an INR between 1.5 and 2.0, we recommended an infusion of 15 mL/kg plasma and 10 mg intravenously vitamin K. We aim to correct warfarin-associated coagulopathy to an INR less than 1.5, and additional plasma may be given if tolerated based on fluid status. For life-threatening bleeding in the setting of warfarin use and an INR greater than 2.0, we use Kcentra and 10 mg intravenously vitamin K. The dose of this 4-factor PCC depends on the pretreatment INR. Four-factor PCCs are not approved for repeat dosing; thus, supportive care, with the use of plasma as needed, should continue after PCC administration. An important theoretic consideration when PCCs are used to address emergent hemorrhage management in the setting of Air Medical Journal 33:6

Figure 2. The protocol for the reversal of warfarin when the INR is ⱕ 2.0.

warfarin therapy is the absence of additional clotting factor replacement in the patient with liver disease. Individuals with significant hepatic dysfunction may have an elevated INR, which does not respond to the administration of a PCC because of the lack of other clotting factors. Thus, for PCC therapy to be effective, in the warfarin-treated patient, we must assume that the remainder of the coagulation cascade is intact.

Summary Points • Studies in coagulation abnormality after injury document an increase in fibrinolysis, which has been associated with additional morbidity and mortality. • Early administration of TXA appears to improve outcome in the setting of severe injury associated with hemorrhage. For the maximum effect, however, this drug should be given within the first 3 hours after injury. • The mechanism of action for TXA as an agent that improves outcome after injury remains unclear. Although the impact of TXA on the coagulation cascade is wellknown, TXA also has anti-inflammatory properties that may also be important in the initial hours after injury. • Additional trials are underway to examine the role of TXA in high-risk patients in the field and with focused problems associated with increased fibrinolysis such as TBI. • Although TXA is an attractive agent to consider in the prehospital setting, there are little or no data regarding an appropriate role for this agent in this application. • For the foreseeable future, the majority of patients receiving oral anticoagulant therapy will be receiving warfarin. • Four-factor PCCs are the most efficient way to reverse INR elevation in patients with life-threatening bleeding receiving warfarin therapy. However, PCCs are only approved for patients with an INR ⬎ 2.0. November-December 2014

• PCCs are not approved for repeat dosing. Plasma and vitamin K therapy should continue after PCC administration. • Patients with severe liver disease may have numerous coagulation factor deficits. Focused factor replacement, as with a PCC, may not be effective in these individuals. David J. Dries, MSE, MD, is assistant medical director for surgical services at HealthPartners Medical Group and professor of surgery and anesthesiology at the University of Minnesota in Minneapolis, MN, and can be reached at [email protected]. Colleen T. Morton, MBBCh, MS, is a medical director of Clinical Coagulation, HealthPartners, Region’s Hospital in St. Paul, MN. 1067-991X/$36.00 Copyright 2014 by Air Medical Journal Associates http://dx.doi.org/:10.1016/j.amj.2014.08.008

249