The risk of thromboembolic events with early intravenous 2- and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: A secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial
BACKGROUND Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism. STUDY DESIGN AND METHODS This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression. RESULTS There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused. DISCUSSION In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage.
The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI): A Randomized, Double-Blind, Placebo-Controlled, Single-Center Trial
Frontiers in immunology. 2020;11:2085
BACKGROUND The hemostatic properties of tranexamic acid (TXA) are well described, but the immunological effects of TXA administration after traumatic injury have not been thoroughly examined. We hypothesized TXA would reduce monocyte activation in bleeding trauma patients with severe injury. METHODS This was a single center, double-blinded, randomized controlled trial (RCT) comparing placebo to a 2 g or 4 g intravenous TXA bolus dose in trauma patients with severe injury. Fifty patients were randomized into each study group. The primary outcome was a reduction in monocyte activation as measured by human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes 72 h after TXA administration. Secondary outcomes included kinetic assessment of immune and hemostatic phenotypes within the 72 h window post-TXA administration. RESULTS The trial occurred between March 2016 and September 2017, when data collection ended. 149 patients were analyzed (placebo, n = 50; 2 g TXA, n = 49; 4 g TXA, n = 50). The fold change in HLA-DR expression on monocytes [reported as median (Q1-Q3)] from pre-TXA to 72 h post-TXA was similar between placebo [0.61 (0.51-0.82)], 2 g TXA [0.57 (0.47-0.75)], and 4 g TXA [0.57 (0.44-0.89)] study groups (p = 0.82). Neutrophil CD62L expression was reduced in the 4 g TXA group [fold change: 0.73 (0.63-0.97)] compared to the placebo group [0.97 (0.78-1.10)] at 24 h post-TXA (p = 0.034). The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group [1.36 (0.87-2.42)] compared to the placebo group [0.46 (0.19-1.69)] at 72 h post-TXA (p = 0.028). There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points. CONCLUSION In trauma patients with severe injury, 4 g intravenous bolus dosing of TXA has minimal immunomodulatory effects with respect to leukocyte phenotypes and circulating cytokine levels. CLINICAL TRIAL REGISTRATION www.ClinicalTrials.gov, identifier NCT02535949.
Bleeding trauma patients with severe injury from the TAMPITI trial (n= 149).
Intravenous tranexamic acid (TXA) 2 g bolus dose (n=49).
Intravenous tranexamic acid 4 g bolus dose (n= 50); Placebo (n= 50).
The median fold change in human leukocyte antigen-DR isotype (HLA-DR) expression on monocytes from pre-TXA to 72 h post-TXA was similar between placebo: 0.61, 2 g TXA: 0.57, and 4 g TXA: 0.57 study groups. Neutrophil CD62L expression was reduced in the 4 g TXA group (fold change: 0.73) compared to the placebo group: 0.97 at 24 h post-TXA. The fold decrease in plasma IL-6 was significantly less in the 4 g TXA group: 1.36 compared to the placebo group: 0.46 at 72 h post-TXA. There were no differences in frequencies of myeloid or lymphoid populations or in classical complement activation at any of the study time points.
A Pilot Trial of Platelets Stored Cold versus at Room Temperature for Complex Cardiothoracic Surgery
BACKGROUND This pilot trial focused on feasibility and safety to provide preliminary data to evaluate the hemostatic potential of cold-stored platelets (2° to 6°C) compared with standard room temperature-stored platelets (20° to 24°C) in adult patients undergoing complex cardiothoracic surgery. This study aimed to assess feasibility and to provide information for future pivotal trials. METHODS A single center two-stage exploratory pilot study was performed on adult patients undergoing elective or semiurgent complex cardiothoracic surgery. In stage I, a two-armed randomized trial, platelets stored up to 7 days in the cold were compared with those stored at room temperature. In the subsequent single-arm stage II, cold storage time was extended to 8 to 14 days. The primary outcome was clinical effect measured by chest drain output. Secondary outcomes were platelet function measured by multiple electrode impedance aggregometry, total blood usage, immediate and long-term (28 days) adverse events, length of stay in intensive care, and mortality. RESULTS In stage I, the median chest drain output was 720 ml (quartiles 485 to 1,170, n = 25) in patients transfused with room temperature-stored platelets and 645 ml (quartiles 460 to 800, n = 25) in patients transfused with cold-stored platelets. No significant difference was observed. The difference in medians between the room temperature- and cold-stored up to 7 days arm was 75 ml (95% CI, -220, 425). In stage II, the median chest drain output was 690 ml (500 to 1,880, n = 15). The difference in medians between the room temperature arm and the nonconcurrent cold-stored 8 to 14 days arm was 30 ml (95% CI, -1,040, 355). Platelet aggregation in vitro increased after transfusion in both the room temperature- and cold-stored platelet study arms. Total blood usage, number of adverse events, length of stay in intensive care, and mortality were comparable among patients receiving cold-stored and room temperature-stored platelets. CONCLUSIONS This pilot trial supports the feasibility of platelets stored cold for up to 14 days and provides critical guidance for future pivotal trials in high-risk cardiothoracic bleeding patients.
Practical Considerations for a Military Whole Blood Program
Mil Med. 2020
INTRODUCTION Prehospital care in the combat environment has always been of great importance to the U.S. military, and trauma resuscitation has remained a cornerstone. More evidence continues to demonstrate the advantages of intervention with early transfusion of blood products at the point of injury. The military has recognized these benefits; as such, the Department of Defense Joint Trauma System and the Committee on Tactical Combat Casualty Care have developed new advanced resuscitation guidelines, which now encourage the use of whole blood (WB) in the prehospital setting. MATERIALS AND METHODS This general review of peer-reviewed journal articles was performed through an extensive electronic search from the databases of PubMed Central (MEDLINE) and the Cochrane Library. RESULTS Based on this literature search, the current evidence suggests that transfusion with WB is safe and efficacious. Additionally, soldier function is preserved after donating fresh WB in the field. Currently, the collection and implementation of WB is accomplished through several different protocol-driven techniques. CONCLUSION WB has become the favored transfusion product as it provides all of the components of blood in a convenient package that is easy to store and transport. Specifically, group O WB containing low titers of anti-A and -B antibodies has become the transfusion product of choice, offering the ability to universally fluid resuscitate patients despite not knowing their blood group. This new ability to obtain low titer group O WB has transformed the approach to the management of hemorrhagic shock in the prehospital combat environment.
Patients from a prehospital combat environment.
Systematic review on the use of whole blood (WB) in prehospital setting.
The collection and implementation of WB is accomplished through several different protocol-driven techniques. WB has become the favored transfusion product as it provides all of the components of blood in a convenient package that is easy to store and transport. Specifically, group O WB containing low titers of anti-A and -B antibodies has become the transfusion product of choice, offering the ability to universally fluid resuscitate patients despite not knowing their blood group.
Blood transfusion for deep space exploration
BACKGROUND Astronauts on exploration missions may be at risk for traumatic injury and medical conditions that lead to life threatening hemorrhage. Resuscitation protocols are limited by the austere conditions of spaceflight. Solutions may be found in low-resource terrestrial settings. The existing literature on alternative blood product administration and walking blood banks was evaluated for applicability to spaceflight. STUDY DESIGN AND METHODS A literature review was done using PubMed and Google Scholar. References were crosschecked for additional publications not identified using the initial search terms. Twenty-seven articles were identified, including three controlled trials, six retrospective cohort analyses, 15 reviews, one case report, and two experimental studies. RESULTS Solutions to blood transfusion in austere settings include lyophilized blood products, hemoglobin-based oxygen carriers (HBOCs), and fresh whole blood. Many of these products are investigational. Protocols for walking blood banks include methods for screening and activating donors, transfusion, and monitoring for adverse reactions. Microgravity and mission limitations create additional challenges for transfusion, including baseline physiologic changes, difficulty reconstituting lyophilized products, risk of air emboli during transfusion, equipment constraints, and limited evacuation and surgical options. CONCLUSION Medical planning for space exploration should consider the possibility of acute blood loss. A model for "floating" blood banks based on terrestrial walking blood bank protocols from austere environments is presented, with suggestions for future development. Constraints on volume, mass, storage, and crew, present challenges to blood transfusion in space and must be weighed against the benefits of expanding medical capabilities.
Transfusion with Cold Stored Platelets in Patients Undergoing Complex Cardiothoracic Surgery with Cardiopulmonary Bypass Circulation
Transfusion. 2017;57((53)):3A.. p3-a03a.
Cold-stored apheresis platelets in treatment of postoperative bleeding in cardiothoracic surgery
Transfusion. 2016;56((S4)):16A.. s29-020b.
Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: a critical appraisal of the medical literature and available alternatives
The Journal of Trauma and Acute Care Surgery. 2015;78((6 Suppl 1)):S70-5.
BACKGROUND Hemorrhage remains the leading cause of preventable trauma-associated mortality. Interventions that improve prehospital hemorrhage control and resuscitation are needed. Tranexamic acid (TXA) has recently been shown to reduce mortality in trauma patients when administered upon hospital admission, and available data suggest that early dosing confers maximum benefit. Data regarding TXA implementation in prehospital trauma care and analyses of alternatives are lacking. This review examines the available evidence that would inform selection of hemostatic interventions to improve outcomes in prehospital trauma management as part of a broader strategy of "remote damage-control resuscitation" (RDCR). METHODS The medical literature available concerning both the safety and the efficacy of TXA and other hemostatic agents was reviewed. RESULTS TXA use in surgery was studied in 129 randomized controlled trials, and a meta-analysis was identified. More than 800,000 patients were followed up in large cohort study. In trauma, a large randomized controlled trial, the CRASH-2 study, recruited more than 20,000 patients, and two cohort studies studied more than 1,000 war casualties. In the prehospital setting, the US, French, British, and Israeli militaries as well as the British, Norwegian, and Israeli civilian ambulance services have implemented TXA use as part of RDCR policies. CONCLUSION Available data support the efficacy and the safety of TXA. High-level evidence supports its use in trauma and strongly suggests that its implementation in the prehospital setting offers a survival advantage to many patients, particularly when evacuation to surgical care may be delayed. TXA plays a central role in the development of RDCR strategies.