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

Spinella, Philip C.; Bochicchio, Kelly; Thomas, Kimberly A.; Staudt, Amanda M; Shea, Susan M.; Schuerer, Douglas; Levy, Jerrold H.; Andrew, P.; Bochicchio, Grant V.

doi:10.1111/trf.16962

Cited by 12 publications

(18 citation statements)

References 41 publications

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“…While there were no differences in age between the three study groups, the bolus plus infusion group had more females (34%) versus single bolus (17%) versus double bolus (16%) ( p = 0.002; Table 1). Similarly, patients in this group had significantly higher median Injury Severity Score (ISS) 24–43 versus single bolus ISS 14–38 versus double bolus ISS (25, 16–34; p = 0.001). Patients who received bolus plus infusion had significantly higher rates of blunt injury, while the double bolus group had a higher proportion of severe abdominal injuries (Table 1).…”

Section: Resultsmentioning

confidence: 88%

“…In view of these potential difficulties in adhering to the trial protocol, alternative dosing strategies have been investigated for trauma hemorrhage. [15][16][17][18][19] The prehospital STAMPP trial found a reduction in mortality with the use of two, sequential 1-g boluses, followed by a 1-g infusion when compared with placebo. 16 In addition, there are theoretical concerns about the prolonged exposure to TXA via an 8-hour infusion during the very dynamic phase of postinjury fibrinolysis.…”

Section: Questionsmentioning

confidence: 99%

“…In clinical practice, the administration of a 1-g infusion over many hours, as per the CRASH-2 protocol, can prove logistically challenging during the initial trauma resuscitation, particularly when patients require a number of life-saving interventions. In view of these potential difficulties in adhering to the trial protocol, alternative dosing strategies have been investigated for trauma hemorrhage 15–19 . The prehospital STAMPP trial found a reduction in mortality with the use of two, sequential 1-g boluses, followed by a 1-g infusion when compared with placebo 16 .…”

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confidence: 99%

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A Comparative Analysis of Tranexamic Acid Dosing Strategies in Traumatic Major Hemorrhage

Gunn,

Stevenson,

Almuwallad

et al. 2023

J Trauma Acute Care Surg

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Introduction Tranexamic acid (TXA) is a life-saving treatment for traumatic hemorrhage, but the optimal dosing regimen remains unknown. Different doses and treatment strategies have been proposed, including single bolus, repeated bolus or bolus plus infusion. The aim of this study was to determine the effect of different TXA dosing strategies on clinical outcomes in bleeding trauma patients. Methods Secondary analysis of a perpetual cohort study from a UK Level 1 trauma center. Adult patients who activated the local major hemorrhage protocol and received TXA were included. The primary outcome was 28-day mortality. Secondary outcomes were 24-hour mortality, multiple organ dysfunction syndrome (MODS), venous thromboembolism (VTE) and ROTEM fibrinolysis. Results Over an 11-year period, 525 patients were included. Three dosing groups were identified: 1 g bolus only (n = 317), 1 g bolus +1 g infusion over 8 hours (n = 80), and 2 g bolus (n = 128). Demographics and admission physiology were similar, but there were differences in injury severity (median ISS: 25, 29 & 25); and admission systolic blood pressure (median SBP: 99, 108, 99 mmHg) across the 1 g, 1 g + 1 g and 2 g groups. 28-day mortality was 21% in each treatment group. The incidence of MODS was significantly higher in the bolus plus infusion group (84%) vs 1 g bolus (64%) and 2 g bolus (62%) group, p = 0.002, but on multivariable analysis was non-significant. VTE rates were similar in the 1 g bolus (4%), 2 g bolus (8%) and bolus plus infusion groups (7%). There was no difference in ROTEM Maximum Lysis at 24 hours: 5% in both the 1 g and 2 g bolus groups vs 4% in bolus plus infusion group. Conclusion Clinical outcomes and 24-hour fibrinolysis state were equivalent across three different dosing strategies of TXA. Single bolus administration is likely preferable to a bolus plus infusion regimen. Level of Evidence Level IV, Therapeutic/Care Management

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Section: Resultsmentioning

confidence: 88%

Section: Questionsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Comparative Analysis of Tranexamic Acid Dosing Strategies in Traumatic Major Hemorrhage

Gunn,

Stevenson,

Almuwallad

et al. 2023

J Trauma Acute Care Surg

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“…The contribution of plasmin is pertinent to major trauma because tranexamic acid is widely used to inhibit fibrinolysis and considered safe. However, there may be an increased risk of thromboembolic events in a subset of trauma patients, 23 warranting a further study to evaluate its interaction with innate hemostatic and immune systems.…”

Section: Fviii Activation and Inhibitionmentioning

confidence: 99%

Factor VIII: A Dynamic Modulator of Hemostasis and Thrombosis in Trauma

Tanaka

Terada

Butt

et al. 2023

Anesthesia &Amp; Analgesia

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A trace amount of thrombin cleaves factor VIII (FVIII) into an active form (FVIIIa), which catalyzes FIXa-mediated activation of FX on the activated platelet surface. FVIII rapidly binds to von Willebrand factor (VWF) after secretion and becomes highly concentrated via VWF-platelet interaction at a site of endothelial inflammation or injury. Circulating levels of FVIII and VWF are influenced by age, blood type (nontype O > type O), and metabolic syndromes. In the latter, hypercoagulability is associated with chronic inflammation (known as thrombo-inflammation). In acute stress including trauma, releasable pools of FVIII/VWF are secreted from the Weibel-Palade bodies in the endothelium and then augment local platelet accumulation, thrombin generation, and leukocyte recruitment. Early systemic increases of FVIII/VWF (>200% of normal) levels in trauma result in a lower sensitivity of contact-activated clotting time (activated partial thromboplastin time [aPTT] or viscoelastic coagulation test [VCT]). However, in severely injured patients, multiple serine proteases (FXa plasmin and activated protein C [APC]) are locally activated and may be systemically released. Severity of traumatic injury correlates with prolonged aPTT and elevated activation markers of FXa, plasmin, and APC, culminating in a poor prognosis. In a subset of acute trauma patients, cryoprecipitate that contains fibrinogen, FVIII/VWF, and FXIII is theoretically advantageous over purified fibrinogen concentrate to promote stable clot formation, but comparative efficacy data are lacking. In chronic inflammation or subacute phase of trauma, elevated FVIII/VWF contributes to the pathogenesis of venous thrombosis by enhancing not only thrombin generation but also augmenting inflammatory functions.

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“…5,6 While often debated, several studies have identified increased thrombotic risks associated with the administration of TXA to injured patients, particularly with higher doses. 7-12 Some data suggests the administration of TXA to patients with normal fibrinolysis may have a negative impact on mortality. 13,14 Further, a meta-analysis conducted in 2016 found both a dose-dependent risk of seizures in cardiothoracic surgery patients who received TXA.…”

Section: Introductionmentioning

confidence: 99%

Are Data Driving Our Ambulances? Liberal Use of Tranexamic Acid in the Prehospital Setting

Brito,

Stettler,

Fram

et al. 2023

The American Surgeon™

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Background Current data on tranexamic acid (TXA) supports early administration for severe hemorrhagic shock. Administration by EMS has been facilitated by developing protocols and standing orders informed by these data. In this study, patterns of TXA use by EMS agencies serving a large level 1 trauma center were examined. We hypothesized that current widespread TXA use often includes administration outside of data-driven indications. Methods The trauma registry at a level 1 trauma center was queried for patients who received TXA. To determine the practice patterns and appropriateness of administration of TXA, patients’ physiologic state in the prehospital environment based on EMS records, physiologic state on arrival to hospital, and interventions performed in both settings were examined. Over 20 separately managed EMS systems that administer TXA transport patients to this trauma center, allowing for a broad survey of practices. Results From 2016 to 2021 1089 patients received TXA, 406 (37.3%) having treatment initiated by EMS services. Of these, the average prehospital systolic blood pressure (SBP) was 108.2 mmHg and initial ED SBP was 107.8 mmHg. Only 58.4% of these patients received blood transfusion after arrival to this trauma center. Compliance with standard indications was low with only 14.6% of administrations meeting any data-driven SBP indication. Similar levels of compliance were seen across high volume EMS services. Discussion Tranexamic acid use has become common in trauma and has been adopted by many EMS systems. These results indicate TXA in the prehospital setting is over-used as administration is not being limited to indications that have shown benefit in prior data.

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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

Cited by 12 publications

References 41 publications

A Comparative Analysis of Tranexamic Acid Dosing Strategies in Traumatic Major Hemorrhage

A Comparative Analysis of Tranexamic Acid Dosing Strategies in Traumatic Major Hemorrhage

Factor VIII: A Dynamic Modulator of Hemostasis and Thrombosis in Trauma

Are Data Driving Our Ambulances? Liberal Use of Tranexamic Acid in the Prehospital Setting

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