Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 18  |  Issue : 4  |  Page : 309-311

Role of tranexamic acid in trauma: Recent updates


Department of Emergency Medicine, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission09-Mar-2020
Date of Decision09-Mar-2020
Date of Acceptance08-Apr-2020
Date of Web Publication19-Oct-2020

Correspondence Address:
Dr. Sandeep Nathanael David
Department of Emergency Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_26_20

Rights and Permissions
  Abstract 


Tranexamic acid (TXA) is a wonder drug in the acute management of hemorrhage in trauma. Recent publication of the CRASH-3 trial results further exemplifies this drug's use in isolated head injury. This article is a review of scientific evidence for TXA in trauma. There is an established role of TXA in trauma with intracranial hemorrhage within 3 h of presentation with 1.5% decrease in mortality of trauma victims with isolated head injury, as per the results of the CRASH-3 trial. However, the optimal dosing and role of the second dose of TXA requires further verification.

Keywords: Head injury, tranexamic acid, trauma, update


How to cite this article:
Jindal A, David SN. Role of tranexamic acid in trauma: Recent updates. Curr Med Issues 2020;18:309-11

How to cite this URL:
Jindal A, David SN. Role of tranexamic acid in trauma: Recent updates. Curr Med Issues [serial online] 2020 [cited 2020 Nov 26];18:309-11. Available from: https://www.cmijournal.org/text.asp?2020/18/4/309/298587




  Background Top


Tranexamic acid (TXA) has been extensively researched upon over the past two decades among patients with various bleeding manifestations. Its role has been emphasized in military and civilian trauma with significant hemorrhage from the results of two large randomized controlled trials, namely MATTERs[1] and CRASH-2,[2] respectively. On the basis of these results, TXA was included in guidelines for the prehospital care of patients with trauma, although patients with isolated traumatic brain injury were specifically excluded.[3] Therefore, the role of TXA among patients with intracranial hemorrhage was a matter of great debate. The CRASH-3 trial[3] which was published in October 2019 attempted to address the uncertainties related to the use of TXA in head-injured patients. This review is aimed to critically appraise the current evidence of the role of TXA in trauma.


  Pathophysiology of Trauma-Induced Coagulopathy Top


Acute blood loss from trauma induces a coagulopathy [Figure 1] as a result of hypovolemic shock, metabolic acidosis, hypothermia, and hemodilution following crystalloid administration during resuscitation. As a result of tissue injury and profuse exsanguination following trauma, there is an increased production of tissue factor which is accompanied by increased thrombin generation and activation. This, in turn, activates the coagulation cascade that leads to fibrin formation. Simultaneously, tissue hypoxia and ischemia from hemorrhagic shock increases the release of tissue-plasminogen activator (t-PA) from endothelial Weibel–Palade bodies causing fibrinolysis. These two mechanisms form the basis of trauma-induced coagulo-fibrinopathy which can be categorized as disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype.[4] A physiological response to such a phenomenon is to produce increased levels of plasminogen activator inhibitor 1 (PAI-1) which is the principal inhibitor of t-PA as it prevents the formation of plasmin. There is a significant delay in the release of PAI-1 in case of hypovolemic shock and hypoxia at the cellular level which worsens the unchecked blood loss due to DIC in the early hours following trauma.[4]
Figure 1: Mechanism of trauma-induced coagulopathy.

Click here to view



  Pharmacological Mechanisms of Tranexamic Acid Top


TXA is a synthetic derivative of the amino acid lysine and has a high affinity for the lysine-binding sites of plasminogen. Thus, it blocks the interaction of plasminogen with the lysine residues of fibrin and exhibits an antifibrinolytic effect.[4] Because the development of DIC associated with the fibrinolytic phenotype may increase the mortality in trauma, TXA is potentially beneficial to patients who have developed hemostatic abnormalities during the early phase of trauma.[5] Conversely, a delayed increase in PAI-1 levels results in the inhibition of fibrinolysis in the later phase. The administration of TXA could accelerate this change and cause detrimental effects when it is used during the fibrinolytic shutdown phase. This has been demonstrated in numerous basic research studies and an exploratory analysis of the CRASH-2 trial,[5],[6] which showed an increase in the prothrombotic state by TXA administration in the later phase of trauma. Therefore, it is important to estimate the coagulation/fibrinolysis status of the patient in order to gain the greatest benefit from TXA administration in patients with severe trauma.


  Evidence of Tranexamic Acid among Head Injury Patients-Crash 3 Trial Top


TXA was hypothesized to reduce intracranial hematoma expansion and thus improves the outcome among such patients. The role of TXA was evaluated among patients with stroke secondary to intracerebral hemorrhage in the TICH-2[7] trial. The results of the study suggested a reduction in early deaths and serious adverse events, but it failed to show a significant difference in the primary objective of functional status 90 days after intracerebral hemorrhage between patients who received TXA and those who received placebo.

The CRASH 3 trial[3] was a multicenter randomized placebo-controlled trial that included 12,639 patients with isolated moderate-to-severe (Glasgow Coma Scale [GCS] <12) traumatic brain injury, out of which 9227 (73%) received treatment within 3 h. The study was powered to detect a relative risk reduction of 15% in 28-day mortality, that is from 20% in the placebo group to 17% in the TXA group [Table 1].
Table 1: Effect of tranexamic acid on head injury-related death in patients randomly assigned within 3 h of injury

Click here to view


Results of the study showed that in 3880 head injury patients, there were 485 deaths among those who received TXA within 3 h of injury with a GCS <12, but >3 with reactive pupils, as compared to 525 deaths among 3757 patients in the placebo group. There was 11% reduction of mortality in the TXA group as compared to the placebo, which varied from 20% less chance to no difference at all. There was an absolute risk reduction in mortality of 1.5% among the TXA group. This, in turn, translated to treating 67 patients with TXA in order to save one extra life. In the Indian scenario, the cost of TXA is approximately Rs. 69 per 500 mg. The total dose of TXA required for the treatment of one patient is 2 g. Therefore, the total cost of treating one patient is approximately Rs. 276, and the cost involved to treat 67 patients to save one extra life approximates to Rs. 18,500.


  Early Initiation of Tranexamic Acid in Trauma Top


There was a modification made in the protocol of the CRASH-3 trial to recruit the patients who present within 3 h of trauma as compared to 8 h previously specified. This was done based on the upcoming evidence[8] at that time and without looking at the interim results of the study. This highlights the importance of early or prehospital administration of the drug, especially in a developing country such as India. A study done by Stein et al.[9] at three Level-1 trauma centers in Switzerland, compared the prehospital administration of TXA with a matched retrospective cohort. The study evaluated the pathophysiological aspects of TXA administration by performing whole blood rotational thromboelastometry and found that:

  1. Reduction in maximum clot firmness from on-scene to the Emergency Department (ED) was significantly less in the TXA group compared to the control group
  2. Fibrinolysis was inhibited by prehospital TXA application
  3. D-dimer production is significantly lower in the TXA group.


This provides pathophysiological evidence of the effectiveness of prehospital administration of TXA among trauma patients.


  Dosing of Tranexamic Acid Top


Both the CRASH 2 and CRASH 3 trials had selected the dosing regimen as loading dose of 1 g of TXA infused over 10 min, followed by an intravenous infusion of 1 g over 8 h in 100 ml of 0.9% normal saline[1],[3] based on previous studies carried out in surgical subjects. However, there is an ongoing trial that is aimed at evaluating the effects of the administration of the second dose of TXA in trauma patients within the hospital setting.[10] The results of this trial will be able to address various concerns regarding the second dose of TXA.


  Adverse Effects of Tranexamic Acid Administration Top


TXA is known to cause vaso-occlusive events such as pulmonary embolism, deep vein thrombosis, fatal or nonfatal stroke, and myocardial infarction. Furthermore, it can cause seizures when given in large doses.[11] This was one reason why TXA was previously not used in patients with isolated head injury. The CRASH 3 trial evaluated the safety of the drug among isolated head injury patients and did not find any significant increase in disability, vaso-occlusive events, or other complications such as seizures or gastrointestinal bleeding in the intervention arm regardless of the time of the administration of the drug. This is contradictory to the hypothesis that delayed administration of TXA may lead to prothrombotic state. The awaited results of ongoing trial on efficacy of the second dosing[10] will also be able to clarify this controversy.


  Tranexamic Acid in Pediatric Trauma Top


Till date, there are no clinical trials published that have evaluated the efficacy of TXA in trauma patients aged < 18 years. A retrospective analysis of the use of TXA in pediatric trauma was done by Eckert et al.,[12] and they found that the use of TXA in severe abdominal/extremity injury or with metabolic acidosis was associated with a decrease in mortality. Although the mechanism of trauma-induced coagulopathy and action of TXA is thought to be similar in adults and children, especially adolescents, there are concerns regarding the increased risk of seizures among children.[13] A multicentric trial labeled, Traumatic Injury Clinical Trial Evaluating TXA in Children trial, is being conducted at four pediatric level 1 trauma centers in the United States.[14] This aims to provide evidence for benefits and adverse effects of TXA in pediatric trauma.


  Conclusion Top


  • Fibrinolytic type of DIC is the main cause of trauma-induced coagulopathy
  • TXA has an established role in reducing mortality in trauma victims with extracranial hemorrhage when given within 3 h of trauma
  • There is benefit of administering TXA to traumatic brain-injured patients, and the results are ready for clinical implementation
  • The timing of initiation of TXA is very crucial, which emphasizes the need for good prehospital care
  • TXA might not be as safe as initially thought and further studies are required to evaluate its side effects in trauma victims.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of TXA on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 2010;376:10.  Back to cited text no. 1
    
2.
Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of TXA in trauma emergency resuscitation (MATTERs) study. Arch Surg 2012;147:113-9.  Back to cited text no. 2
    
3.
CRASH-3 Trial Collaborators. Effects of TXA on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): A randomised, placebo-controlled trial. Lancet 2019;394:1713-23.  Back to cited text no. 3
    
4.
Nishida T, Kinoshita T, Yamakawa K. TXA and trauma-induced coagulopathy. J Intensive Care 2017;5:5.  Back to cited text no. 4
    
5.
CRASH-2 Collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377:1096-101, 1101.e1-2.  Back to cited text no. 5
    
6.
Roberts I, Edwards P, Prieto D, Joshi M, Mahmood A, Ker K, et al. Tranexamic acid in bleeding trauma patients: An exploration of benefits and harms. Trials 2017;18:48.  Back to cited text no. 6
    
7.
Sprigg N, Flaherty K, Appleton JP, Salman RA, Bereczki D, Beridze M, et al. TXA for hyperacute primary IntraCerebral haemorrhage (TICH-2): An international randomised, placebo-controlled, phase 3 superiority trial. Lancet 2018;391:2107-15.  Back to cited text no. 7
    
8.
Shiraishi A, Kushimoto S, Otomo Y, Matsui H, Hagiwara A, Murata K, et al. Effectiveness of early administration of TXA in patients with severe trauma: Early administration of TXA in patients with severe trauma. Br J Surg 2017;104:710-7.  Back to cited text no. 8
    
9.
Stein P, Studt JD, Albrecht R, Müller S, von Ow D, Fischer S, et al. The impact of prehospital TXA on blood coagulation in trauma patients. Anesthesia Analgesia 2018;126:522-9.  Back to cited text no. 9
    
10.
Evaluation of the Safety and Efficacy of the Second Dose of TXA – Full Text View; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT03846973?cond=tranexamic+acid&draw=2&rank=1. [Last accessed on 2020 Jan 14].  Back to cited text no. 10
    
11.
Ramirez RJ, Spinella PC, Bochicchio GV. Tranexamic acid update in trauma. Crit Care Clin 2017;33:85-99.  Back to cited text no. 11
    
12.
Eckert M, Wertin T, Tyner S, Nelson D, Izenberg S, Martin M. TXA administration to pediatric trauma patients in a combat setting: The pediatric trauma and TXA study (PED-TRAX). J Trauma Acute Care Surg 2014;77:852-8.  Back to cited text no. 12
    
13.
Loi MM, Derderian SC, Bennett TD. TXA and seizures in pediatric trauma. Pediatr Crit Care Med 2018;19:1177-8.  Back to cited text no. 13
    
14.
Nishijima DK, VanBuren J, Hewes HA, Myers SR, Stanley RM, Adelson PD, et al. Traumatic injury clinical trial evaluating tranexamic acid in children (TIC-TOC): study protocol for a pilot randomized controlled trial. Trials 2018;19:593. https://doi.org/10.1186/s13063-018-2974-z.  Back to cited text no. 14
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Background
Pharmacological ...
Evidence of Tran...
Early Initiation...
Dosing of Tranex...
Adverse Effects ...
Tranexamic Acid ...
Conclusion
Pathophysiology ...
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed183    
    Printed4    
    Emailed0    
    PDF Downloaded34    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]