Friday, August 18, 2017

TXA Isn’t For Everyone: Fibrinolysis Shutdown in Traumatically Injured Patients

Tranexamic acid (TXA), an antifibrinolytic agent used to prevent clot breakdown in hemorrhaging trauma patients, has been shown in the CRASH-2, MATTERS, and PED-TRAX trials to reduce overall mortality in adult and pediatric patients.1-3 Additional mortality benefits were seen in the MATTERS trial among patients who received a massive transfusion protocol (MTP) with a number needed to treat (NNT) of 15 in the overall cohort compared to a NNT of 7 in MTP cohort.2 Although CRASH-2 is not without its criticism,4 TXA has been widely recommended for the treatment of traumatically injured patients.5 However, recent trials in mature trauma systems have shown conflicting results for mortality and increased rates of venous thromboembolism (VTE) with TXA.6-8


table 2.pngViscoelastic assays, such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM), are becoming increasingly popular tools to guide resuscitation compared to older, less helpful tests, such as aPTT and PT/INR. Both Taming the SRU9 and LITFL10 have excellent reviews of TEG, but briefly, TEG measures the dynamics of clot development, stabilization/strength, and dissolution providing a glimpse into a patient’s real-time hemostatic state.10 Emerging research utilizing TEG has identified 3 distinct fibrinolysis phenotypes among traumatically injured patients: hyperfibrinolysis, physiologic fibrinolysis  (i.e., normal), and fibrinolysis shutdown.11,12 These phenotypes are based on the Ly30 which measures the percentage of clot lysis 30 minutes after maximum amplitude (see Table 1).11



Hyperfibrinolysis patients have high levels of circulating endogenous tissue plasminogen activator (tPA) compared to fibrinolysis shutdown patients whose majority of tPA is complexed with plasminogen activator inhibitor 1 (PAI-1) resulting in undetectable free tPA levels.13  Moore et al completed a bi-institutional study of two Level 1 Trauma Centers who analyzed rapid TEGs drawn within 1 hour of injury in severely injured patients, defined as an Injury Severity Score (ISS) of greater than 15, in attempts to identify a fibrinolysis spectrum and determine effects of fibrinolysis phenotypes on post-injury outcomes.12 Patients were excluded if they were on anticoagulant therapy or received antifibrinolytics prior to TEG. A total of 2,540 patients were analyzed with a median ISS of 25 and an overall mortality of 21%. Fibrinolysis shutdown was the most common phenotype seen in 46% of patients, followed by physiologic fibrinolysis in 36%, and hyperfibrinolysis in 18%.  Mortality was highest in hyperfibrinolysis patients (34%), followed fibrinolysis shutdown (23%) and physiologic fibrinolysis (15%). Hyperfibrinolysis patients were more likely to expire early from hemorrhage compared to either other group. Fibrinolytic shutdown patients on the other hand, tended to have delayed mortality secondary to traumatic brain injury or organ dysfunction.12


Meizoso et al completed another study comparing TEGs drawn upon ICU admission to results drawn 1 week later among 182 traumatically injured patients. They also identified fibrinolysis shutdown as the most common phenotype (58%) compared to only 4% of patients with hyperfibrinolysis. After 1 week, 78 patients had an additional TEG drawn showing 44% of patients were in “persistent shutdown” and 56% had an improvement in their Ly30 and were categorized as “transient shutdown.” Both persistent and transient shutdown groups has similar ICU and hospital length of stays, but the persistent shutdown group experienced significantly higher mortality (21% vs 5%).14


Meizoso et al’s results echo those of Moore et al in that fibrinolysis shutdown was the most common phenotype seen amongst severely injured trauma patients. However, Meizoso’s much lower proportion of patients with hyperfibrinolysis is likely attributed to the time in which the TEGs were drawn. Moore’s were drawn within 1 hour of injury compared to Meizoso’s drawn at the time of ICU admission. A TEG drawn at ICU admission reflects post-resuscitation hemostasis, and combined with the potential for survivor bias (as we know hyperfibrinolysis patients are at increased risk for early mortality due to exsanguination) likely resulted in the much lower incidence of hyperfibrinolysis seen in Meizoso’s cohort compared to Moore’s (4% vs 18%).


So where does TXA fit into current trauma resuscitation? If we assume almost half of all trauma patients coming to our trauma bay are in fibrinolysis shutdown, the subsequent empiric administration of TXA without a TEG result seems risky.  Data from mature trauma systems have shown TXA to only be of benefit in shocked patients8  but based on the work by Moore et al, patients in shock can be hyperfibrinolytic or in fibrinolysis shutdown.11,12 Data are still conflicting regarding injury mechanisms predisposing patients to one particular phenotype.12,14 Per Moore et al, it “remains unclear why patients with a similar degree of shock and injury severity could have substantially different levels of fibrinolysis.”13 Rapid TEG is the only way to reliably identify patients who may potentially benefit from the administration of TXA (i.e., hyperfibrinolysis; currently unknown if physiologic fibrinolysis would benefit) and which patients may potentially be harmed (fibrinolysis shutdown).


This raises the question, should all TXA be withheld until after TEG results are available? Pre-hospital TXA administration is increasing.15 Are we doing our patients a disservice by administering a therapy which will potentially further worsen their hemostasis? Or does early administration of TXA offer more benefit (and therefore outweigh the risk of administration to patients in fibrinolysis shutdown) than if given later when TEG results have been drawn and resulted? The PATCH Study16and STAAMP Trial17 are currently recruiting patients in attempt to answer this question. Additionally, the COAST Score18 is a prehospital tool under study in Queensland, Australia which seeks to identify patients more likely to develop acute traumatic coagulopathy. The score ranges from 0-7 with points based on blood pressure, temperature, vehicular entrapment, presence of major chest injury, and potential for intraabdominal or pelvic injury.  A score of > 3 is “a good predictor of patients requiring TXA.” However, as stated above, patients with similar injury patterns and shock can still have different fibrinolysis phenotypes so this tool may not be completely accurate.


There is unfortunately little data regarding the use of TXA based on in-hospital TEG results. The best so far was a retrospective review completed by Harvin et al which identified traumatically injured patients with an admission Ly30 > 3% (i.e., hyperfibrinoloysis) stratified by the administration of TXA or not. Similar to Meizoso’s study, only 6% of the total trauma population was found to be in hyperfibrinolysis on admission and was included for analysis (1,032 of 17,629 patients). Although the TXA group was more severely injured, had a lower GCS and BP, received more blood products, and were more likely to go immediately to the operating room, after multivariate adjustment there was no difference in in-hospital mortality between groups. Additionally, there was no difference in the repeat Ly30s between TXA and non-TXA treated patients (repeat Ly30 median 0.0% vs 0.4%, respectively, p=0.096). Even in the population most likely to benefit from TXA (as all patients were hyperfibrinolytic), TXA therapy did not improve outcomes and the non-TXA treated patients had similar resolution of their hyperfibrinolytic state based on repeat Ly30s. As a result, the authors conclude that “the effectiveness of TXA in mature Level 1 trauma center[s] with rapid prehospital transport, access to early blood products, and a ready operating room is unclear.”19


Also, does the 3-hour window of time of injury to TXA administration from the CRASH-2 exploratory analysis still apply?20 We know patient’s fibrinolysis phenotype can change during the course of their resuscitation and hospital stay.14,19 Would a prolonged state of hyperfibrinolysis beyond 3 hours from time of injury exclude them from a potentially life-saving therapy? CRASH-2 patients were a different population compared to Moore and Meizoso’s patients, so can you extrapolate those results to these populations?


Additionally, does the dosing protocol from CRASH-2 (1 g bolus followed by 1 g over 8-hours) still make sense? As stated, patient’s fibrinolysis phenotypes change during resuscitation. Patients who present to the ED in one phenotype may soon be in fibrinolysis shutdown in the ICU and an 8-hour infusion of TXA would not be wise. A recent “Commentary and Conversation: Interactive Social Media Discussion about Persistent Fibrinolysis Shutdown” was held by the Journal of the American College of Surgeons and published online21 on April, 25 2017. Dr. Karim Brohi himself had this to say: “Regarding the necessity of a second TXA dose, probably not. No published studies, but our local data suggests [an] initial 1 g bolus sufficient in [the] vast majority of cases.”


Or, is all this over-exaggerated? Should we base our therapeutic decisions for TXA on the results of a trial with over 20,000 patients instead of studies with one-tenth (or less) that number? Obviously additional studies are needed with prospective, randomized, TEG-driven protocols, but unfortunately, at this point we may have more questions than answers. Maybe the most important question now is whether or not this data will result in any change in how you think about TXA in your trauma patients? I know it has for me.



Scott Dietrich, PharmD
@PCC_PharmD
Emergency Medicine Pharmacist
University of Colorado Health – North




References:
  1. CRASH-2 Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusions in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet. 2010;376(9734):23-32
  2. Morrison JJ, Dubose JJ, Rasmussen TD, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERS) study. Arch Surg. 2012;147(2):113-119
  3. Eckert MJ, Wertin TM, Tyner SD, Nelson DW, Izenberg S, Martin MJ. Tranexamic acid administration to pediatric trauma patients in a combat setting: the pediatric trauma and tranexamic acid study (PED-TRAX). J Trauma Acute Care Surg. 2014;77(6):852-858
  4. Binz S, McCollester J, Thomas S, Miller J, Pohlman T, Waxman D, Shariff F, Tracy R, Wash M. CRASH-2 study of tranexamic acid to treat bleeding in trauma: a controversy fueled by science and social media. J Blood Transf. 2015;2015:874920
  5. SMACC “Karim Brohi on tranexamic acid in trauma.” https://www.smacc.net.au/2015/10/karim-brohi-on-tranexamic-acid-in-trauma/ [accessed 5/4/2017].
  6. Swendsen H, Galante J, Utter G, Bateni S, Scherer L, Schermer C. Tranexamic acid use in trauma: effective but not without consequences. J Trauma & Treatment. 2013;2(4)
  7. Valle EJ, Allen CJ, Van Haren RM, Jouria JM, Li H, livingstone AS, Namias N, Schulman CI, Proctor KG. Do all trauma patients benefit from tranexamic acid? J Trauma Acute Care Surg. 2014;76(6):1373-1378
  8. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg. 2015;261(2):390-394
  9. Hill J. Thromboelastography aka The TEG. Aug, 16 2015.  http://www.tamingthesru.com/blog/grand-rounds/teg
  10. Nikson C. Thromboelastogram (TEG). July, 11 2014. https://lifeinthefastlane.com/ccc/thromboelastogram-teg/
  11. Moore et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown - spectrum of post-injury fibrinolysis and relevance to TXA therapy -- J Trauma. 2014;77(6):811-817
  12. Moore et al. Acute fibrinolysis shutdown after injury occurs frequently and increases mortality -- J Am Coll Surg. 2016;222(4):347-355
  13. Moore HB, Moore EE, Gonzalez E, Hansen KC, Dzieciatkowska M, Chapman MP, Sauaia A, West B, Banerjee A, Silliman CC. Hemolysis exacerbates hyperfibrinolysis, whereas plateolysis shuts down fibrinolysis: evolving concepts of the spectrum of fibrinolysis in response to severe injury. Shock. 2015;43(1):39-46.
  14. Meizoso JP, Karcutskie CA, Ray JJ, Namias N, Schulman CI, Proctor KG. Persistent fibrinolysis shutdown is associated with increased mortality in severely injured trauma patients. J Am Coll Surg. 2017;224(4):575-582
  15. Napolitano LM. Prehospital tranexamic acid: what is the current evidence? Trauma Surg and Acute Care Open. 2017;2:1-7
  16. Clinicaltrials.gov, “Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH Study).” https://clinicaltrials.gov/ct2/show/NCT02187120
  17. Clinicaltrials.gov, “Study of Tranexamic Acid During Air Medical Prehospital Transport Trial (STAAMP Trial).” https://clinicaltrials.gov/ct2/show/NCT02086500
  18. Clinical Quality & Patient Safety Unit. “Clinical Practice Procedures: Assessment/COAST score.” October, 2016. https://www.ambulance.qld.gov.au/docs/clinical/cpp/CPP_COAST%20score.pdf
  19. Harvin JA, Pierce CA, Mims MM, Hudson JA, Podbielski JM, Wade CE, Holcomb JB, Cotton BA. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg. 2015;78(5):905-909
  20. CRASH-2 Collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomized trial. Lancet. 2011;377(9771):1096-1101
  21. Commentary and Conversation: RAS-ACS and JACS Hosted Interactive Social Media Discussion about Persistent Fibrinolysis Shutdown. April 7, 2017. http://www.journalacs.org/RAS-ACS-discussion-2017-04

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