#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Effect of tranexamic acid administration on acute traumatic coagulopathy in rats with polytrauma and hemorrhage


Autoři: Xiaowu Wu aff001;  Avi Benov aff002;  Daniel N. Darlington aff001;  Jeffrey D. Keesee aff001;  Bin Liu aff001;  Andrew P. Cap aff001
Působiště autorů: Coagulation and Blood Research Program, United States Army Institute of Surgical Research, Fort Sam Houston, Texas, United States of America aff001;  Department of Surgery “A”, Meir Medical Center, Kfar Saba and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0223406

Souhrn

Trauma and hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model. Tranexamic Acid (TXA) is used as an anti-fibrinolytic agent to reduce surgical bleeding if administered prior to or during surgery, and to improve survival in trauma if given early after trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in trauma and determine whether administration of TXA as a supplement to FWB resuscitation could attenuate the established ATC in a rat model simulating prehospital resuscitation of polytrauma and hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on plasmin-induced fibrinolysis required pre-incubation of TXA and plasmin prior to clot initiation. In the rat model, ATC was induced by polytrauma followed by 40% hemorrhage. One hour after trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before trauma (TXA-BT), or 45min after trauma prior to resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real trauma patients (TXA-AT group). A single dose of TXA prior to trauma significantly delayed the onset of ATC from 30min to 120min after trauma as measured by a rise in prothrombin time (PT). The plasma d-dimer as well as plasminogen/fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to resuscitation (TXA-AT). In conclusion: Limited prehospital trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of resuscitation by attenuation of acute lung injury. By contrast, TXA given prior to trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory d-dimer, and delayed development of coagulopathy independent of reduction of fibrinogen levels following trauma. These findings highlight the importance of early administration of TXA in trauma, and suggest that further optimization of dosing protocols in trauma to exploit TXA’s various sites and modes of action may further improve patient outcomes.

Klíčová slova:

Blood – Resuscitation – Surgical and invasive medical procedures – Trauma surgery – Traumatic injury – Plasmins – Fibrinolysis


Zdroje

1. Rhee P, Joseph B, Pandit V, Aziz H, Vercruysse G, Kulvatunyou N, et al. Increasing trauma deaths in the United States. Ann Surg. 2014;260(1):13–21. doi: 10.1097/SLA.0000000000000600 24651132

2. Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, et al. Death on the battlefield (2001–2011): implications for the future of combat casualty care. J Trauma Acute Care Surg. 2012;73(6 Suppl 5):S431–7.

3. Niles SE, McLaughlin DF, Perkins JG, Wade CE, Li Y, Spinella PC, et al. Increased mortality associated with the early coagulopathy of trauma in combat casualties. J Trauma. 2008;64(6):1459–63; discussion 63–5. doi: 10.1097/TA.0b013e318174e8bc 18545109

4. Pidcoke HF, Aden JK, Mora AG, Borgman MA, Spinella PC, Dubick MA, et al. Ten-year analysis of transfusion in Operation Iraqi Freedom and Operation Enduring Freedom: increased plasma and platelet use correlates with improved survival. J Trauma Acute Care Surg. 2012;73(6 Suppl 5):S445–52.

5. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Holcomb JB. Warm fresh whole blood is independently associated with improved survival for patients with combat-related traumatic injuries. J Trauma. 2009;66(4 Suppl):S69–76.

6. Butler FK, Holcomb JB, Schreiber MA, Kotwal RS, Jenkins DA, Champion HR, et al. Fluid Resuscitation for Hemorrhagic Shock in Tactical Combat Casualty Care: TCCC Guidelines Change 14-01—2 June 2014. J Spec Oper Med. 2014;14(3):13–38. 25344706

7. Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124(5):608–13. doi: 10.1016/j.thromres.2009.06.034 19660788

8. Johansson PI, Sorensen AM, Perner A, Welling KL, Wanscher M, Larsen CF, et al. Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study. Crit Care. 2011;15(6):R272. doi: 10.1186/cc10553 22087841

9. Chapman MP, Moore EE, Moore HB, Gonzalez E, Gamboni F, Chandler JG, et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg. 2016;80(1):16–23; discussion -5. doi: 10.1097/TA.0000000000000885 26491796

10. Raza I, Davenport R, Rourke C, Platton S, Manson J, Spoors C, et al. The incidence and magnitude of fibrinolytic activation in trauma patients. Journal of thrombosis and haemostasis: JTH. 2013;11(2):307–14. doi: 10.1111/jth.12078 23176206

11. Wu X, Darlington DN, Cap AP. Procoagulant and fibrinolytic activity after polytrauma in rat. Am J Physiol Regul Integr Comp Physiol. 2016;310(4):R323–9. doi: 10.1152/ajpregu.00401.2015 26632604

12. Darlington DN, Craig T, Gonzales MD, Schwacha MG, Cap AP, Dubick MA. Acute coagulopathy of trauma in the rat. Shock. 2013;39(5):440–6. doi: 10.1097/SHK.0b013e31829040e3 23481505

13. collaborators C-, 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(9771):1096–101, 101 e1-2. doi: 10.1016/S0140-6736(11)60278-X 21439633

14. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113–9. doi: 10.1001/archsurg.2011.287 22006852

15. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg. 2013;148(3):218–25. doi: 10.1001/jamasurg.2013.764 23670117

16. Boutonnet M, Abback P, Le Sache F, Harrois A, Follin A, Imbert N, et al. Tranexamic acid in severe trauma patients managed in a mature trauma care system. J Trauma Acute Care Surg. 2018;84(6S Suppl 1):S54–S62.

17. Tengborn L, Blomback M, Berntorp E. Tranexamic acid—an old drug still going strong and making a revival. Thromb Res. 2015;135(2):231–42. doi: 10.1016/j.thromres.2014.11.012 25559460

18. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054. doi: 10.1136/bmj.e3054 22611164

19. Collaborators WT. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105–16. doi: 10.1016/S0140-6736(17)30638-4 28456509

20. collaborators C-t, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, 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(9734):23–32. doi: 10.1016/S0140-6736(10)60835-5 20554319

21. Cap AP. Plasmin: a driver of hemovascular dysfunction. Blood. 2016;128(20):2375–6. doi: 10.1182/blood-2016-09-735720 27856467

22. Wu X, Dubick MA, Schwacha MG, Cap AP, Darlington DN. Tranexamic Acid Attenuates The Loss of Lung Barrier Function in a Rat Model of Polytrauma And Hemorrhage With Resuscitation. Shock. 2017;47(4):500–5. doi: 10.1097/SHK.0000000000000758 27648695

23. Chen J, Wu X, Keesee J, Liu B, Darlington DN, Cap AP. Limited Resuscitation With Fresh or Stored Whole Blood Corrects Cardiovascular and Metabolic Function in a Rat Model of Polytrauma and Hemorrhage. Shock. 2017;47(2):208–16. doi: 10.1097/SHK.0000000000000748 27648698

24. Mischke R, Wolling H. Influence of fibrinogen degradation products on thrombin time, activated partial thromboplastin time and prothrombin time of canine plasma. Haemostasis. 2000;30(3):123–30. doi: 10.1159/000022534 11014962

25. Haverkate F, Timan G, Nieuwenhuizen W. Anticlotting properties of fragments D from human fibrinogen and fibrin. Eur J Clin Invest. 1979;9(4):253–5. doi: 10.1111/j.1365-2362.1979.tb00881.x 118016

26. Chin TL, Moore EE, Moore HB, Gonzalez E, Chapman MP, Stringham JR, et al. A principal component analysis of postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis. Surgery. 2014;156(3):570–7. doi: 10.1016/j.surg.2014.04.030 24962188

27. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2017;376(2):136–48. doi: 10.1056/NEJMoa1606424 27774838

28. Chapman MP, Moore EE, Ramos CR, Ghasabyan A, Harr JN, Chin TL, et al. Fibrinolysis greater than 3% is the critical value for initiation of antifibrinolytic therapy. J Trauma Acute Care Surg. 2013;75(6):961–7; discussion 7. doi: 10.1097/TA.0b013e3182aa9c9f 24256667

29. Wygrecka M, Marsh LM, Morty RE, Henneke I, Guenther A, Lohmeyer J, et al. Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood. 2009;113(22):5588–98. doi: 10.1182/blood-2008-08-170837 19182206

30. Lighvani S, Baik N, Diggs JE, Khaldoyanidi S, Parmer RJ, Miles LA. Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT. Blood. 2011;118(20):5622–30. doi: 10.1182/blood-2011-03-344242 21940822

31. Gong Y, Hart E, Shchurin A, Hoover-Plow J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest. 2008;118(9):3012–24. doi: 10.1172/JCI32750 18677407

32. Carter DW, Prudovsky I, Kacer D, Soul T, Kumpel C, Pyburn K, et al. Tranexamic acid suppresses the release of mitochondrial DAMPs and reduces lung inflammation in a murine burn model. J Trauma Acute Care Surg. 2019;86(4):617–24. doi: 10.1097/TA.0000000000002177 30589751

33. Peng Z, Ban K, LeBlanc A, Kozar RA. Intraluminal tranexamic acid inhibits intestinal sheddases and mitigates gut and lung injury and inflammation in a rodent model of hemorrhagic shock. J Trauma Acute Care Surg. 2016;81(2):358–65. doi: 10.1097/TA.0000000000001056 27027557

34. Darlington DN, Gonzales MD, Craig T, Dubick MA, Cap AP, Schwacha MG. Trauma-Induced Coagulopathy Is Associated with a Complex Inflammatory Response in the Rat. Shock. 2015;44 Suppl 1:129–37.


Článek vyšel v časopise

PLOS One


2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

plice
INSIGHTS from European Respiratory Congress
nový kurz

Současné pohledy na riziko v parodontologii
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií
Autoři: prof. MUDr. Petr Němec, Ph.D.

Střevní příprava před kolonoskopií
Autoři: MUDr. Klára Kmochová, Ph.D.

Všechny kurzy
Kurzy Podcasty Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#