Hypofibrinolysis induced by tranexamic acid does not influence inflammation and mortality in a polymicrobial sepsis model

Autoři: Yzabella Alves Campos Nogueira aff001;  Loredana Nilkenes Gomes da Costa aff001;  Carlos Emilio Levy aff001;  Fernanda Andrade Orsi aff001;  Franciele de Lima aff001;  Joyce M. Annichinno-Bizzacchi aff001;  Erich Vinicius De Paula aff001
Působiště autorů: School of Medical Sciences, University of Campinas, Campinas, SP, Brazil aff001;  Federal University of Piaui, Parnaiba, PI, Brazil aff002;  Hematology and Hemotherapy Center, University of Campinas, Campinas, SP, Brazil aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226871


The biological relevance of fibrinolysis to the host response to sepsis is illustrated by pathogens such as S. pyogenes and Y. pestis, whose virulence factors are proteins that challenge the balance between pro- and anti-fibrinolytic factors of the host, and by the consistent finding of hypofibrinolysis in the early stages of sepsis. Whether this hypofibrinolytic response is beneficial or detrimental to the host, by containing the spread of pathogens while at the same time limiting the access of immune cell to infectious foci, is still a matter of debate. Tranexamic acid (TnxAc) is an antifibrinolytic agent that is being increasingly used to prevent and control bleeding in conditions such as elective orthopedic surgery, trauma, and post-partum-hemorrhage, which are frequently followed by infection and sepsis. Here we used a model of polymicrobial sepsis to evaluate whether hypofibrinolysis induced by TnxAc influenced survival, tissue injury and pathogen spread. Mice were treated with two doses of TnxAc bid for 48h, and then sepsis was induced by cecal ligation and puncture. Despite the induction of hypofibrinolysis by TnxAc, no difference could be observed in survival, tissue injury (measured by biochemical and histological parameters), cytokine levels or pathogen spread. Our results contribute with a new piece of data to the understanding of the complex interplay between fibrinolysis and innate immunity. While our results do not support the use of TnxAc in sepsis, they also address the thrombotic safety of TnxAc, a low cost and widely used agent to prevent bleeding.

Klíčová slova:

Blood – Blood plasma – Fibrinolysis – Inflammation – Kidneys – Mouse models – Sepsis – Thrombosis


1. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149: 38–44. doi: 10.1016/j.thromres.2016.11.007 27886531

2. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13: 34–45. doi: 10.1038/nri3345 23222502

3. Fiusa MML, Carvalho-Filho MA, Annichino-Bizzacchi JM, De Paula E V. Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective. BMC Med. 2015;13: 105. doi: 10.1186/s12916-015-0327-2 25943883

4. Gando S, Levi M, Toh C-H. Disseminated intravascular coagulation. Nat Rev Dis Prim. 2016;2: 16037. doi: 10.1038/nrdp.2016.37 27250996

5. Bergmann S, Hammerschmidt S. Fibrinolysis and host response in bacterial infections. Thromb Haemost. 2007;98: 512–20. 17849039

6. Gando S. Role of fibrinolysis in sepsis. Semin Thromb Hemost. 2013;39: 392–9. doi: 10.1055/s-0033-1334140 23446914

7. Raaphorst J, Johan Groeneveld AB, Bossink AW, Erik Hack C. Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients. Thromb Haemost. 2001;86: 543–9. 11522001

8. Tipoe TL, Wu WKK, Chung L, Gong M, Dong M, Liu T, et al. Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis. Front Immunol. 2018;9: 1218. doi: 10.3389/fimmu.2018.01218 29967603

9. Sodeinde OA, Subrahmanyam Y V, Stark K, Quan T, Bao Y, Goguen JD. A surface protease and the invasive character of plague. Science. 1992;258: 1004–7. doi: 10.1126/science.1439793 1439793

10. Loof TG, Deicke C, Medina E. The role of coagulation/fibrinolysis during Streptococcus pyogenes infection. Front Cell Infect Microbiol. 2014;4: 128. doi: 10.3389/fcimb.2014.00128 25309880

11. McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs. 2012;72: 585–617. doi: 10.2165/11209070-000000000-00000 22397329

12. Tengborn L, Blombäck M, Berntorp E. Tranexamic acid–an old drug still going strong and making a revival. Thromb Res. 2015;135: 231–242. doi: 10.1016/j.thromres.2014.11.012 25559460

13. CRASH-2 trial collaborators, 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 (London, England). 2010;376: 23–32. doi: 10.1016/S0140-6736(10)60835-5

14. WOMAN Trial Collaborators H, Roberts I, Fawole B, Chaudhri R, El-Sheikh M, Akintan A, et al. 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 (London, England). 2017;389: 2105–2116. doi: 10.1016/S0140-6736(17)30638-4 28456509

15. Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 2009;4: 31–6. doi: 10.1038/nprot.2008.214 19131954

16. Schultz G, Tedesco MM, Sho E, Nishimura T, Sharif S, Du X, et al. Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice. Arterioscler Thromb Vasc Biol. 2010;30: 1363–70. doi: 10.1161/ATVBAHA.109.202259 20431069

17. Kłak M, Anäkkälä N, Wang W, Lange S, Jonsson I-M, Tarkowski A, et al. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis. Scand J Infect Dis. 2010;42: 351–8. doi: 10.3109/00365540903510690 20100112

18. Joshi N, Kopec AK, Towery K, Williams KJ, Luyendyk JP. The antifibrinolytic drug tranexamic Acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury. J Pharmacol Exp Ther. 2014;349: 383–92. doi: 10.1124/jpet.113.210880 24633426

19. Huet O, Ramsey D, Miljavec S, Jenney A, Aubron C, Aprico A, et al. Ensuring animal welfare while meeting scientific aims using a murine pneumonia model of septic shock. Shock. 2013;39: 488–94. doi: 10.1097/SHK.0b013e3182939831 23603767

20. Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris; relation to gender, age and acute-phase reaction. Results of the ECAT Angina Pectoris Study Group. Thromb Haemost. 1995;73: 561–7. 7495059

21. Alves GSA, Orsi FA, Santiago-Bassora FD, Quaino SKP, Montalvão SAL, Paula EV de, et al. Laboratory evaluation of patients with undiagnosed bleeding disorders. Blood Coagul Fibrinolysis. 2016;27: 500–505. doi: 10.1097/MBC.0000000000000444 26825625

22. Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost. 2007;5 Suppl 1: 24–31. doi: 10.1111/j.1538-7836.2007.02519.x 17635705

23. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune responses to sepsis. Virulence. Landes Bioscience; 2014;5: 36–44. doi: 10.4161/viru.25436 23774844

24. Opal SM. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit Care Med. 2000;28: S77–80. doi: 10.1097/00003246-200009001-00017 11007204

25. Ahrenholz DH, Simmons RL. Fibrin in peritonitis. I. Beneficial and adverse effects of fibrin in experimental E. coli peritonitis. Surgery. 1980;88: 41–7. 6992321

26. Polk HC, Fry DE. Radical peritoneal debridement for established peritonitis. The results of a prospective randomized clinical trial. Ann Surg. 1980;192: 350–5. doi: 10.1097/00000658-198009000-00010 6998389

27. van Veen SQ, Meijers JCM, Levi M, van Gulik TM, Boermeester MA. Effects of intra-abdominal administration of recombinant tissue plasminogen activator on coagulation, fibrinolysis and inflammatory responses in experimental polymicrobial peritonitis. Shock. 2007;27: 534–41. doi: 10.1097/01.shk.0000246897.27574.1b 17438459

28. van Deventer SJ, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990;76: 2520–6. 2124934

29. Renckens R, Roelofs JJTH, Florquin S, de Vos AF, Pater JM, Lijnen HR, et al. Endogenous tissue-type plasminogen activator is protective during Escherichia coli-induced abdominal sepsis in mice. J Immunol. 2006;177: 1189–96. doi: 10.4049/jimmunol.177.2.1189 16818777

30. Guo Y, Li J, Hagström E, Ny T. Beneficial and Detrimental Effects of Plasmin(ogen) during Infection and Sepsis in Mice. Chakravortty D, editor. PLoS One. 2011;6: e24774. doi: 10.1371/journal.pone.0024774 21931850

31. Kager LM, Wiersinga WJ, Roelofs JJTH, Meijers JCM, Levi M, Van’t Veer C, et al. Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram-negative sepsis (melioidosis). J Thromb Haemost. 2011;9: 2020–8. doi: 10.1111/j.1538-7836.2011.04473.x 21848642

32. Kager LM, Wiersinga WJ, Roelofs JJTH, Meijers JCM, Levi M, van’t Veer C, et al. Endogenous tissue-type plasminogen activator impairs host defense during severe experimental gram-negative sepsis (melioidosis)*. Crit Care Med. 2012;40: 2168–2175. doi: 10.1097/CCM.0b013e31824ea05e 22564963

33. Lim JH, Woo C-H, Li J-D. Critical role of type 1 plasminogen activator inhibitor (PAI-1) in early host defense against nontypeable Haemophilus influenzae (NTHi) infection. Biochem Biophys Res Commun. 2011;414: 67–72. doi: 10.1016/j.bbrc.2011.09.023 21945446

34. Renckens R, Roelofs JJTH, Bonta PI, Florquin S, de Vries CJM, Levi M, et al. Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia. Blood. 2007;109: 1593–601. doi: 10.1182/blood-2006-05-025197 17032919

35. Shao Z, Nishimura T, Leung LLK, Morser J. Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model. J Thromb Haemost. 2015;13: 1090–102. doi: 10.1111/jth.12956 25851247

36. Fox MA. Tranexamic acid: how much is enough? Anesth Analg. 2010;111: 580–1; author reply 581. doi: 10.1213/ANE.0b013e3181e2914d 20664102

37. Dallaku K, Shakur-Still H, Beaumont D, Roberts I, Huque S, Delius M, et al. No effect of tranexamic acid on platelet function and thrombin generation (ETAPlaT) in postpartum haemorrhage: a randomised placebo-controlled trial. Wellcome open Res. Wellcome Open Res; 2019;4: 21. doi: 10.12688/wellcomeopenres.14977.1 31223662

38. Risch A, Dorscheid E, Stein G, Seyfert UT, Grundmann U. [The effect of aprotinin and tranexamic acid on fibrinolysis and thrombin generation during cardiopulmonary bypass]. Anaesthesist. Anaesthesist; 2000;49: 279–85. doi: 10.1007/s001010050829 10840537

39. Asakura H, Sano Y, Yoshida T, Omote M, Ontachi Y, Mizutani T, et al. Beneficial effect of low-molecular-weight heparin against lipopolysaccharide-induced disseminated intravascular coagulation in rats is abolished by coadministration of tranexamic acid. Intensive Care Med. 2004;30: 1950–5. doi: 10.1007/s00134-004-2349-7 15480547

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden