Influence of Tranexamic Acid on Inflammatory Signaling in Trauma

Abstract

Plasmin generation in trauma patients has wide-ranging effects, from breakdown of clots to remodeling the extracellular matrix. An evolving recognition of plasmin as a critical effector molecule in various inflammatory signals and pathways has rendered the study of plasmin(ogen) and its regulation by upstream activators and downstream targets and inhibitors key to understanding the inflammatory responses to trauma. Tranexamic acid, a widely available lysine analogue medication on the World Health Organization's list of essential medicines, has rapidly become one of the most commonly implemented adjunct treatments for bleeding after traumatic injury in clinical practice. In this article, we review the effects, both anti- and proinflammatory, of tranexamic acid, with a focus on the injured trauma patient.

Keywords

tranexamic acid - inflammation - trauma - complement - coagulopathy

• References

• 1 Khan M, Jehan F, Bulger EM. , et al; PROPPR Study Group. Severely injured trauma patients with admission hyperfibrinolysis: is there a role of tranexamic acid? Findings from the PROPPR trial. J Trauma Acute Care Surg 2018; 85 (05) 851-857
• 2 Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: how should we use it?. J Trauma Acute Care Surg 2013; 74 (06) 1575-1586
• 3 Abdel MP, Chalmers BP, Taunton MJ. , et al. Intravenous versus topical tranexamic acid in total knee arthroplasty: both effective in a randomized clinical trial of 640 patients. J Bone Joint Surg Am 2018; 100 (12) 1023-1029
• 4 Collaborators WT. ; WOMAN Trial Collaborators. 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): 2105-2116
• 5 Roberts I, Shakur H, Afolabi A. , et al; CRASH-2 collaborators. 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): 1096-1101 , 1101.e1–1101.e2
• 6 Shakur H, Roberts I, Bautista R. , et al; CRASH-2 trial collaborators. 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
• 7 Valle EJ, Allen CJ, Van Haren RM. , et al. Do all trauma patients benefit from tranexamic acid?. J Trauma Acute Care Surg 2014; 76 (06) 1373-1378
• 8 Harvin JA, Peirce CA, Mims MM. , et al. The impact of tranexamic acid on mortality in injured patients with hyperfibrinolysis. J Trauma Acute Care Surg 2015; 78 (05) 905-909 , discussion 909–911
• 9 Cotton BA, Harvin JA, Kostousouv V. , et al. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg 2012; 73 (02) 365-370 , discussion 370
• 10 Barrett CD, Moore HB, Kong YW. , et al. Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator-dependent manner. J Trauma Acute Care Surg 2019; 86 (01) 101-107
• 11 Gebbink MF, Bouma B, Maas C, Bouma BN. Physiological responses to protein aggregates: fibrinolysis, coagulation and inflammation (new roles for old factors). FEBS Lett 2009; 583 (16) 2691-2699
• 12 Jimenez JJ, Iribarren JL, Lorente L. , et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care 2007; 11 (06) R117
• 13 Later AF, Sitniakowsky LS, van Hilten JA. , et al. Antifibrinolytics attenuate inflammatory gene expression after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145 (06) 1611-1616 , 1616.e1–1616.e4
• 14 Wang D, Luo ZY, Yu ZP. , et al. The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: a randomized controlled trial. J Thromb Haemost 2018; 16 (12) 2442-2453
• 15 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 (02) 358-365
• 16 Teng Y, Feng C, Liu Y, Jin H, Gao Y, Li T. Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock-induced acute lung injury in rats. Exp Anim 2018; 67 (03) 313-320
• 17 Yee BE, Wissler RN, Zanghi CN, Feng C, Eaton MP. The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro. Anesth Analg 2013; 117 (04) 767-772
• 18 Rozen L, Faraoni D, Sanchez Torres C. , et al. Effective tranexamic acid concentration for 95% inhibition of tissue-type plasminogen activator induced hyperfibrinolysis in children with congenital heart disease: a prospective, controlled, in-vitro study. Eur J Anaesthesiol 2015; 32 (12) 844-850
• 19 Niego B, Horvath A, Coughlin PB, Pugsley MK, Medcalf RL. Desmoteplase-mediated plasminogen activation and clot lysis are inhibited by the lysine analogue tranexamic acid. Blood Coagul Fibrinolysis 2008; 19 (04) 322-324
• 20 Picetti R, Shakur-Still H, Medcalf RL, Standing JF, Roberts I. What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagul Fibrinolysis 2019; 30 (01) 1-10
• 21 Boyette LB, Macedo C, Hadi K. , et al. Phenotype, function, and differentiation potential of human monocyte subsets. PLoS One 2017; 12 (04) e0176460
• 22 Saha P, Geissmann F. Toward a functional characterization of blood monocytes. Immunol Cell Biol 2011; 89 (01) 2-4
• 23 Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 2014; 5: 491
• 24 Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring Harb Perspect Biol 2015; 7 (05) a016303
• 25 Syrovets T, Tippler B, Rieks M, Simmet T. Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway. Blood 1997; 89 (12) 4574-4583
• 26 Syrovets T, Jendrach M, Rohwedder A, Schüle A, Simmet T. Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKbeta-mediated NF-kappaB activation. Blood 2001; 97 (12) 3941-3950
• 27 Walker PF, Foster AD, Rothberg PA, Davis TA, Bradley MJ. Tranexamic acid decreases rodent hemorrhagic shock-induced inflammation with mixed end-organ effects. PLoS One 2018; 13 (11) e0208249
• 28 Draxler DF, Awad MM, Hanafi G. , et al. Tranexamic acid influences the immune response, but not bacterial clearance in a model of post-traumatic brain injury pneumonia. J Neurotrauma 2019; 36 (23) 3297-3308
• 29 Draxler DF, Daglas M, Fernando A. , et al. Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis. J Thromb Haemost 2019; 17 (12) 2174-2187
• 30 Reichel CA, Lerchenberger M, Uhl B. , et al. Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature. PLoS One 2011; 6 (02) e17229
• 31 Eun JC, Moore EE, Banerjee A. , et al. Leukotriene b4 and its metabolites prime the neutrophil oxidase and induce proinflammatory activation of human pulmonary microvascular endothelial cells. Shock 2011; 35 (03) 240-244
• 32 Krauss AH, Nieves AL, Spada CS, Woodward DF. Determination of leukotriene effects on human neutrophil chemotaxis in vitro by differential assessment of cell motility and polarity. J Leukoc Biol 1994; 55 (02) 201-208
• 33 Barrett CD, Hsu AT, Ellson CD. , et al. Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy. Clin Exp Immunol 2018; 194 (01) 103-117
• 34 Vercellotti GM, Yin HQ, Gustafson KS, Nelson RD, Jacob HS. Platelet-activating factor primes neutrophil responses to agonists: role in promoting neutrophil-mediated endothelial damage. Blood 1988; 71 (04) 1100-1107
• 35 Collen D. Natural inhibitors of fibrinolysis. J Clin Pathol Suppl (R Coll Pathol) 1980; 14: 24-30
• 36 Li X, Syrovets T, Genze F. , et al. Plasmin triggers chemotaxis of monocyte-derived dendritic cells through an Akt2-dependent pathway and promotes a T-helper type-1 response. Arterioscler Thromb Vasc Biol 2010; 30 (03) 582-590
• 37 Mortier A, Van Damme J, Proost P. Regulation of chemokine activity by posttranslational modification. Pharmacol Ther 2008; 120 (02) 197-217
• 38 Lorenz N, Loef EJ, Kelch ID. , et al. Plasmin and regulators of plasmin activity control the migratory capacity and adhesion of human T cells and dendritic cells by regulating cleavage of the chemokine CCL21. Immunol Cell Biol 2016; 94 (10) 955-963
• 39 Amara U, Flierl MA, Rittirsch D. , et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185 (09) 5628-5636
• 40 Chapman MP, Moore EE, Moore HB. , 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 (01) 16-23 , discussion 23–25
• 41 Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE. Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 2014; 41 (06) 514-521
• 42 Hijazi N, Abu Fanne R, Abramovitch R. , et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood 2015; 125 (16) 2558-2567
• 43 Okusawa S, Dinarello CA, Yancey KB. , et al. C5a induction of human interleukin 1. Synergistic effect with endotoxin or interferon-gamma. J Immunol 1987; 139 (08) 2635-2640
• 44 Khameneh HJ, Ho AW, Laudisi F. , et al. C5a regulates IL-1β production and leukocyte recruitment in a murine model of monosodium urate crystal-induced peritonitis. Front Pharmacol 2017; 8: 10
• 45 Grant AL, Letson HL, Morris JL. , et al. Tranexamic acid is associated with selective increase in inflammatory markers following total knee arthroplasty (TKA): a pilot study. J Orthop Surg Res 2018; 13 (01) 149
• 46 Reust DL, Reeves ST, Abernathy III JH. , et al. Temporally and regionally disparate differences in plasmin activity by tranexamic acid. Anesth Analg 2010; 110 (03) 694-701
• 47 Bezerra JA, Currier AR, Melin-Aldana H. , et al. Plasminogen activators direct reorganization of the liver lobule after acute injury. Am J Pathol 2001; 158 (03) 921-929
• 48 Silva MM, Thelwell C, Williams SC, Longstaff C. Regulation of fibrinolysis by C-terminal lysines operates through plasminogen and plasmin but not tissue-type plasminogen activator. J Thromb Haemost 2012; 10 (11) 2354-2360
• 49 Guo RF, Ward PA. Role of C5a in inflammatory responses. Annu Rev Immunol 2005; 23: 821-852
• 50 van den Eijnden-Schrauwen Y, Kooistra T, de Vries RE, Emeis JJ. Studies on the acute release of tissue-type plasminogen activator from human endothelial cells in vitro and in rats in vivo: evidence for a dynamic storage pool. Blood 1995; 85 (12) 3510-3517
• 51 Emeis JJ, van den Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A, Lupu F. An endothelial storage granule for tissue-type plasminogen activator. J Cell Biol 1997; 139 (01) 245-256
• 52 Novak ML, Bryer SC, Cheng M. , et al. Macrophage-specific expression of urokinase-type plasminogen activator promotes skeletal muscle regeneration. J Immunol 2011; 187 (03) 1448-1457
• 53 Clowes AW, Clowes MM, Au YP, Reidy MA, Belin D. Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery. Circ Res 1990; 67 (01) 61-67
• 54 Shen Y, Guo Y, Du C, Wilczynska M, Hellström S, Ny T. Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations. PLoS One 2012; 7 (12) e51303
• 55 Schäfer BM, Maier K, Eickhoff U, Todd RF, Kramer MD. Plasminogen activation in healing human wounds. Am J Pathol 1994; 144 (06) 1269-1280
• 56 Carmeliet P, Moons L, Herbert JM. , et al. Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 1997; 81 (05) 829-839
• 57 Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. Am J Pathol 2000; 157 (01) 177-187
• 58 Takada A, Takada Y. Conversion of Glu-plasminogen to plasmin by urokinase in the presence of tranexamic acid. Thromb Res 1981; 22 (04) 437-443
• 59 Afsharimani B, Cabot PJ, Parat MO. Effect of lysine antifibrinolytics and cyclooxygenase inhibitors on the proteolytic profile of breast cancer cells interacting with macrophages or endothelial cells. Br J Anaesth 2014; 113 (Suppl. 01) i22-i31
• 60 Dewyer NA, Sood V, Lynch EM. , et al. Plasmin inhibition increases MMP-9 activity and decreases vein wall stiffness during venous thrombosis resolution. J Surg Res 2007; 142 (02) 357-363
• 61 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 (09) 3012-3024
• 62 Pusateri AE, Weiskopf RB, Bebarta V. , et al; US DoD Hemorrhage and Resuscitation Research and Development Steering Committee. Tranexamic acid and trauma: current status and knowledge gaps with recommended research priorities. Shock 2013; 39 (02) 121-126