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Semin Thromb Hemost 2022; 48(05): 568-595
DOI: 10.1055/s-0042-1742741
Review Article

Tranexamic Acid and Its Potential Anti-Inflammatory Effect: A Systematic Review

Søren Hauge Okholm
1   Department of Clinical Medicine, Health, Aarhus University, Aarhus C, Denmark
,
Jan Krog
2   Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus C, Denmark
,
Anne-Mette Hvas
1   Department of Clinical Medicine, Health, Aarhus University, Aarhus C, Denmark
3   Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus C, Denmark
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Abstract

Tranexamic acid (TXA) is an antifibrinolytic drug primarily used for reducing blood loss in patients with major bleedings. Animal and cell studies have shown that TXA might modulate the inflammatory response by either enhancing or inhibiting cytokine levels. Furthermore, recent human studies have found altered inflammatory biomarkers in patients receiving TXA when compared with patients who did not receive TXA. In this systematic review we investigated the effect of TXA on inflammatory biomarkers in different patient groups. A systematic literature search was conducted on the databases PubMed and Embase to identify all original articles that investigated inflammatory biomarkers in patients receiving TXA and compared them to a relevant control group. The review was performed according to the PRISMA guidelines, and the literature search was performed on November 29, 2021. Thirty-three studies were included, among which 14 studies compared patients receiving TXA with patients getting no medication, another 14 studies investigated different dosing regimens of TXA, and finally five studies examined the administration form of TXA. The present review suggests that TXA has an anti-inflammatory effect in patients undergoing orthopaedic surgery illustrated by decreased levels of C-reactive protein and interleukin-6 in patients receiving TXA compared with patients receiving no or lower doses of TXA. However, the anti-inflammatory effect was not found in patients undergoing cardiac surgery, pediatric craniosynostosis patients, or in rheumatoid arthritis patients. The inflammatory response was not affected by administration form of TXA (oral, intravenous, or topical). In conclusion, an anti-inflammatory effect of TXA was consistently found among orthopaedic patients only.

Keywords

tranexamic acid - inflammation - antiinflammation - antifibrinolytics


Publication History

Article published online:
30 May 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 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
    Google Scholar
  • 2 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
    Google Scholar
  • 3 Henry DA, Carless PA, Moxey AJ. et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011; (01) CD001886
    PubMedGoogle Scholar
  • 4 Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron FX, Roberts I. Antifibrinolytic Trials Collaboration. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet 2018; 391 (10116): 125-132
    Google Scholar
  • 5 Foley JH. Plasmin(ogen) at the nexus of fibrinolysis, inflammation, and complement. Semin Thromb Hemost 2017; 43 (02) 135-142
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Godier A, Hunt BJ. Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease. J Thromb Haemost 2013; 11 (01) 26-34
    CrossrefPubMedGoogle Scholar
  • 7 Foley JH, Walton BL, Aleman MM. et al. Complement activation in arterial and venous thrombosis is mediated by plasmin. EBioMedicine 2016; 5: 175-182
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 Carter DW, Prudovsky I, Kacer D. 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 (04) 617-624
    CrossrefPubMedGoogle Scholar
  • 11 Bergmann CB, Singer KE, Caldwell C, Goodman M. Tranexamic acid administration modulates innate and adaptive immunity in a murine model of traumatic brain injury. Shock 2020; 53: 125-126
    PubMedGoogle Scholar
  • 12 Chu C, Yang C, Wang X. et al. Early intravenous administration of tranexamic acid ameliorates intestinal barrier injury induced by neutrophil extracellular traps in a rat model of trauma/hemorrhagic shock. Surgery 2020; 167 (02) 340-351
    CrossrefPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 Forbat E, Al-Niaimi F, Ali FR. The emerging importance of tranexamic acid in dermatology. Clin Exp Dermatol 2020; 45 (04) 445-449
    CrossrefPubMedGoogle Scholar
  • 15 Sun N, Chen C, Niu Y-Q, Zhong SM. The influence of tranexamic acid on skin barrier function and inflammation in rosacea. J Clin Dermatol 2013; 42: 345-347
    PubMedGoogle Scholar
  • 16 Abdelrazik H. Combination of skin micro-needling and topical application of tranexamic acid and vitamin C: new clinical application: a pilot study for treatment of persistent post acne erythema. J Am Acad Dermatol 2016; 74: AB4
    CrossrefPubMedGoogle Scholar
  • 17 Liberati A, Altman DG, Tetzlaff J. et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700
    CrossrefPubMedGoogle Scholar
  • 18 National Heart Lung and Blood Institute. Study Quality Assessment Tools. Accessed July 2021 at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
    PubMedGoogle Scholar
  • 19 Draxler DF, Yep K, Hanafi G. et al. Tranexamic acid modulates the immune response and reduces postsurgical infection rates. Blood Adv 2019; 3 (10) 1598-1609
    CrossrefPubMedGoogle Scholar
  • 20 Zhang S, Xu H, Xie J, Cao G, Lei Y, Pei F. Tranexamic acid attenuates inflammatory effect and modulates immune response in primary total knee arthroplasty: a randomized, placebo-controlled, pilot trial. Inflammopharmacology 2020; 28 (04) 839-849
    CrossrefPubMedGoogle Scholar
  • 21 Zhang Z, Wang LN, Yang X. et al. The effect of multiple-dose oral versus intravenous tranexamic acid in reducing postoperative blood loss and transfusion rate after adolescent scoliosis surgery: a randomized controlled trial. Spine J 2021; 21 (02) 312-320
    CrossrefPubMedGoogle Scholar
  • 22 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
    CrossrefPubMedGoogle Scholar
  • 23 Wang D, Yang Y, He C. et al. Effect of multiple doses of oral tranexamic acid on haemostasis and inflammatory reaction in total hip arthroplasty: a randomized controlled trial. Thromb Haemost 2019; 119 (01) 92-103
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Tang Y, Wen Y, Li W, Li H, Yang Y, Liu Y. The efficacy and safety of multiple doses of oral tranexamic acid on blood loss, inflammatory and fibrinolysis response following total knee arthroplasty: a randomized controlled trial. Int J Surg 2019; 65: 45-51
    CrossrefPubMedGoogle Scholar
  • 25 Huang Z, Xie X, Li L. et al. Intravenous and topical tranexamic acid alone are superior to tourniquet use for primary total knee arthroplasty: a prospective, randomized controlled trial. J Bone Joint Surg Am 2017; 99 (24) 2053-2061
    CrossrefPubMedGoogle Scholar
  • 26 Fenger-Eriksen C, Rasmussen M, Juul N, Krog J, Hvas AM. Effect of tranexamic acid on markers of inflammation in children undergoing craniofacial surgery. Acta Anaesthesiol Scand 2021; 65 (01) 34-39
    CrossrefPubMedGoogle Scholar
  • 27 Cao G, Xie J, Huang Z. et al. Efficacy and safety of multiple boluses of oral versus intravenous tranexamic acid at reducing blood loss after primary total knee arthroplasty without a tourniquet: a prospective randomized clinical trial. Thromb Res 2018; 171: 68-73
    CrossrefPubMedGoogle Scholar
  • 28 Jiménez JJ, Iribarren JL, Brouard M. et al. Safety and effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial. J Cardiothorac Surg 2011; 6: 138
    CrossrefPubMedGoogle Scholar
  • 29 Luo Y, Releken Y, Yang D, Yue Y, Liu Z, Kang P. Effects of carbazochrome sodium sulfonate combined with tranexamic acid on hemostasis and inflammation during perioperative period of total hip arthroplasty: a randomized controlled trial. Orthop Traumatol Surg Res 2021; 103092: 103092
    PubMedGoogle Scholar
  • 30 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
    CrossrefPubMedGoogle Scholar
  • 31 Cao G, Huang Z, Xie J. et al. The effect of oral versus intravenous tranexamic acid in reducing blood loss after primary total hip arthroplasty: a randomized clinical trial. Thromb Res 2018; 164: 48-53
    CrossrefPubMedGoogle Scholar
  • 32 Casati V, Della Valle P, Benussi S. et al. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgery: comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 2004; 128 (01) 83-91
    CrossrefPubMedGoogle Scholar
  • 33 Goobie SM, Staffa SJ, Meara JG. et al. High-dose versus low-dose tranexamic acid for paediatric craniosynostosis surgery: a double-blind randomised controlled non-inferiority trial. Br J Anaesth 2020; 125 (03) 336-345
    CrossrefPubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar
  • 35 Jules-Elysee KM, Tseng A, Sculco TP. et al. Comparison of topical and intravenous tranexamic acid for total knee replacement: a randomized double-blinded controlled study of effects on tranexamic acid levels and thrombogenic and inflammatory marker levels. J Bone Joint Surg Am 2019; 101 (23) 2120-2128
    CrossrefPubMedGoogle Scholar
  • 36 Later AFL, 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
    CrossrefPubMedGoogle Scholar
  • 37 Lei Y, Xie J, Huang Q, Huang W, Pei F. Additional benefits of multiple-dose tranexamic acid to anti-fibrinolysis and anti-inflammation in total knee arthroplasty: a randomized controlled trial. Arch Orthop Trauma Surg 2020; 140 (08) 1087-1095
    CrossrefPubMedGoogle Scholar
  • 38 Lei Y, Xie J, Xu B, Xie X, Huang Q, Pei F. The efficacy and safety of multiple-dose intravenous tranexamic acid on blood loss following total knee arthroplasty: a randomized controlled trial. Int Orthop 2017; 41 (10) 2053-2059
    CrossrefPubMedGoogle Scholar
  • 39 Lei YT, Xie JW, Huang Q, Huang W, Pei FX. The antifibrinolytic and anti-inflammatory effects of a high initial-dose tranexamic acid in total knee arthroplasty: a randomized controlled trial. Int Orthop 2020; 44 (03) 477-486
    CrossrefPubMedGoogle Scholar
  • 40 Rasmussen GG, Brandslund I, Urfe P. et al. Lack of effect of tranexamic acid on rheumatoid arthritis. Scand J Rheumatol 1984; 13 (04) 369-373
    CrossrefPubMedGoogle Scholar
  • 41 Wang F, Nan L, Feng X. et al. The efficacy and safety of multiple-dose intravenous tranexamic acid in reducing perioperative blood loss in patients with thoracolumbar burst fracture. Clin Neurol Neurosurg 2020; 193: 105766
    CrossrefPubMedGoogle Scholar
  • 42 Wu KT, Siu KK, Ko JY, Chou WY, Kuo SJ, Hsu YH. Tranexamic acid reduces total blood loss and inflammatory response in computer-assisted navigation total knee arthroplasty. BioMed Res Int 2019; 2019: 5207517
    PubMedGoogle Scholar
  • 43 Xie J, Hu Q, Ma J, Huang Q, Pei F. Multiple boluses of intravenous tranexamic acid to reduce hidden blood loss and the inflammatory response following enhanced-recovery primary total hip arthroplasty: a randomised clinical trial. Bone Joint J 2017; 99-B (11) 1442-1449
    CrossrefPubMedGoogle Scholar
  • 44 Xie J, Ma J, Yao H, Yue C, Pei F. multiple boluses of intravenous tranexamic acid to reduce hidden blood loss after primary total knee arthroplasty without tourniquet: a randomized clinical trial. J Arthroplasty 2016; 31 (11) 2458-2464
    CrossrefPubMedGoogle Scholar
  • 45 Yoshida M, Ono S, Shimizu Y. et al. Usefulness of tranexamic acid administration during sagittal split ramus osteotomy. J Craniofac Surg 2021; 32 (01) 273-276
    CrossrefPubMedGoogle Scholar
  • 46 Changjun C, Xin Z, Yue L. et al. Tranexamic acid attenuates early post-operative systemic inflammatory response and nutritional loss and avoids reduction of fibrinogen in total hip arthroplasty within an enhanced recovery after surgery pathway. Int Orthop 2021; 45 (11) 2811-2818
    CrossrefPubMedGoogle Scholar
  • 47 Kang BX, Li YL, Xu H. et al. Effect of multiple doses of intravenous tranexamic acid on perioperative blood loss in total knee arthroplasty: a randomized controlled study. Orthop Surg 2021; 13 (01) 126-133
    CrossrefPubMedGoogle Scholar
  • 48 van der Laan WH, Ronday HK, TeKoppele JM, Breedveld FC, Huizinga TW, Verheijen JH. No therapeutic effect of plasmin antagonist tranexamic acid in rheumatoid arthritis. A double-blind placebo-controlled pilot study. Clin Exp Rheumatol 2003; 21 (03) 359-362
    PubMedGoogle Scholar
  • 49 Chen TT, Jiandong-Liu, Wang G, Jiang SL, Li LB, Gao CQ. Combined treatment of ulinastatin and tranexamic acid provides beneficial effects by inhibiting inflammatory and fibrinolytic response in patients undergoing heart valve replacement surgery. Heart Surg Forum 2013; 16 (01) E38-E47
    CrossrefPubMedGoogle Scholar
  • 50 Li W. et al. Application of tranexamic acid for the perioperative period of patients undergoing scoliosis correction surgery. Farmacia 2020; 68: 1081-1090
    CrossrefPubMedGoogle Scholar
  • 51 Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun 2018; 70: 61-75
    CrossrefPubMedGoogle Scholar
  • 52 Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-inflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci 2015; 2015: 507151
    CrossrefPubMedGoogle Scholar
  • 53 Orlowsky EW, Kraus VB. The role of innate immunity in osteoarthritis: when our first line of defense goes on the offensive. J Rheumatol 2015; 42 (03) 363-371
    CrossrefPubMedGoogle Scholar
  • 54 Attur M, Krasnokutsky S, Statnikov A. et al. Low-grade inflammation in symptomatic knee osteoarthritis: prognostic value of inflammatory plasma lipids and peripheral blood leukocyte biomarkers. Arthritis Rheumatol 2015; 67 (11) 2905-2915
    CrossrefPubMedGoogle Scholar
  • 55 Valiathan R, Ashman M, Asthana D. Effects of ageing on the immune system: infants to elderly. Scand J Immunol 2016; 83 (04) 255-266
    CrossrefPubMedGoogle Scholar
  • 56 Matsuda M, Huh Y, Ji RR. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth 2019; 33 (01) 131-139
    CrossrefPubMedGoogle Scholar
  • 57 Oros M, Oros Jar M, Grabar V. Steroids and L-Lysine aescinate for acute radiculopathy due to a herniated lumbar disk. Medicina (Kaunas) 2019; 55 (11) E736
    CrossrefPubMedGoogle Scholar
  • 58 Masouros P, Antoniou G, Nikolaou VS. Efficacy and safety of tranexamic acid in hip fracture surgery. How does dosage affect outcomes: A meta-analysis of randomized controlled trials. Injury 2021; S0020-1383 (21)00844-5
    PubMedGoogle Scholar