title: The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro.
abstract: BACKGROUND
  Neonates are at high risk for bleeding complications after cardiovascular surgery. Activation of intravascular fibrinolysis is one of the principal effects of cardiopulmonary bypass that causes poor postoperative hemostasis. Antifibrinolytic medications such as tranexamic acid are often used as prophylaxis against fibrinolysis, but concentration/effect data to guide dosing are sparse for adults and have not been published for neonates. Higher concentrations of tranexamic acid than those necessary for inhibition of fibrinolysis may have adverse effects. Therefore, we investigated the concentration of tranexamic acid necessary to inhibit activated fibrinolysis in neonatal plasma.
  
  
  METHODS
  We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of tranexamic acid were added to aliquots of the pooled plasma before maximally activating fibrinolysis with high-dose tissue-type plasminogen activator. Thromboelastography was then performed with the primary outcome variable being lysis at 30 minutes. These procedures were repeated on pooled adult normal plasma and dilutions of neonatal plasma.
  
  
  RESULTS
  The minimum concentrations of tranexamic acid to completely prevent fibrinolysis were 6.54 μg/mL (95% confidence interval, 5.19-7.91) for neonatal plasma and 17.5 μg/mL (95% confidence interval, 14.59-20.41) for adult plasma. Neonatal plasma requires a significantly lower concentration than adult plasma (P < 0.0001, 2-sided Wald test).
  
  
  CONCLUSIONS
  Our data establish the minimal effective concentration of tranexamic acid necessary to completely prevent fibrinolysis in neonatal plasma in vitro. These data may be useful in designing a dosing scheme for tranexamic acid appropriate for neonates.
authors.affiliation: From the Departments of Anesthesiology and Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
authors.forename: Branden E
authors.initials: BE
authors.lastname: Yee
authors.forename: Richard N
authors.initials: RN
authors.lastname: Wissler
authors.forename: Christine N
authors.initials: CN
authors.lastname: Zanghi
authors.forename: Changyong
authors.initials: C
authors.lastname: Feng
authors.forename: Michael P
authors.initials: MP
authors.lastname: Eaton
mesh_terms: D000933:Antifibrinolytic Agents / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D005312:Fetal Blood / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D014148:Tranexamic Acid / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid
references.citation: Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med. 2004;30:1873–81
references.citation: Eaton MP. Antifibrinolytic therapy in surgery for congenital heart disease. Anesth Analg. 2008;106:1087–100
references.citation: Albisetti M. The fibrinolytic system in children. Semin Thromb Hemost. 2003;29:339–48
references.citation: Kuhle S, Male C, Mitchell L. Developmental hemostasis: pro- and anticoagulant systems during childhood. Semin Thromb Hemost. 2003;29:329–38
references.citation: Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P. Development of the human coagulation system in the full-term infant. Blood. 1987;70:165–72
references.citation: Ries M, Easton RL, Longstaff C, Zenker M, Corran PH, Morris HR, Dell A, Gaffney PJ. Differences between neonates and adults in tissue-type-plasminogen activator (t-PA)-catalyzed plasminogen activation with various effectors and in carbohydrate sequences of fibrinogen chains. Thromb Res. 2001;103:173–84
references.citation: Ries M, Easton RL, Longstaff C, Zenker M, Morris HR, Dell A, Gaffney PJ. Differences between neonates and adults in carbohydrate sequences and reaction kinetics of plasmin and alpha(2)-antiplasmin. Thromb Res. 2002;105:247–56
references.citation: Parmar N, Albisetti M, Berry LR, Chan AK. The fibrinolytic system in newborns and children. Clin Lab. 2006;52:115–24
references.citation: Chauhan S, Bisoi A, Modi R, Gharde P, Rajesh MR. Tranexamic acid in paediatric cardiac surgery. Indian J Med Res. 2003;118:86–9
references.citation: Levin E, Wu J, Devine DV, Alexander J, Reichart C, Sett S, Seear M. Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid. Thromb Haemost. 2000;83:54–9
references.citation: Reid RW, Zimmerman AA, Laussen PC, Mayer JE, Gorlin JB, Burrows FA. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg. 1997;84:990–6
references.citation: Zonis Z, Seear M, Reichert C, Sett S, Allen C. The effect of preoperative tranexamic acid on blood loss after cardiac operations in children. J Thorac Cardiovasc Surg. 1996;111:982–7
references.citation: Grassin-Delyle S, Couturier R, Abe E, Alvarez JC, Devillier P, Urien S. A practical tranexamic acid dosing scheme based on population pharmacokinetics in children undergoing cardiac surgery. Anesthesiology. 2013;118:853–62
references.citation: Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N Y Acad Sci. 1968;146:642–58
references.citation: Spiel AO, Mayr FB, Firbas C, Quehenberger P, Jilma B. Validation of rotation thrombelastography in a model of systemic activation of fibrinolysis and coagulation in humans. J Thromb Haemost. 2006;4:411–6
references.citation: Gallimore MJ, Harris SL, Tappenden KA, Winter M, Jones DW. Urokinase induced fibrinolysis in thromboelastography: a model for studying fibrinolysis and coagulation in whole blood. J Thromb Haemost. 2005;3:2506–13
references.citation: Nielsen VG, Cohen BM, Cohen E. Elastic modulus-based thrombelastographic quantification of plasma clot fibrinolysis with progressive plasminogen activation. Blood Coagul Fibrinolysis. 2006;17:75–81
references.citation: Koster A, Börgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 2013;110:34–40
references.citation: Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg. 2012;93:148–54
references.citation: Hocker JR, Saving KL. Fatal aortic thrombosis in a neonate during infusion of epsilon-aminocaproic acid. J Pediatr Surg. 1995;30:1490–2
references.citation: Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology. 2001;95:1525–7
references.citation: Jaggers JJ, Neal MC, Smith PK, Ungerleider RM, Lawson JH. Infant cardiopulmonary bypass: a procoagulant state. Ann Thorac Surg. 1999;68:513–20
references.citation: Miller BE, Guzzetta NA, Tosone SR, Levy JH. Rapid evaluation of coagulopathies after cardiopulmonary bypass in children using modified thromboelastography. Anesth Analg. 2000;90:1324–30
references.citation: Petăjă J, Peltola K, Sairanen H, Leijala M, Kekomäki R, Vahtera E, Siimes MA. Fibrinolysis, antithrombin III, and protein C in neonates during cardiac operations. J Thorac Cardiovasc Surg. 1996;112:665–71
references.citation: Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth. 1989;3:181–8
references.citation: Chauhan S, Das SN, Bisoi A, Kale S, Kiran U. Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac Vasc Anesth. 2004;18:141–3
references.citation: Chauhan S, Kumar BA, Rao BH, Rao MS, Dubey B, Saxena N, Venugopal P. Efficacy of aprotinin, epsilon aminocaproic acid, or combination in cyanotic heart disease. Ann Thorac Surg. 2000;70:1308–12
references.citation: McClure PD, Izsak J. The use of epsilon-aminocaproic acid to reduce bleeding during cardiac bypass in children with congenital heart disease. Anesthesiology. 1974;40:604–8
references.citation: Rao BH, Saxena N, Chauhan S, Bisoi AK, Venugopal P. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss. Indian J Med Res. 2000;111:57–61
references.citation: Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 1999;13:304–8
references.citation: Chauhan S, Bisoi A, Kumar N, Mittal D, Kale S, Kiran U, Venugopal P. Dose comparison of tranexamic acid in pediatric cardiac surgery. Asian Cardiovasc Thorac Ann. 2004;12:121–4
references.citation: Giordano R, Palma G, Poli V, Palumbo S, Russolillo V, Cioffi S, Mucerino M, Mannacio VA, Vosa C. Tranexamic acid therapy in pediatric cardiac surgery: a single-center study. Ann Thorac Surg. 2012;94:1302–6
references.citation: Shimizu K, Toda Y, Iwasaki T, Takeuchi M, Morimatsu H, Egi M, Suemori T, Suzuki S, Morita K, Sano S. Effect of tranexamic acid on blood loss in pediatric cardiac surgery: a randomized trial. J Anesth. 2011;25:823–30
references.citation: Varela Crespo CA, Sanabria Carretero P, Palomero Rodríguez MA, Tormo las de Heras C, Rodríguez Pérez E, Goldman Tarlousky L. Effect of tranexamic acid on postoperative bleeding in pediatric heart surgery. Rev Esp Anestesiol Reanim. 2007;54:155–61
references.citation: Glick R, Green D, Ts’ao C, Witt WA, Yu AT, Raimondi AJ. High does epsilon-aminocaproic acid prolongs the bleeding time and increases rebleeding and intraoperative hemorrhage in patients with subarachnoid hemorrhage. Neurosurgery. 1981;9:398–401
references.citation: Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010;110:350–3
references.citation: Tsementzis SA, Meyer CH, Hitchcock ER. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg). 1992;35:74–8
references.citation: Furtmüller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, Redl H. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid (A) receptor antagonistic effect. J Pharmacol Exp Ther. 2002;301:168–73
references.citation: Lecker I, Wang DS, Romaschin AD, Peterson M, Mazer CD, Orser BA. Tranexamic acid concentrations associated with human seizures inhibit glycine receptors. J Clin Invest. 2012;122:4654–66
references.citation: Eriksson O, Kjellman H, Pilbrant A, Schannong M. Pharmacokinetics of tranexamic acid after intravenous administration to normal volunteers. Eur J Clin Pharmacol. 1974;7:375–80
references.citation: Andersson L, Eriksson O, Hedlund PO, Kjellman H, Lindqvist B. Special considerations with regard to the dosage of tranexamic acid in patients with chronic renal diseases. Urol Res. 1978;6:83–8
references.citation: Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, Butterworth J. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology. 2002;97:390–9
references.citation: Nuttall GA, Gutierrez MC, Dewey JD, Johnson ME, Oyen LJ, Hanson AC, Oliver WC Jr. A preliminary study of a new tranexamic acid dosing schedule for cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22:230–5
references.citation: Soslau G, Horrow J, Brodsky I. Effect of tranexamic acid on platelet ADP during extracorporeal circulation. Am J Hematol. 1991;38:113–9
references.citation: Fichera C, Ferrauto A. On the antifibrinolytic activity of 6-aminocaproic acid (6-ACA). Thromboelastographic observations. Boll Soc Ital Biol Sper. 1961;37:1174–6
references.citation: Edwards RM, Naik-Mathuria BJ, Gay AN, Olutoye OO, Teruya J. Parameters of thromboelastography in healthy newborns. Am J Clin Pathol. 2008;130:99–102
references.citation: Ekert H, Sheers M. Pre- and post-operative studies of fibrinolysis and prothrombin in cyanotic congenital heart disease. Haemostasis. 1974;3:158–66
references.citation: Miller BE, Guzzetta NA, Tosone SR, Miller JL, Flunker AR, Silvey EM, Levy JH. Tissue factor-activated thromboelastograms in children undergoing cardiac surgery: baseline values and comparisons. Anesth Analg. 2003;97:1289–93
references.citation: Eisses MJ, Chandler WL. Cardiopulmonary bypass parameters and hemostatic response to cardiopulmonary bypass in infants versus children. J Cardiothorac Vasc Anesth. 2008;22:53–9