Individualized Perioperative Antifibrinolytic Therapy: The Next Goal in Cardiac Surgery?

Antifibrinolytic therapy is a pharmacologic cornerstone of multimodal blood conservation program in cardiac surgery with or without cardiopulmonary bypass (CPB).1Dhir A Tempe DK. Anemia and patient management surgery–Literature review current evidence.J Cardiothorac Vasc Anesth. 2018; 32: 2726-2742Abstract Full Text PDF PubMed Scopus (17) Google Scholar The administration antifibrinolytic agents during CPB lowers both perioperative loss requirements for transfusion allogeneic products. It 1A recommendation adult surgical procedures CPB2American Society Anesthesiologists Task Force on Perioperative Blood ManagementPractice guidelines management: An updated report.Anesthesiology. 2015; 122: 241-275Crossref (401) Scholar, 3Boer C Meesters MI Milojevic M et al.2017 EACTS/EACTA Guidelines surgery.J 88-120Abstract (159) 4Kozek-Langenecker SA Ahmed AB Afshari al.Management severe bleeding: from the European Anaesthesiology: First update 2016.Eur J Anaesthesiol. 2017; 34: 332-395Crossref (337) 5Raphael Mazer CD Subramani S al.Society Cardiovascular Clinical Practice Improvement Advisory bleeding hemostasis patients.J 2019; 33: 2887-2899Abstract (41) 1B pediatric surgery.6Faraoni D Meier New HV al.Patient neonates children undergoing surgery: 2019 NATA Guidelines.J 3249-3263Abstract (39) Since withdrawal aprotinin market 2008 because safety concerns,7Sniecinski RM Chen EP Makadia SS al.Changing to tranexamic acid results increased use products recombinant factor VIIa aortic requiring hypothermic arrest.J 2010; 24: 959-963Abstract (32) Scholar,8Koster Faraoni Levy JH update.Anesthesiology. 123: 214-221Crossref (59) (TXA) Ɛ-aminocaproic (EACA) have become 2 most extensively used agents.1Dhir Both TXA EACA are synthetic lysine analogs that able occupy lysine-binding sites plasminogen. They, thereby, prevent efficient conversion plasminogen by endogenous tissue activator (tPA) plasmin degradation fibrin, finally stabilizing clot formation.9Bolliger Tanaka KA. Tranexamic vascular clot-stabilising activity.Br Anaesth. 2020; 124: 4-6Abstract (5) In setting CPB, thought be equivalent their general ability reduce surgery.8Koster Scholar,10Faraoni Rahe Cybulski KA Use antifibrinolytics Where we now?.Paediatr 29: 435-440Crossref (12) Despite having similar structures, mechanisms action, pharmacodynamics including intravenous application, renal elimination, comparable plasma half-time about 2-to-3 hours,8Koster Scholar,11Taam Yang QJ Pang KS al.Current evidence future directions use, efficacy, dosing major procedures.J 782-790Abstract (10) relevant pharmacokinetics regimens differ.8Koster Of note, 6 to-10 times more potent molecular basis.2American Scholar,12Commentary D. Epsilon-aminocaproic versus acid, David Goliath antifibrinolytics.JCVTS Open. https://doi.org/10.1016/j.xjon.2020.05.011Abstract (1) Further, worldwide than earlier developed EACA.13Henry DA Carless PA Moxey AJ al.Anti-fibrinolytic minimising transfusion.Cochrane Database Syst Rev. 2011; 3CD001886PubMed approved United States Canada alone,8Koster but being administered off-label some units Europe.14Martin K Breuer T Gertler R al.Tranexamic epsilon-aminocaproic acid: Efficacy paediatric surgery.Eur Surg. 39: 892-897Crossref (63) Therefore, number quality studies investigated regimens, benefits, risks largely outweigh those EACA,8Koster Scholar,13Henry further data needed. this issue Journal Cardiothoracic Vascular Anesthesia, Strauss al. evaluated regimen patients surgery. 21 patients, whom two-thirds were male half underwent coronary artery surgery, concentrations different fibrinolysis markers measured.15Strauss E.R. Dahmane E Judd al.A pharmacokinetic pharmacodynamic investigation an Epsilon-amniocaproic designed context bypass.J 35: 406-417Abstract authors proposed described best 3-compartment disposition model. they found using institutional regimen, above suggested threshold 130 µg/mL all after CPB. According additional simulation models, doubling continuous infusion g/h together boluses 5 g would resulted levels supposed However, did not correlate changes D-dimer as surrogate fibrinolytic activity. Fibrinolysis one multiple pathomechanisms associated surgery.16Bolliger D, Lance MD, Siegemund M. Point-of-care platelet function monitoring: Implications inhibitors [e-pub ahead print]. doi: 10.1053/j.jvca.2020.07.050. Accessed September 3, 2020.Google triggered release tPA fibrin formation fully suppressed despite systemic heparinization.17Ide Bolliger Taketomi al.Lessons saga: Current perspective 96-106Crossref (43) Elevated might persist up hours surgery.15Strauss Scholar,17Ide Scholar,18Chandler WL Velan T. Secretion inhibitor 1 bypass.Thromb Res. 2003; 112: 185-192Abstract (29) Although prophylactic guidelines,2American 6Faraoni recommendations optimal length administration, target concentration, been specified yet. For TXA, typical include bolus 10-to-30 mg/kg at beginning followed 2-to-10 mg/kg/h until weaning sternal closure. Some abstain second end CPB.19Gerstein NS Brierley JK Windsor al.Antifibrinolytic noncardiac comprehensive overview update.J 31: 2183-2205Abstract (34) general, these aim concentration >10-to-20 µg/mL, which inhibition 80%.8Koster Scholar,20Picetti Shakur-Still H Medcalf RL al.What needed inhibit fibrinolysis? systematic studies.Blood Coagul Fibrinolysis. 30: 1-10Crossref (47) High-dose 10 described11Taam Scholar,21Fassl Matt P Eckstein F al.Transfusion proximal circulatory arrest: Effect thromboelastometry-guided management.J 2013; 27: 1181-1188Abstract (54) result >100 presumably must suppress any activity.8Koster clear whether high-dose clinically advantageous reducing products; however, obviously higher risk postoperative seizures.8Koster Scholar,22Myles PS Smith JA Forbes coronary-artery surgery.N Engl Med. 376: 136-148Crossref (176) 23Couture Lebon JS Laliberte al.Low-dose reduces nonischemic seizures 1611-1617Abstract (20) 24Guo Gao X Ma Y al.Different dose regimes methods meta-analysis randomized trials.BMC Anesthesiol. 19: 129Crossref (25) it remains unclear necessary local site. included 100-to-150 anesthesia induction 15-to-30 mg/kg/h. addition, 5-to-10 often priming solution Specific uncommon. Typical between 100 150 µg/mL,15Strauss Scholar,19Gerstein >250 also described.10Faraoni values reflect 6-to-10 lower potency compared TXA. potentially seizure impairment.14Martin present study was rather uncommon, initial 5-g before protamine started incision.15Strauss This presumed limited activity due total-to-subtotal thrombin full-dose heparinization, high heparin reversal total amount EACA, side effects. Accordingly, reported highest administration.15Strauss Evaluating adequate suppression challenge. Exact determinations universally available require extensive laboratory testing. can viscoelastic recent cohort 3,000 testing possibility assessing individual demonstrated effect levels.25Besser V, Albert A, Sixt SU, influence 10.1053/j.jvca.2020.03.040. interindividual variability, allow antifibrinolytics. elevated normal prothrombotic necessarily hyperfibrinolysis represent risk. latter explain missing correlation study,15Strauss cut-off concerning specific diagnostic therapeutic decisions Viscoelastic testing, thromboelastography rotational thromboelastometry, provide helpful information degree ongoing fibrinolysis. tests sensitive suitable assessment spiking assay 100-to-400 ng/mL induce fibrinolysis.26Bolliger Szlam Molinaro RJ al.Thrombin generation anti-factor IX treated spiked VIII bypassing VIIa.Haemophilia. 16: 510-517PubMed 27Kuiper GJ Kleinegris MC van Oerle al.Validation modified thromboelastometry approach detect activity.Thromb J. 2016; 14: 1Crossref 28Kupesiz Rajpurkar Warrier I al.Tissue induced fibrinolysis: Standardization method thromboelastography.Blood 21: 320-324Crossref (33) technique complex only performed research laboratories. Nevertheless, titration antifibrinolytics, recently case report extracorporeal membrane oxygenation.29Seelhammer TG Mangla Demirci O titrate abatement lysis-induced hemorrhagic complications venoarterial oxygenation.J 1059-1062Abstract (3) al.15Strauss had well-acknowledged limitations: First, low, minor percentage preoperative impairment. Second, discussed above. Third, variations modalities, techniques, fluid will affect exposure definitively. Using other changing techniques example, former 15 fitting 2-compartment model TXA30Yang Jerath Bies RR al.Pharmacokinetic modeling simulations impairment.Biopharm Drug Dispos. 36: 294-307Crossref (23) findings15Strauss applicable institutions, populations, summary, considered cost-effective alternative provided important neither nor approved. Further larger populations warranted define better efficacy peak concentrations, adverse Finally, point-of-care monitoring individualized optimally stages All decare no conflicts interest. Pharmacokinetic Pharmacodynamic Investigation ε-Aminocaproic Acid Regimen Designed Cardiac Surgery With Cardiopulmonary BypassJournal AnesthesiaVol. 35Issue 2PreviewObjective: To investigate ε-aminocaproic (CPB).Design: Prospective observational sampling measure (fibrinogen, D-dimer, α2-antiplasmin, activator-plasminogen [tPA-PAI-1] complex).Setting: Single-center, tertiary medical center.Participants: Patients who 2018 mitral valve replacement/repair grafting. Full-Text