Successful Antithrombin Administration in Andexanet Alfa-Associated Heparin Resistance

ANDEXANET ALFA (Ondexxya, Portola Pharmaceuticals, San Francisco, CA) is a modified recombinant inactivated human factor Xa. Although it currently only approved to reverse the effects of direct Xa (FXa) inhibitors, andexanet alfa initially was developed as reversal agent for and indirect FXa inhibitors.1Lu G. DeGuzman F.R. Hollenbach S.J. et al.A specific antidote anticoagulation by inhibitors coagulation Xa.Nat Med. 2013; 19: 446-451Crossref PubMed Scopus (547) Google Scholar The acts decoy molecule that reversibly binds consequently temporarily inhibits anticoagulant effects. In vitro studies showed binding affinity heparin-bound antithrombin suggested an inhibitory effect against heparin-induced coagulopathy.2Yeh C.H. Fredenburgh J.C. Weitz J.I. real decoy: An Xa–directed anticoagulants.Circ Res. 113: 954-957Crossref (16) Scholar, 3Lu Reversal alfa, universal inhibitors. 2015. Available at: https://ash.confex.com/ash/2015/webprogramscheduler/Paper81760.html. Accessed September 29, 2020Google 4Pine P. Lu Canivel D. al.Andexanet reverses enoxaparin associated bleeding in rabbit acute hemorrhage model.Blood. 2016; 128: 1445Crossref Andexanet use authorities United States Europe rivaroxaban apixaban individuals with life-threatening or uncontrolled bleeding5Heo Y.-A. alfa: First global approval.Drugs. 2018; 78: 1049-1055Crossref (65) after fast-track approval procedure.6Patel S. Steen Widening path window opportunity FDA non-vitamin K oral antidotes agents.J Thromb Thrombolysis. 41: 285-292Crossref (2) Consequently, there limited clinical experience, especially cardiovascular surgery, concomitant cardiopulmonary bypass (CPB). During routine CPB, high-dose unfractionated heparin (UFH) prevents consumptive coagulopathy formation thrombi within CPB circuit patient's circulation. Prior treatment can pose difficulties achieving adequate during UFH.7Watson C.J. Zettervall S.L. Hall M.M. al.Difficult intraoperative heparinization following administration.Clin Pract Cases Emerg 2019; 3: 390-394Crossref 8Flaherty Connors J.M. Singh urgent before aortic surgery requiring bypass: A case report.A Pract. 13: 271-273Crossref 9Eche I.M. Elsamadisi Wex N. al.Intraoperative unresponsiveness endovascular repair ruptured abdominal aneurysm administration rivaroxaban.Pharmacotherapy. 39: 861-865Crossref (10) antithrombin, combination UFH, may overcome these difficulties. 72-year-old man tachycardiomyopathy, atrium flutter, atrial fibrillation underwent elective radiofrequency ablation procedure. addition 5 mg twice daily, his regular medication consisted 2.5 bisoprolol, 100 amiodarone, 1 bumetanide, 25 spironolactone, 40 omeprazole. He had normal renal function no other relevant comorbidities. procedure, patient cardiac tamponade. Initially, percutaneous pericardial drain placed, 500 mL bloody fluid removed. However, transthoracic echocardiography still accumulation pericardium. Since taken last dose early on day intervention plasma level 108 ng/mL (30-353 ng/mL) estimated, therapy low-dose (400 bolus followed 4 mg/minute infusion two hours) initiated. Due further hemodynamic deterioration, decision made place surgical drain. After median sternotomy pericardiotomy, inspection heart revealed left ventricular free wall rupture. surgeon decided close defect under bypass. According local procedures, intravenous 25,000 IE UFH administered achieve activated clotting time (ACT) between 400 480 seconds initiation CPB. addition, standard 2,000 tranexamic acid given. first measured ACT (I-STAT Alinity, Abbott, Princeton, NJ) 214 (reference range, 80-160 seconds). additional were given, minimal impact controls (263 Over next 20 minutes, total 30,000 without significant ACT. initiated despite 258 due instability. As went on, found operating field sign inadequate anticoagulation. Additionally, ACT, ROTEM used verify effect. 773 (INTEM) versus 237 (HEPTEM) indicated sufficient UFH. It supposed observed resistance be linked antithrombin–heparin complexes. continuous terminated immediately, 1,000 IU (Antithrombin III, Takeda Pharmaceutical Company) administered. Subsequently, measurements out range (>999 seconds), applied. timeline operative course outlined Figure 1. Separation from attempted 143 minutes 68 cross-clamp time. Weaning unsuccessful hypokinesia akinesia lateral placement bovine patch. For postoperative support, converted into veno-arterial extracorporeal membrane oxygenation (VA ECMO) admitted intensive care unit. patients received one pool platelets, g fibrinogen, 1,250 recovered blood via Cellsaver unit transfer. complexity this VA ECMO, authors carefully 250 protamine sulphate at end considering time-dependent elimination half-life heparin; afterwards 153 seconds. Fig. weaned ECMO sixth day. weaning activity 87% (normal 80%-120%). Written informed consent publication obtained patient. To authors’ knowledge, reported successful alfa-associated supplementation antithrombin. patient, alfa's presence led very high doses (1,250 IU/kg) emergency low visualization implied insufficient crucial if chosen Heparin does not have potentiates which endogenous serine protease inhibitor irreversibly various coagulant enzymes, such thrombin (Fig 2, A). Binding enhances 300, inactivates thrombin, well factors IX, X, XI, XII.10Olson S.T. Björk I. Role protein conformational changes, surface approximation cofactors heparin-accelerated antithrombin-proteinase reactions.Adv Exp Med Biol. 1992; 313: 155-165Crossref (34) Scholar,11Hirsh J. Bauer K.A. Donati M.B. al.Parenteral anticoagulants: American College Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).Chest. 2008; 133: 141S-159SAbstract Full Text PDF (598) reduced ability inhibit fibrin called "heparin resistance". Clinically conditions present are lack increased clearance, elevation protein, VIII fibrinogen concentrations.12Finley A. Greenberg C. sensitivity resistance: Management bypass.Anesth Analg. 116: 1210-1222Crossref (99) data demonstrated inhibition evidence.2Yeh their B). Furthermore, heparin–antithrombin-activated complexes, rendering ineffective C). suspected resistance. Administration plasma-derived resulted measurement supported assumption D). Further laboratory research needed evaluate hypothesis shown experience using minimal. There controlled trials. Currently, off-label use.13Connolly Milling T.J. Eikelboom J.W. major inhibitors.N Engl J 375: 1131-1141Crossref (525) date, report documented undergoing CPB.8Flaherty Likewise, altered responsiveness alfa. administering 80,000 434 achieved, could performed any thromboembolic complications. another report, Eche al. described response who presented aneurysm.9Eche unable intraoperatively supratherapeutic sustained thrombosis pelvic vasculature. broader availability lead number administration. Clinicians should aware interaction recommend interruption required surgery. considered occurs. Both interventions promising strategy risk overdosing. investigation clarify mechanism action heparinized both settings.