Successful Antithrombin Administration in Andexanet Alfa-Associated Heparin Resistance

Abstract

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

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