Successful Use of Bivalirudin for Cardiac Transplantation in a Child With Heparin-induced Thrombocytopenia

Successful Use of Bivalirudin for Cardiac Transplantation in a Child With Heparin-induced Thrombocytopenia Christopher S. D. Almond, MD, MPH,a James Harrington, MD,b Ravi Thiagarajan, MD, MPH,a,b Christine N. Duncan, MD,c,d Robert LaPierre, BS, CCP,e David Halwick, BS, RRT,b Elizabeth D. Blume, MD,a Pedro J. del Nido, MD,e Ellis J. Neufeld, MD, PhD,c,d and Francis X. McGowan, MD, PhDb Bivalirudin, a direct thrombin inhibitor, has recently emerged as a promising option for anti-coagulation during cardiopulmonary bypass in patients who cannot receive heparin. There is limited experience with the use of bivalirudin in children. We present the case of a child with heparin-induced thrombocytopenia with thrombosis (HIT Type II) who underwent successful orthotopic cardiac transplantation using bivalirudin as the primary anti-coagulant for cardiopulmonary bypass. J Heart Lung Transplant 2006;25:1376 –9. Copyright © 2006 by the International Society for Heart and Lung Transplantation.

Heparin-induced thrombocytopenia (HIT) is a prominent complication of heparin therapy and can be associated with significant morbidity and mortality. Primary therapy for HIT involves discontinuation of heparin and the use of an alternative anti-coagulant when continued anti-coagulation is necessary. Bivalirudin (Angiomax, The Medicines Co., Parsippany, NJ) is an intravenous direct thrombin inhibitor that has been used successfully in adult patients undergoing percutaneous coronary intervention.1 Bivalirudin’s relatively short half-life, elimination predominantly by intravascular proteolysis, and anti-coagulant effects that appear to be associated with dose-dependent changes in conventional clotting assays, make it an attractive option for patients who need cardiac surgery and are intolerant to heparin. Several studies have reported successful use of bivalirudin for adult cardiopulmonary bypass patients.2–5 To our knowledge, no reports are available describing the use of bivalirudin in children for cardiopulmonary bypass, or for pediatric heart transplantation. We present the case of a 5-year-old girl with HIT Type II, who was successfully bridged to transplant using argatroban as the primary anti-coagulant while on extraFrom the Departments of aCardiology, bAnesthesiology and cMedicine, Division of Hematology, Children’s Hospital, Boston, Massachusetts; dDana Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; and eDepartment of Cardiac Surgery, Children’s Hospital Boston, Boston, Massachusetts. Submitted September 27, 2005; revised June 22, 2006; accepted August 20, 2006. Reprint requests: Christopher S. D. Almond, MD, Department of Cardiology, Division of Cardiac Critical Care, Bader 3, Children’s Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02215. Telephone: 617-255-6329. Fax: 617-734-9930. E-mail: [email protected] Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2006.08.005

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corporeal membrane oxygenation (ECMO), followed by bivalirudin as the primary anti-coagulant for orthotopic cardiac transplantation. CASE REPORT A 5-year-old girl with complex congenital heart disease was referred to Children’s Hospital Boston for an attempt at two-ventricle repair, after initial palliation with a bidirectional Glenn procedure during infancy. Postoperatively, her course was complicated by cardiac arrest and severe left ventricular dysfunction requiring extra-corporeal circulatory support (ECMO) for 29 days, and severe bleeding requiring multiple re-explorations of the chest. By Day 5 post-operatively, there was little evidence of myocardial recovery and the patient was listed for heart transplantation. On ECMO Day 14, a diagnosis of heparin-induced thrombocytopenia with thrombosis (HIT Type II) was made after the patient developed acute thrombocytopenia (platelet count 41,000/mm3) and thrombosis of the distal extremities, in association with a positive test for platelet factor 4 (PF4) antibodies, as measured by PF4 enzyme-linked immunosorbent assay (ELISA). Heparin was immediately discontinued and the patient was started on an argatroban infusion (2 ␮g/kg/min without bolus), which was titrated to maintain an activated clotting time (ACT) of 180 to 220 seconds (Table 1). Despite increasing the argatroban infusion by 6-fold because of circuit thrombi as flows were weaned, we found it difficult to achieve ACT values of ⬎400 seconds consistently. On Day 29 post-operatively, the patient was decannulated successfully from ECMO, and transitioned from argatroban to warfarin 24 hours later. She remained supported on dopamine, milrinone and mechanical ventilation while awaiting a suitable donor heart. On Day 54 post-operatively, a donor heart became available and the patient was brought to the operating

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Table 1. Argatroban Protocol Used During ECMO, and Updated Bivalirudin Protocol for Cardiopulmonary Bypass Direct thrombin inhibitor Argatroban dosing used during ECMO Initial intravenous (IV) argatroban dose: and initiate continuous IV infusion: Argatroban added to ECMO circuit prime:

Frequency of argatroban monitoring

Target ACT Bivalirudin dosing during cardiopulmonary bypass Initial bivalirudin dosing (pre-CPB) Initial intravenous (IV) bivalirudin bolus Begin continuous IV infusion Bivalirudin added to pump circuit Target anti-coagulant monitoringa If sub-therapeutic ACT (or ECT) Bivalirudin dosing and monitoring while on CPB Continue fixed-rate IV infusion

Frequency of anti-coagulant monitoring If sub-therapeutic ACT (or ECT) Special steps at end of CPB Stop bivalirudin infusion 15 min prior to expected separation from CPB

Alternative approach

Dose, comment 100 ␮g/kg over 3–5 min, unless therapeutically anti-coagulated on heparin, in which no bolus is given 2 ␮g/kg/min 50 ␮g per 750 ml of circuit prime, unless already on ECMO and therapeutically anti-coagulated on heparin, in which no circuit prime dose is given 60-min intervals once the patient is on a stable infusion; 5–10 minutes after a bolus is completed or dose change using the activated clotting time 180–220 s

1.0 mg/kg 2.5 mg/kg/h (42 ␮g/kg/min) 50 mg ⱖ2.5-fold baseline ACT, using either the ACT-Kaolin (Hemochron), ACT-Plus, ACT-T (International Technidyne) or ECT Give addition bolus (0.1–0.5 mg/kg) 2.5 mg/kg/h until 15 min prior to expected separation from CPB (if CPB not terminated in 20 min, then an additional 0.5 mg/kg bolus is given, and infusion at 2.5 mg/kg/h is re-started) Every 15–30 min Give additional bolus (0.1–0.5 mg/kg) Promptly (within 10 min post-separation from CPB) empty pump volume into cell saverb (replacing with crystalloid, e.g., sodium citrate), thus avoiding the need for post-separation bivalirudin boluses to circuit; process blood for re-infusion with cell saver to remove bivalirudin After separation from CPB, promptly reconnect arterial and venous lines, clamp out arterial filter, give residual blood to the patient, refill the CPB with saline, re-circulate, add bivalirudin (50 mg), and then start a continuous infusion at 50 mg/h into the circuit. Later, this volume may be processed by cell saver (for re-infusion) or discarded

ACT, activated clotting time; CPB, cardiopulmonary bypass; ECT, ecarin clotting time. a The minimum target bivalirudin concentration (⬃10 ␮g/ml) corresponds approximately to the minimum threshold levels (⬎2.5-fold baseline) for the four different monitoring assays listed above. b Adapted from the Evolution-ON study protocol (which required the use of a cell saver), and Warkentin et al. Ann Thorac Surg, 2003. Copyright 2003, with permission from the Society for Thoracic Surgeons.

room. In preparation for bypass, the circuit was primed with a 50-mg loading dose of bivalirudin. Bivalirudin was initially administered to the patient at approximately 10% of the recommended adult dose7 (0.15 mg/kg intravenous bolus followed by an infusion at 0.25 mg/kg/hour). Repeated bolus doses of bivalirudin were administered and the infusion rate was rapidly titrated upward over 30 minutes to maintain an ACT of ⬎400 seconds (Figure 1). The donor heart was washed before implantation with heparin-free cardioplegia, including the aortic root and coronaries. Intravenous prostacyclin was administered just before and during allograft implantation to prevent platelet aggregation in the distal coronaries, in the event that residual heparin

was present. Significant bleeding occurred after separation from cardiopulmonary bypass that improved with administration of packed erythrocytes, fresh-frozen plasma, recombinant factor VIIa and ultrafiltration. Bleeding resolved within 12 hours, at which time a low-dose argatroban infusion (2 ␮g/kg/min) was resumed. The patient was extubated on Day 8 posttransplant, transferred to the ward on Day 33, and discharged from the hospital on Day 40. Repeat ELISA for heparin-dependent antibody was negative 3 and 10 months later. During cardiopulmonary bypass, serial samples were collected for post hoc analysis of serum bivalirudin levels, which were measured by high-performance liq-

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Figure 1. Dose–response curve demonstrting the relationship between the bivalirudin dose, bivalirudin concentration and the activated clotting time (ACT) during cardiopulmonary bypass for orthotopic cardiac transplantation. The thick black line represents the bivalirudin infusion rate, whereas bivalirudin boluses are quantified along the x-axis. The serum concentration of bivalirudin (denoted by the shaded triangle) is plotted against time (along the right-sided y-axis). The activated clotting time (plotted in seconds along the left-side y-axis) was measured using two methods: Hemochron 401 (ITC, Edison, NJ), denoted by a shaded square; and ACTPlus (Medtronic, Minneapolis, MN), denoted by a plus sign.

uid chromatography.6 Informed consent was obtained from the family. The protocol was approved by the Committee on Clinical Investigation, Children’s Hospital Boston. DISCUSSION We have described a child with heparin-induced thrombocytopenia with thrombosis (HIT Type II) who underwent successful orthotopic cardiac transplantation using bivalirudin as the primary anti-coagulant for cardiopulmonary bypass after a successful bridge-totransplant course where argatroban was used as the primary anti-coagulant for veno-arterial ECMO. Although the data are limited, the incidence of HIT in pediatric patients is approximately 1% to 2%, similar to the incidence of HIT reported in adults.7 To our knowledge, this is the first report describing successful use of bivalirudin for pediatric cardiopulmonary bypass, or for pediatric orthotopic heart transplantation. Options for safe and effective anti-coagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia are limited.8 Platelet inhibition with intravenous prostaglandin E1 or prostacyclinbased regimens were not chosen because of concerns for systemic hypotension and reliability.9 –11 Ancrod was not chosen because of the risk of hemorrhage, lack of a reversal agent, and limited ability to monitor the degree of anti-coagulation intra-operatively.12 Danaproid sodium is no longer commercially available; in

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addition, it is difficult to monitor intra-operatively, and has a long half-life.13 Direct thrombin inhibitors—anticoagulants that bind directly to thrombin interfering with its interaction with substrates14— have emerged as potential options. However, experience with intravenous direct thrombin inhibitors such as argatroban and bivalirudin for cardiopulmonary bypass are limited,14 and few or no clinical data are available in children. Argatroban was chosen as the primary anti-coagulant for ECMO before transplant because of prior institutional experience with argatroban on ECMO, and the successful published experience.15,16 However, at higher ACTs we observed a non-linear ACT response, similar to that described by Malherbe et al, wherein argatroban was used as the primary anti-coagulant for cardiopulmonary bypass in an infant with heparininduced thrombocytopenia.17 Bivalirudin was chosen as the primary anti-coagulant for cardiopulmonary bypass during transplantation for several reasons. First, we believed that bivalirudin’s effect was more likely to be reliably measured by standard ACT, and more likely to yield a linear dose response at ACTs ⬎400 seconds. Second, bivalirudin’s shorter half-life (25 to 34 minutes, compared with 40 to 50 minutes for argatroban) and potential elimination by dialysis18 suggested its effect could be better controlled (in lieu of an available reversal agent), particularly in a patient with a history of significant post-operative bleeding. Third, the minimal organ-based elimination associated with bivalirudin was appealing in this patient whose surgery placed her at significant risk for perioperative right ventricular dysfunction and secondary hepatic insufficiency. We detected acceptable post-operative bleeding and no significant thrombotic complications associated with bivalirudin for cardiopulmonary bypass. We were able to monitor the degree of anti-coagulation intraoperatively using the ACT, because ecarin clotting time (ECT) monitoring, previously suggested for bivalirudin management with extracorporeal circuits,19 was not available. Although the ECT is said to be superior to ACT for monitoring anti-coagulation with bivalirudin,20,21 recent experience has suggested that a modification of ACT (phospholipid added to the contact activator, ACTPlus) may be an acceptable alternative.22 In this patient we found good agreement between standard and modified ACT assays. Interestingly, increases in bivalirudin concentration appeared to be generally correlated with increases in the ACT. Subsequently, the presence of decreased bivalirudin concentrations (which occurred rapidly, consistent with its short half-life) was accompanied by slow normalization of the ACT. It is unclear whether the observed dissociation between bivalirudin concentration and ACT represents a lingering effect of bivalirudin, or whether it

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occurred for other reasons, such as depressed fibrinogen levels. Of note, although our patient received activated Factor VIIa due to persistent bleeding in the early post-operative period, it is difficult to know whether its administration expedited hemostasis given that platelets, fresh-frozen plasma and ultrafiltration were administered concurrently. In summary, bivalirudin is a direct thrombin inhibitor with properties that make it a possible alternative for anti-coagulation in patients who cannot receive heparin. Pediatric cardiopulmonary bypass and heart transplantation may be successfully performed using bivalirudin as the primary anti-coagulant. Studies to determine the pharmacokinetics and pharmacodynamics of bivalirudin in infants and children undergoing cardiopulmonary bypass are warranted. REFERENCES 1. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289: 853– 63. 2. Gordon G, Rastegar H, Schumann R, Deiss-Shrem J, Denman W. Successful use of bivalirudin for cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. J Cardiothorac Vasc Anesthesiol 2003;17:632–5. 3. Koster A, Spiess B, Chew DP, et al. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 2004;93:356 –9. 4. Vasquez JC, Vichiendilokkul A, Mahmood S, Baciewicz FA Jr. Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 2002;74:2177–9. 5. Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor, and its reversal with modified ultrafiltration during heart transplantation in a patient with heparin-induced thrombocytopenia. J Heart Lung Transplant 2005;24:222–5. 6. Farthing D, Larus T, Fakhry I, Gehr T, Prats J, Sica D. Liquid chromatography method for determination of bivalirudin in human plasma and urine using automated ortho-phthalaldehyde derivatization and fluorescence detection. J Chromatogr B Anal Technol Biomed Life Sci 2004;802:355–9. 7. Risch L, Huber AR, Schmugge M. Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res 2006;118:123–35.

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8. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76:2121–31. 9. Addonizio VP Jr, Fisher CA, Kappa JR, Ellison N. Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374). Surgery 1987;102:796 – 807. 10. Palatianos GM, Foroulis CN, Vassili MI, et al. Preoperative detection and management of immune heparin-induced thrombocytopenia in patients undergoing heart surgery with iloprost. J Thorac Cardiovasc Surg 2004;127:548 –54. 11. Shorten G, Comunale ME, Johnson RG. Management of cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia using prostaglandin E1 and aspirin. J Cardiothorac Vasc Anesthesiol 1994;8:556 – 8. 12. Zulys VJ, Teasdale SJ, Michel ER, et al. Ancrod (Arvin) as an alternative to heparin anticoagulation for cardiopulmonary bypass. Anesthesiology 1989;71:870 –7. 13. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993;70:554 – 61. 14. Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028 – 40. 15. Johnston N, Wait M, Huber L. Argatroban in adult extracorporeal membrane oxygenation. J Extra Corpor Technol 2002;34:281– 4. 16. Kawada T, Kitagawa H, Hoson M, Okada Y, Shiomura J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin N Am 2000;14: 445–57. 17. Malherbe S, Tsui BC, Stobart K, Koller J. Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology 2004;100:443–5. 18. Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg 2004;98: 1635–9. 19. Koster A. Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass. Anesth Analg 2003;96:1316 –9. 20. Cho L, Kottke-Marchant K, Lincoff AM, et al. Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentrations. Am J Cardiol 2003;91:1110 –3. 21. Casserly IP, Kereiakes DJ, Gray WA, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res 2004;113:115–21. 22. Jabr K, Johnson JH, McDonald MH, et al. Plasma-modified ACT can be used to monitor bivalirudin (Angiomax) anticoagulation for on-pump cardiopulmonary bypass surgery in a patient with heparin-induced thrombocytopenia. J Extra Corpor Technol 2004;36:174 –7.