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Anesthesia & Analgesia:
doi: 10.1213/ane.0b013e318196cd51
Cardiovascular Anesthesiology: Case Report

Successful Use of Bivalirudin for Combined Carotid Endarterectomy and Coronary Revascularization with the Use of Cardiopulmonary Bypass in a Patient with an Elevated Heparin-Platelet Factor 4 Antibody Titer

Avery, Edwin G. MD*; Hilgenberg, Alan D. MD†; Cambria, Richard P. MD‡; Beckerly, Rena MD*; Donnelly, Anne M. RN*; Laposata, Michael MD, PhD§

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From the *Division of Cardiac Anesthesia, Department of Anesthesia and Critical Care, Massachusetts General Hospital Heart Center, †Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital Heart Center, ‡Division of Vascular Surgery, Department of Surgery, Massachusetts General Hospital Vascular Center, and §Division of Laboratory Medicine, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Massachusetts.

Accepted for publication September 13, 2008.

Supported by The Medicines Company in association with Protocol no. TMC-BIV-02-03 from grant no. 212867.

Edwin G. Avery, MD, has participated in funded research with The Medicines Company and served as a paid consultant to The Medicines Company.

Address correspondence and reprint requests to Edwin G. Avery, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital Heart Center, 55 Fruit St., Boston, MA 02114. Address e-mail to eavery@partners.org.

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Abstract

We report a combined carotid endarterectomy and coronary revascularization surgery with cardiopulmonary bypass using bivalirudin for systemic anticoagulation in a patient with a positive titer for the heparin-platelet factor 4 antibody. The patient experienced procedural success for both the carotid and coronary surgeries. Increased blood and blood product transfusion was required postoperatively.

Treating a patient with heparin-induced thrombocytopenia (HIT) for cardiac surgery represents a problem for clinicians. We report a combined carotid endarterectomy (CEA) and coronary revascularization surgery requiring cardiopulmonary bypass (CPB) using bivalirudin, a direct thrombin inhibitor. HIT was diagnosed based on both clinical and laboratory evidence.

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CASE REPORT

A 60-yr-old man with an elevated heparin-platelet factor 4 (Hep-PF 4) antibody titer presented for a combined procedure that included a left CEA and four-vessel coronary artery bypass grafting (CABG) on CPB. The patient’s medical history was significant for multivessel coronary artery disease (CAD), left carotid stenosis, a stroke 5 mo before this procedure that was temporally related to heparin administration for angiography, diabetes mellitus Type II, and peripheral vascular disease. His preoperative left ventricular ejection fraction was 47% by nuclear imaging.

The patient had confirmed CAD with worsening anginal symptoms in the setting of a positive Hep-PF 4 antibody titer (optical density [O.D.] = 1.790; O.D. control value = 0.443) (Asserchrom PF4, Diagnostica Stago, Parsippany, NJ) that remained positive for 5 mo. Preoperatively, his platelet count was 287 th/mm3 (normal, 150–350 th/mm3), prothrombin time was 13.1 s (normal, 11.3–13.3), and the activated partial thromboplastin time was 26.5 s (normal, 22.1–35.1).

The decision was made to proceed to combined CEA/CABG surgery using bivalirudin to provide anticoagulation. Informed consent was obtained and the patient was enrolled into institutional review board-approved protocol no. TMC-BIV-02-03. Intraoperative monitoring included electroencephalography (18 leads), radial arterial catheterization, pulmonary artery catheterization, and transesophageal echocardiography. Fentanyl, propofol, and cisatrcurium were administered for anesthesia induction and maintenance along with the addition of isoflurane. Hemodynamic stability was maintained using norepineprine, dopamine, and nitroglycerin as needed.

Bivalirudin (Angiomax®, The Medicines Company, Parsippany, NJ) was administered as an IV bolus of 0.75 mg/kg using actual body weight (81 kg) and an infusion of 1.75 mg · kg−1 · h−1 for the carotid surgery using recommended dosing for percutaneous coronary intervention. CEA was performed using shunting and patch angioplasty. Anticoagulation was increased for the initiation of CPB by an additional IV dose of 0.75 mg/kg bivalirudin and the infusion was increased to 2.5 mg · kg−1 · h−1 and stopped 15 min before CPB separation. CPB total time was 161 min. Anticoagulation was monitored with the activated clotting time (ACT) test (ACT+, Medtronic, Minneapolis, MN; Hemochron 401 and Hemochron Jr. Signature+, ITC, Edison, NJ) and thromboelastography (TEG®) (Hemoscope Corp., Niles, IL). Plasma samples were obtained for post hoc analysis of bivalirudin concentration using a high performance liquid chromatography fluorescence-based assay.1 The goal ACT value for the carotid portion of the procedure was >300 s and >400 s for the CPB portion.3 ACT and TEG correlations to bivalirudin concentrations are presented in Table 1. ACT+ data are displayed in Figure 1. Correlations (R2) were calculated using Microsoft® Excel 2000 software.

Table 1
Table 1
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Figure 1
Figure 1
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Post-CPB intraoperative transesophageal echocardiography revealed a small, filamentous thrombus attached to the heparin-free pulmonary artery catheter in the right atrium; follow-up ultrasound examination on the third postoperative day did not reveal any intracardiac thrombus. Chest tube drainage was 2505 mL during the first 12 postoperative hours. Blood product administration during the first 12 postoperative hours included: 4 U of red blood cells, 5 U of fresh frozen plasma, 10 U of cryoprecipitate, and 1 single donor unit of platelets. Bleeding decreased over time and after transfusion therapy. The activated partial thromboplastin test 2.5 h after CPB separation peaked at 91 s and decreased to 38.5 s 9.5 h after CPB separation. The fibrinogen level 5 h after CPB separation was 135 mg/dL (normal, 150–400). Antifibrinolytic therapy was not administered because of concerns regarding HIT and potential prothrombotic complications. The patient was tracheally extubated on postoperative day 1 without complications. Follow-up at 6 mo revealed a patent left internal carotid artery by ultrasound examination and a significant reduction in myocardial ischemia compared with preoperative nuclear imaging.

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DISCUSSION

We report the successful use of bivalirudin for a combined surgical procedure (left CEA and CABG on CPB) in a patient with an elevated Hep-PF 4 antibody titer.2 Bivalirudin has been reported as a potential alternative to heparin and protamine.3–6 We proceeded surgically despite a persistently elevated (i.e., more than 5 mo) Hep-PF 4 antibody titer because of unstable angina. In a patient with less severe CAD, we would have chosen to defer his surgery until his Hep-PF 4 antibody titer decreased to below a positive value. We chose bivalirudin for anticoagulation because his history was consistent with HIT and included a stroke that was temporally related to heparin administration with a significant decrease in his platelet count (i.e., 40%) in the presence of a high titer of the Hep-PF 4 antibody ([O.D.] 1.790 with an O.D. control value of 0.443).7

The intraoperative use of bivalirudin for cardiac surgery involving CPB is complex and may be associated with increased risk of hemorrhage.6 Bivalirudin’s anticoagulant effect is monitored using the ACT,2 and the ACT provided a better correlation with measured plasma bivalirudin concentrations than TEG. Among three ACT tests, the ACT+ provided the overall strongest correlation within the measured range of plasma bivalirudin concentrations (R2 = 0.88). High plasma concentrations of bivalirudin were detected by ACT and directly measured in this patient, which may account for the increased chest tube drainage observed. We transfused hemostatic blood products because hemostatic tests suggested coagulopathy. Additional clinical trials are needed to establish the role of bivalirudin in patients with HIT requiring cardiac surgery.

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ACKNOWLEDGMENTS

The authors acknowledge the excellent clinical care provided to this patient by Dr. Michael Jaff and the assistance provided by Dr. Warren Sandberg with statistical analysis of the data.

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REFERENCES

1. 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 2004;802:355–9

2. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg 2003;76:638–48

3. Koster A, Spiess B, Chew DP, Krabatsch T, Tambeur L, DeAnda A, Hetzer R, Kuppe H, Smedira NG, Lincoff AM. 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. Merry AF, Raudkivi PJ, Middleton NG, McDougall JM, Nand P, Mills BP, Webber BJ, Frampton CM, White HD. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:925–31

5. Koster A, Dyke CM, Aldea G, Smedira NG, McCarthy HL, Aronson S, Hetzer R, Avery E, Spiess B, Lincoff AM. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007;83:572–7

6. Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL, Kirshner R, Lincoff AM, Spiess BD. A comparison of bivalirudin to heparin with protamine in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006;131:533–9

7. Chilver-Stainer L, Lammle B, Alberio L. Titre of anti-heparin/PF 4-antibodies and extent of in vivo activation of the coagulation and fibrinolytic systems. Thromb Haemost 2004;91:276–82

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