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Ann Thorac Surg 2004;77:711-713
© 2004 The Society of Thoracic Surgeons

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Case report

Failure of argatroban anticoagulation during off-pump coronary artery bypass surgery

^a Departments of Anesthesiology and Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Accepted for publication April 11, 2003.

^* Address reprint requests to Dr Cannon, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009, USA
e-mail: marcann{at}wfubmc.edu

	Abstract

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Heparin-induced antibodies create vexing problems during cardiac surgery. Although alternative medications have been used for intraoperative anticoagulation, the results have been sufficiently variable that no one medication is recommended. In our case, due to the poor reversibility of the antithrombin agents, argatroban was chosen as a heparin substitute due to its short half-life and its anticoagulation assessment using the activated clotting time (ACT). Unfortunately, our experience was that argatroban does not provide adequate anticoagulation during off-pump coronary bypass surgery, even when the ACT is maintained at more than 380 sec.

	Introduction

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Heparin-induced thrombocytopenia occurs in approximately 4% of the adult cardiac surgical population, and poses a unique problem for patients requiring intraoperative anticoagulation [1–3]. Several alternative drugs, including danaparoid, hirudin, and argatroban, have been used for intraoperative anticoagulation with varying results [3]. Unlike heparin and related medications, these alternative drugs do not form the platelet factor 4 (PF 4)-heparin antigen and thus do not trigger the immune response underlying heparin-induced thrombocytopenia. Furthermore, unlike heparin, hirudin and argatroban directly inhibit thrombin, preventing thrombin-fibrin complex formation. Argatroban specifically binds to the catalytic site of thrombin preventing fibrin conversion. With either hirudin or argatroban the adequacy of anticoagulation can be assessed using activated clotting time (ACT), activated partial thromboplastin time (aPTT), or thrombin time (TT). Though TT is a recognized method of anticoagulation assessment, it is too sensitive a test for use with thrombin inhibitors. Heparin alternatives have been described in multiple different forms of extracorporeal circulation (ECC), but less comprehensively in "off-pump" coronary artery bypass (OPCAB) surgery. The following describes the difficulties we experienced maintaining adequate systemic anticoagulation despite increasing argatroban doses and a markedly prolonged ACT in OPCAB.

A 74-year-old male presented to our hospital with unstable angina. His past medical history was notable for a previous percutaneous coronary intervention, atrial fibrillation, cerebrovascular disease with stroke, and previous renal cell carcinoma. After admission, the patient underwent a left-heart catheterization revealing normal left-ventricular function, 60% stenosis of the left main coronary artery, and an occluded (previously stented) right coronary artery. Despite intensive medical management including intravenous heparin (aPTT ranging between 55 to 80 seconds), the patient continued to have anginal pain at rest. He was referred for surgical treatment of his coronary artery disease. At this time, the patient's platelet count had decreased from 110,000/dL to 69,000/dL. A heparin antibody test was performed using an escalating quantitative heparin assay. It was positive for heparin antibodies. After consultation with a hematologist, the collective decision was made to anticoagulate the patient during OPCAB with argatroban, based on the short half-life of argatroban and the perceived reduced risk of excessive postoperative hemorrhage relative to other heparin alternatives. Though the use of argatroban for cardiac surgery is off-label, this was discussed with the patient during his consent for surgery and anesthesia.

Anesthesia was induced with fentanyl, midazolam, and pancuronium, and maintained with isoflurane. A pulmonary artery catheter and right radial artery catheter were placed. Before incision, 200 µg of argatroban was given intravenously and a drip of 2 µg · kg^-1 · min^-1 was begun. Baseline ACT was 144 seconds; 15 and 30 minutes after the loading dose the ACTs were 193 and 230 seconds, respectively. During the distal saphenous vein anastomosis to the posterior descending coronary artery, a new clot was identified in the vein graft and in the pericardium. The ACT at this time (155 minutes after the loading dose) was 278 seconds. The clot was removed from both the graft and the pericardium, and the argatroban drip was increased to 5 µg · kg^-1 · min^-1. Approximately 10 minutes later, all anastomoses were complete and the argatroban was discontinued. Due to the intraoperative thrombotic events, the attending surgeon requested that argatroban be restarted. The ACT on reinstitution of the argatroban (approximately 20 minutes after the initial discontinuation) at 5 µg · kg^-1 · min^-1 was 208 seconds. Five minutes later a white clot was noted in the vein graft a second time; the vein graft was abandoned in favor of a right internal mammary artery graft. Activated partial thromboplastin time and ACT measured were 61.9 seconds and 276 seconds, respectively. The argatroban was increased to 8 µg · kg^-1 · min^-1. The ACT 15 minutes later was 289 seconds. Thirty minutes later, the ACT increased to 372 seconds (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. ACT (sec) is plotted from the initial bolus of the argatroban to every ACT until the end of surgery. The x axis indicates time (min) from the initial bolus to the completion of the case. Line = Series 1. (ACT = activated clotting time.)

	Comment

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The argatroban loading and maintenance doses that we used, were described by Kawada and colleagues as adequate for left-heart bypass while producing an ACT range of 200 to 250 seconds [4]. We assumed that an OPCAB procedure would be no more prone to thrombosis than left-heart bypass, and that anticoagulation sufficient for left-heart bypass would be more than sufficient for OPCAB. The degree of heparin anticoagulation during OPCAB surgery varies from institution to institution [5, 6]. Our practice is to maintain the ACT at 230 to 270 seconds. Previous research suggests that argatroban inhibits thrombogenesis to the same extent as heparin [7, 8], and that the ACT would be an adequate monitor thereof. False elevations of the ACT can occur with hypothermia, thrombocytopenia, and acute severe hemodilution. However, none of these occurred during this surgery (the minimum temperature in this case was 36.6°C). Nevertheless, argatroban failed to provide adequate anticoagulation despite increasing doses and a prolonged ACT.

The platelet count was not measured intraoperatively, but was 68,000/dL immediately postoperatively, consistent with the preoperative platelet count. The patient received no drugs (such as aprotinin) that might falsely increase the ACT. Other causes for graft occlusion were considered intraoperatively. Graft and anastomotic patency were confirmed on two occasions. Kawada reported several experiences where a clot was noticed in the surgical field during left heart bypass despite argatroban infusion sufficient to prolong the ACT to 200 to 250 seconds [4]. This report and our experiences suggest that the ACT may not be an adequate monitor of argatroban anticoagulation.

The patient had no past history of venous thromboembolism. There was a history of cerebrovascular disease with stroke, albeit as a complication of atrial fibrillation. Since there was no history of coagulation abnormalities preoperatively, and no such issues were apparent postoperatively, the patient did not undergo further evaluation. The patient was discharged to home on his maintenance warfarin regimen as well as clopidogrel 75 mg PO QD. Six-month follow-up was negative for thromboembolic events; however, the patient was diagnosed with metastatic rectal carcinoma 9 months after his coronary artery surgery. Although malignancies can produce a hypercoagulable state, this would not explain clot formation with increased argatroban doses and markedly prolonged ACTs. The lack of thromboembolic events postoperatively further downplays any significant role of a hypercoagulable state during cardiac surgery.

Despite previous reports that argatroban and heparin increase the ACT similarly for a comparable degree of anticoagulation, we found evidence that an ACT exceeding 300 seconds with argatroban does not produce the same clinical results as heparin during OPCAB. One could theorize that antiplatelet activity, as well as profibrinolytic actions, underlie heparin's greater protection from thrombosis compared to argatroban at similar ACT values [8]. We strongly believe that thorough dose-response versus ACT evaluations should occur to assist in the clinical setting. Being unaware of any data supporting higher ACTs in heparin-induced thrombocytopenia patients and no nationally accepted ACT management protocols for OPCAB surgery, we look forward to further investigations. Although the OPCAB procedure was selected for this patient in part to take advantage of the lesser anticoagulation requirements, our experience argues that when using argatroban as a heparin substitute for OPCAB surgery, the target ACT should be comparable to that for full cardiopulmonary bypass.

	References

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1. Trossaert M., Gaillard A., Commin P.L., Amiral J., Vissac A.M., Fressinaud E. High incidence of anti-heparin/platelet factor 4 antibodies after cardiopulmonary bypass surgery. Br J Haematol 1998;101:653-655.[Medline]
2. Pouplard C., May M.A., Iochmann S., et al. Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implications for heparin-induced thrombocytopenia. Circulation 1999;99:2530-2536.[Abstract/Free Full Text]
3. Wilhelm M.J., Schmid C., Kececioglu D., Mollhoff T., Ostermann H., Scheld H.H. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996;61:920-924.[Abstract/Free Full Text]
4. Kawada T., Kitagawa H., Hoson M., Okada Y., Shiomura J. Clinical application of argatroban as an alternative anticoagulant for extracorporeal circulation. Hematol Oncol Clin North Am 2000;14:445-457.[Medline]
5. D'Ancona G., Donias H.W., Karamanoukian R.L., Bergsland J., Karamanoukian H.L. OPCAB therapy survey: off-pump clopidogrel, aspirin or both therapy survey. Heart Surg Forum 2001;4:354-358.[Medline]
6. Carrier M., Robitaille D., Perrault L.P., et al. Heparin versus danaparoid in off-pump coronary bypass grafting: results of a prospective randomized clinical trial. J Thorac Cardiovasc Surg 2003;125:325-329.[Abstract/Free Full Text]
7. Walenga J.M., Fasanella A.R., Iqbal O., et al. Coagulation laboratory testing in patients treated with argatroban. Semin Thromb Hemost 1999;25(Suppl 1):61-66.
8. Berry C.N., Girardot C., Lecoffre C., Lunven C. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost 1994;72:381-386.[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert D. Riley Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cannon, M. A. Articles by Hyland, J. M. Search for Related Content PubMed PubMed Citation Articles by Cannon, M. A. Articles by Hyland, J. M. Related Collections Extracorporeal circulation