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Ann Thorac Surg 2005;79:696-698
© 2005 The Society of Thoracic Surgeons

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Case report

Off-Pump Coronary Artery Bypass Grafting in a Heparin-Induced Thrombocytopenia Type II Patient Using Hirudin

^a London Bridge Hospital, London, United Kingdom

Accepted for publication September 8, 2003.

^* Address reprint requests to Dr Carr, Department of Cardiothoracic Surgery, King's College Hospital, London SE5 9RS, UK
noahalkh{at}talk21.com

	Abstract

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Heparin is routinely used for anticoagulation during cardiopulmonary bypass; it is fast acting, is easily monitored, and has an antidote. Heparin-induced thrombocytopenia (HIT) can be a life-threatening condition requiring an alternative anticoagulant (hirudin) if cardiac surgical intervention is considered. At full anticoagulant doses, the effects of hirudin are difficult to monitor; therefore, we present a case in which off-pump coronary artery bypass grafting was performed in an HIT patient in whom the lower doses of hirudin could safely be monitored with easily available tests.

	Introduction

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Anticoagulation during cardiopulmonary bypass (CPB) requires a fast-acting anticoagulant, reliable monitoring of the effect, and an effective antidote to restore coagulation after discontinuing CPB. The intravenous administration of heparin and its neutralization by protamine are performed routinely for CPB.

Heparin-induced thrombocytopenia (HIT) is separated into 2 different types on the basis of clinical presentation and pathophysiologic mechanism. Type I is an early (within 4 days), mild form of thrombocytopenia, with platelets rarely less than 100 x 10⁹/L. It is caused by nonimmunologic mechanisms, and there are no major sequelae [1].

Type II is a delayed (5 to 12 days), more severe form of thrombocytopenia and is caused by immunologic mechanisms with sequelae that can be life threatening. Heparin-induced thrombocytopenia type II causes thromboembolic disorders producing severe morbidity and mortality. The profound activation of the coagulation system occurs through platelet activation, endothelial activation, and heparin neutralization. Arterial and venous thromboses occur, as well as disseminated intravascular coagulation, cerebral thrombosis, myocardial infarction, skin lesions, and ischemic injury to limbs. These patients should not receive heparin in any form, including the use of heparin-bonded materials used in CPB circuits. Agents with similar structures to heparin can cause cross-reactivity and should be avoided [1].

Heparin-induced thrombocytopenia is an indication for the use of an alternative anticoagulant. Lepirudin (Hoechst Marion Roussel, Aventis Pharma Ltd, West Malling, Kent, UK) is a recombinant form of hirudin (purified from Hirudo medicinalis leech saliva) that is highly specific and a potent direct thrombin inhibitor, with no effects on platelets. Systemic clearance is proportional to the glomerular filtration rate and creatinine clearance, and in patients with renal impairment, it is possible to lower plasma hirudin levels by hemofiltration [2]. The benefits of lepirudin are an immediate onset, a short half-life (30 to 60 minutes), and no cross-reaction with heparin-induced antibodies, but there is no known reversal agent. Monitoring the effect of higher doses requires the Ecarin clotting time (ECT), and it is recommended to maintain the ECT test between 200 and 300 seconds to avoid clot formation [2, 3]. The activated clotting time (ACT) and the activated partial thromboplastin time (APTT) have been found to be unreliable to monitor hirudin effects at the higher levels required for CPB because they lose linearity at the higher doses of lepirudin, but the APTT is the accepted coagulation test for therapeutic lower levels of lepirudin [3].

We discuss a patient with HIT type II who was suitable for off-pump coronary artery bypass grafting (OPCABG) and in whom hirudin anticoagulation could safely be used with APTT measures, thus avoiding ECT monitoring, which was not readily available. We also compared laboratory and near-patient APTT testing.

A 64-year-old woman of Middle Eastern origin was admitted for an elective coronary artery bypass graft. She was known to have HIT type II (disseminated intravascular coagulation and hyperpigmentation). One year previously, she had had a myocardial infarction and had a further episode of unstable angina with pulmonary edema. She was an insulin-dependent diabetic. A coronary angiogram had shown left anterior descending artery and right coronary artery stenoses with impaired left ventricular function, with an ejection fraction of less than 40%. The patient's preoperative platelet count (232 x 10⁹/L), clotting screen, and renal function were normal, and she was negative for the antibody that mediates HIT type II at the time of the procedure. She was 1.51 m tall and weighed 83 kg.

In view of the patient's heparin sensitivity, it was felt that if OPCABG could be performed, it might minimize the need for anticoagulation with heparin alternatives. OPCABG x 2 was performed; after the stabilization of the left anterior descending artery with the Octopus 3 (Medtronic Inc, Minneapolis, MN), a half dose of hirudin (10 mg of lepirudin [Refludan, Hoechst Marion Roussel, Aventis Pharma Ltd, West Malling, Kent, UK]) was given intravenously, and the left internal mammary artery was anastomosed to the left anterior descending artery over a 1.5-mm shunt (Flo-Thru, Biovascular Inc, St Paul, MN). Both laboratory and near-patient APTT tests were performed every 15 minutes throughout the operation and 1 minute after lepirudin administration (Table 1). The right coronary artery was opened, a 2.5-mm shunt (Flo-Thru, Biovascular Inc, St Paul, MN) was inserted, and the long saphenous vein was anastomosed in a routine fashion. The vein graft was then filled with hirudin-saline solution, and the top end was anastomosed to the ascending aorta. There were no ischemic changes on electrocardiography. During the operation, a cell-saving device (Dideco, Compact-Advanced, Mirandola, Italy) was used, using citrate for anticoagulation (ACDA Solution, Baxter Healthcare Ltd, Norfolk, UK) to salvage any blood loss. No heparin was used in the flushes for the arterial and venous transducers.

	Comment

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Heparin induces anticoagulation by potentiating the activity of antithrombin III, which inhibits thrombin and activated factor X. Hirudin is a direct thrombin inhibitor and does not require antithrombin III as a cofactor [4]. Heparin-induced thrombocytopenia type II is due to heparin-induced antibodies, usually immunoglobulin G, that interact with complexes of heparin and platelet factor 4, leading to platelet activation causing aggregation and thrombus formation. The risk for HIT type II varies with the dose and type of heparin, with full doses of unfractionated heparin giving the highest risk [1]. Laboratory assays for diagnosing HIT are unfortunately unreliable [5], and not all patients express the antibody, with only 50% found to have the antibody in the series described by Nuttall and colleagues [6].

One molecule of hirudin binds to one molecule of thrombin, thus affecting all thrombin-dependent coagulation assays. The APTT may not give adequate information for overdosing but would provide enough information to prevent underdosing. With the ECT, a dose-response curve must be constructed for each patient, aprotinin should be used, and forced diuresis at the end of CPB should be produced [4]. The dose for our patient was calculated as half that for full anticoagulation for CPB, and an APTT of more than 2.5 times normal was chosen as the target for OPCABG [5]. The ACT test was performed for reasons of clinical standards required by the hospital, and the laboratory and near-patient APTT tests were performed for comparison.

The advantages of performing OPCABG in such an HIT patient include the dose of hirudin being at the lower level, so that monitoring can be performed safely without specialized equipment [5]. If CPB had been required, the protocol would have been an intravenous loading dose of 0.25 mg/kg and a dose of 0.20 mg/L added to the pump prime (target level, 2.0 µg/mL blood). Doses of 2 to 5mg/L or a continuous infusion of 0.5 mg/min are given throughout CPB as monitoring indicates [4]. In this patient, the hirudin dose for bypass was 16.6 mg, and the bolus dose was 20.75 mg. Also, in the series by Nuttall and colleagues [6], hirudin patients whose operations were performed on CPB had excessive bleeding and a high rate of reoperation. By using lower doses with OPCABG, these complications might be avoidable.

	References

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1. Brieger DB, Mak KH, Kottke-Marchant K, Topol EJ. Heparin-induced thrombocytopenia: a review. J Am Coll Cardiol. 1998;31(7):1449–1459[Abstract/Free Full Text]
2. Fabrizio MC. Use of Ecarin clotting time (ECT) with lepirudin therapy in heparin-induced thrombocytopenia and cardiopulmonary bypass. J Extra Corpor Technol. 2001;33(2):117–125[Medline]
3. Potzsch B, Madlener K, Seelig C, Reiss CF, Greinacher A, Muller-Berghaus G. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass—assessment of the whole blood Ecarin clotting time. Thromb Haemost. 1997;77(5):920–925[Medline]
4. Von Segesser LK, Mueller X, Marty B, Horisberger J, Como A. Alternatives to unfractionated heparin for anticoagulation in cardiopulmonary bypass. Perfusion. 2001;16(5):411–416[Abstract/Free Full Text]
5. Koster A, Kuppe H, Crystal GJ, Mertzlufft F. Cardiovascular surgery without cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II using anticoagulation with recombinant hirudin. Anaesth Analg. 2000;90(2):292–298[Free Full Text]
6. Nuttall GA, Oliver WC, Santrach PJ, et al. Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Anaesth Analg. 2003;96(2):344–350[Abstract/Free Full Text]

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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): Cornélia S. Carr Jatin B. Desai Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carr, C. S. Articles by Desai, J. B. Search for Related Content PubMed PubMed Citation Articles by Carr, C. S. Articles by Desai, J. B. Related Collections Coronary disease