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Ann Thorac Surg 2003;75:577-579
© 2003 The Society of Thoracic Surgeons

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Case report

Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use

^a Institute of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
^b Department of Anesthesiology and Critical Care, Heart and Diabetes Center, Mecklenburg/Vorpommern, Karlsburg, Germany
^c Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center, Mecklenburg/Vorpommern, Karlsburg, Germany

Accepted for publication August 19, 2002.

* Address reprint requests to Dr Lubenow, Ernst-Moritz-Arndt Universität, Institut für Immunologie und Transfusionsmedizin, Abteilung Transfusionsmedizin, Klinikum, Sauerbruchstrasse, 17489 Greifswald, Germany
e-mail: lubenow{at}uni-greifswald.de

	Abstract

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Heparin-induced thrombocytopenia (HIT), a serious complication of heparin therapy, mandates heparin cessation and alternative anticoagulation. We report a patient with a history of HIT who successfully underwent cardiopulmonary bypass (CPB) using short-term reexposure to heparin and perioperative therapy with argatroban. No bleeding complications or HIT-related problems occurred. The pharmacokinetics of argatroban, especially its hepatic rather than renal elimination, makes it the drug of choice for some HIT patients in whom other alternative anticoagulants (eg, danaparoid and hirudin) are less well suited. Because of interference with the international normalized ratio (INR), switching from argatroban to oral anticoagulants is not straightforward.

	Introduction

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Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy mandating heparin cessation and alternative anticoagulation therapy. The direct thrombin inhibitors argatroban [1] and hirudin [2] and the heparinoid danaparoid [3] have been used as alternative anticoagulants for HIT patients. In HIT antibodies develop that bind platelet factor 4/heparin complexes, leading to platelet activation, thrombocytopenia, and possible thrombosis. In as many as 50% of cardiac surgery patients who receive unfractionated heparin HIT antibodies will develop and in as many as 2% of these patients clinical HIT will develop [4]. HIT antibodies are transient, typically being undetectable 12 weeks after the acute episode. Because boostering of antibodies requires several days, short-term reexposure to heparin during cardiopulmonary bypass (CPB) may be safe in patients who lack circulating HIT antibodies if heparin is strictly avoided preoperatively and postoperatively [5]. We describe a patient with a history of HIT who successfully underwent CPB using heparin and was managed perioperatively with argatroban (GlaxoSmithKline, Philadelphia, PA).

A 44-year-old woman who had undergone unilateral nephrectomy several years earlier because of renal tuberculosis had chronic renal failure (serum creatinine 189 µmol/L) and a history of HIT complicated by stroke (4 months earlier) and now required aortic valve replacement for aortic stenosis. Before cardiac surgery, removal of two teeth was necessary. She was receiving phenprocoumon (target international normalized ratio [INR] >2.5) because of atrial fibrillation related to aortic stenosis and renal artery embolism. HIT antibodies were undetectable by heparin-induced platelet activation assay and also by enzyme-linked immunosorbent assay (HAT 45TM; GTI, Brookfield, WI) preoperatively.

After stopping phenprocoumon, intravenous argatroban 1 to 1.9 µg · kg^-1 · min^-1 was administered, adjusted to achieve an activated partial thromboplastin time (aPTT) 1.5 to 3 times base line. Argatroban was stopped 1 hour before dental surgery, which was performed without major hemorrhage, and restarted immediately thereafter.

Argatroban was again stopped 2 hours before the expected time of CPB during cardiac surgery. Unfractionated heparin was administered during CPB according to standard protocol and completely reversed by protamine afterwards. The overall operation time for the insertion of a mechanical valve (Medtronic Hall, Medtronic, Minneapolis, MN) was 148 minutes, clamp time was 58 minutes, and bypass time was 79 minutes. There was no increased bleeding tendency. A cell-saving device was not used. Chest drain output amounted to 520 mL at 48 hours postoperatively (350 mL at 24 hours), and 3 U each of packed red cells and fresh frozen plasma but no platelet concentrates were transfused. Volume substitution with other infusions (eg, hydroxyethyl starch) was not administered.

Argatroban was restarted 9 hours after surgery at 0.1 to 0.15 µg · kg^-1 · min^-1; phenprocoumon was restarted on postoperative day 2. Because argatroban prolongs the INR the drug was stopped and hirudin was given on postoperative day 4 in order to evaluate the INR without interference by argatroban. Therapeutic oral anticoagulation thus monitored was achieved on day 5. No HIT-related complications occurred and no HIT antibodies were detected in the postoperative period.

	Comment

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Increasingly patients with serologically confirmed HIT in their medical history have to be managed in different clinical circumstances such as CPB. For patients with a history of HIT reexposure to heparin is usually avoided by using alternative anticoagulants: argatroban, a direct thrombin inhibitor with a less than 60-minute half-life that is eliminated by the liver pathway [1]; hirudin, a direct thrombin inhibitor with a half-life of less than 60 minutes that can, however, be prolonged in renal failure to more than 200 hours [2]; and danaparoid, a heparinoid exhibiting mainly anti-Xa activity with a half-life of about 25 hours [3]. CPB using argatroban anticoagulation has been performed successfully in dogs; however, clinical data are limited in that setting [1, 6]. In addition, HIT patients have successfully undergone CPB using danaparoid [2] or hirudin [4] but these alternative anticoagulants lack antidotes and that lack can become problematic if bleeding occurs. During the high-dose anticoagulation CPB requires, specialized bedside monitoring is necessary if danaparoid (ie, anti-Xa activity) or hirudin (ie, ecarin clotting time) is used. These monitoring methods are not widely available. Because of these safety and monitoring concerns short-term reexposure to heparin has been successfully applied during CPB in patients with a history of HIT [5]. The case we report confirms this strategy and indicates that perioperative anticoagulant management with argatroban is feasible.

As the patient required long-term anticoagulation before surgery and had reduced renal function, argatroban, which is eliminated hepatically with a short half-life, was favored over danaparoid or hirudin. Preoperative argatroban therapy allowed continuing anticoagulation, which was mandatory owing to atrial fibrillation and aortic stenosis, until 2 hours preoperatively without risking additional anticoagulatory effects with heparin during CPB. Because argatroban increases the INR overlapping oral anticoagulation was not straightforward. To assess whether oral anticoagulation was therapeutic argatroban was stopped after 3 days of concurrent anticoagulation and hirudin was given briefly. During hirudin treatment the effectiveness of oral anticoagulation could be accurately determined and when the INR was in the therapeutic range, hirudin was stopped. That is especially important because during the initial phase of vitamin K antagonism the anticoagulant protein C is reduced quicker than the procoagulant clotting factors. Stopping the concurrent parenteral anticoagulation during this phase would greatly increase the risk of thromboembolic complications. Although guidelines for monitoring the transition from argatroban to warfarin therapy are now available [1] determining the appropriate time when sufficient oral anticoagulation has been achieved can be problematic in some patients.

There did not seem to be a boostering of HIT antibodies caused by the heparin reexposure and no HIT-related problems occurred. Whether the short duration, the high dose, or the immediate reversal of heparin prevented the anamnestic immune response is unclear.

For HIT patients for whom heparin exposure during surgery is planned the perioperative anticoagulant agent’s half-life and monitoring requirements should be considered. For patients needing therapeutic anticoagulation before surgery the long half-life of danaparoid may increase intraoperative and postoperative bleeding risk; the same applies to the use of hirudin for patients with renal impairment. Under such circumstances, argatroban with its short half-life independent of renal function seems to be better suited. Argatroban and hirudin are routinely monitored using aPTTs. Danaparoid monitoring requires an anti factor-Xa assay. Because argatroban prolongs the INR, overlapping oral anticoagulation if needed may be less complicated with danaparoid or hirudin.

We conclude that argatroban can provide successful perioperative anticoagulation for the patient with a history of HIT who undergoes CPB using heparin anticoagulation. Furthermore argatroban therapy has particular utility in HIT patients with renal failure, for whom danaparoid and hirudin pose increased bleeding risks.

	Acknowledgments

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The editorial assistance of Marcie J. Hursting, PhD, DABCC, is greatly appreciated.

	References

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1. Lewis B.E., Hursting M.J. Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin T.E., Greinacher A., eds. Heparin-induced thrombocytopenia, 2nd ed New York: Marcel Dekker, 2001:381-407.
2. Lubenow N., Greinacher A. Heparin-induced thrombocytopenia. Recommendations for optimal use of recombinant hirudin. BioDrugs 2000;14:109-125.[Medline]
3. Chong B.H., Magnani H.N. Danaparoid for the treatment of heparin-induced thrombocytopenia. In: Warkentin T.E., Greinacher A., eds. Heparin-induced thrombocytopenia, 2nd ed New York: Marcel Dekker, 2001:323-348.
4. Warkentin T.E., Sheppard J.-A.I., Horsewood P., Simpson P.J., Moore J.C., Kelton J.G. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;96:1703-1708.[Abstract/Free Full Text]
5. Pötzsch B., Klövekorn W.P., Madlener K. Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med 2000;343:515.[Free Full Text]
6. Furukawa K., Ohteki H., Hirahara K., Narita Y., Koga S. The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations. J Thorac Cardiovasc Surg 2001;122:1255-1256.[Free Full Text]

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