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Ann Thorac Surg 2000;70:2160-2161
© 2000 The Society of Thoracic Surgeons

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Case report

Cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia II and impaired renal function using heparin and the platelet GP IIb/IIIa inhibitor tirofiban as anticoagulant

^a Department of Anesthesia, Deutsches Herzzentrum Berlin, Berlin, Germany
^b Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany

Accepted for publication May 14, 2000.

Address reprint requests to Dr Koster, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13305 Berlin
e-mail: koster{at}dhzb.de

	Abstract

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In a patient with heparin-induced thrombocytopenia II and impaired renal function, anticoagulation during cardiopulmonary bypass was successfully performed by the use of unfractionated heparin and the platelet glycoprotein IIb/IIIa inhibitor tirofiban. Postoperative antithrombotic therapy with recombinant hirudin was immediately initiated. This regimen for anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia II appears to be particularly appropriate for patients with impaired renal function or for hospitals without special experience with other alternative anticoagulation strategies.

	Introduction

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Heparin-induced thrombocytopenia (HIT) is a serious immune-mediated complication, which in cardiac surgery is associated with high morbidity and mortality [1]. Therefore, in patients diagnosed with HIT, an alternative anticoagulation should be instituted. This poses a problem in patients who have to undergo cardiac surgery that involves cardiopulmonary bypass (CPB), because all currently used alternatives are associated with relevant drawbacks, particularly in patients with impaired renal function [2].

Antagonists of the platelet glycoprotein (GP) IIb/IIIa receptor provide effective inhibition of heparin antibody-stimulated platelet aggregation in vitro [3, 4]. We report for the first time on the use of unfractionated heparins (UFH) combined with the platelet GP IIb/IIIa inhibitor tirofiban for anticoagulation during CPB in a patient diagnosed with HIT II and impaired renal function and who underwent cardiac surgery.

A 45-year-old female patient was admitted to our hospital for redo mitral valve replacement because of recurrent thromboses of the artificial valve. During preoperative heparinization, the patient suffered from embolism of toes III and IV of the right foot at the tips of the toes, which at first was attributed to thrombotic material from the valve. However, because of a concomitant decrease of the platelet count from 270,000/µL to 60,000/µL over 3 days, heparin-induced thrombocytopenia was suspected and the diagnosis was confirmed by the heparin-induced platelet aggregation assay [5]. Anticoagulation was immediately switched to the direct thrombin inhibitor recombinant hirudin (Refludan; Hoechst, Frankfurt, Germany) with a target activated partial thromboplastin time (aPTT) of 40 to 60 seconds. Within the next 4 days, the platelet count increased to 267,000/µL. Because of increasing clinical symptoms of mitral valve regurgitation, surgery was performed on the fourth day after the diagnosis of HIT. Considering the impaired renal function (creatinine 2.2 mg/dL), anticoagulation of CPB was performed with UFH and tirofiban.

Recombinant hirudin was stopped shortly before surgery. Tirofiban (Aggrastat; MSD, Haar, Germany) was administered 10 minutes before the cannulation for CPB according to the RESTORE protocol with a bolus infusion of 10 µg/kg and a continuous infusion of 0.15 µg/kg/min. Thereafter, a bolus of UFH 300 IU/kg (Liquemin; Roche, Grenzach Whylen, Germany) was given. The target for the kaolin activated clotting time (ACT) was 480 seconds. No further heparinization was necessary during perfusion to maintain this ACT value. The continuous infusion of tirofiban was stopped after opening of the aortic clamp approximately 60 minutes before cessation of CPB. During perfusion at intervals of 30 minutes, the antiplatelet effect of tirofiban was controlled by ADP (20 µmol/L) -induced platelet aggregometry and the point-of-care platelet activating factor-accelerated HEMOSTATUS II (Medtronic Inc, Parker, CO) whole-blood platelet function test [6]. Both assays revealed a potent inhibition of platelet aggregation below 25% (ADP mean, 13% ± 3.7% SD; HEMOSTATUS II, 15% ± 4.7% SD) during the entire period of perfusion.

The duration of CPB was 150 minutes. A total of 1.76 g of tirofiban was given. After termination of CPB, the total volume of blood of the CPB was infused into the patient, protamine was administered according to the calculation of the Hepcon HMS (Medtronic Inc), and the total reversal of heparin was controlled. Thereafter, 2 units of red blood cell concentrates and 6 units of fresh-frozen plasma were transfused. One hour after the termination of CPB, the ACT was 140 seconds and the HEMOSTATUS II platelet function test revealed a recovery of the platelet function to 50%, whereas the ADP-stimulated platelet aggregation was 30%.

Postoperative investigation of the CPB found no clot formation in the system. Immediately after arrival in the intensive care unit, antithrombotic therapy with recombinant hirudin was restarted to an aPTT of 60 to 80 seconds. The postoperative blood loss during the first 12 hours amounted to 250 mL. The platelet count after arrival in the ICU was 150,000/µL and increased to 210,000/µL over the next day. The patient was discharged from the intensive care unit after 12 hours. She revealed no clinical signs of thromboses or embolisms. The D-dimer levels (range of reference 130 to 200 µg/L, AUTO Dimertest; Organon Technika, Eppelheim, Germany) obtained immediately after surgery were 298 µg/l, 174 µg/L 12 hours after surgery, and 154 µg/L 48 hours postoperatively.

	Comment

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The heparinoid Orgaran and recombinant hirudin have been successfully employed for the anticoagulation of CPB in patients with HIT II. In cases of impaired renal function, both drugs are associated with severe bleeding complications because of a persistent anticoagulant effect [2]. Another alternative option is the combination of conventional heparinization with a potent antiplatelet agent to inhibit the HIT II-induced platelet aggregation. Prostaglandins have been used for this purpose [7]. The advantage of such a concept is that the anticoagulant effect can be easily reversed by protamine and, if necessary, by the transfusion of platelet concentrates. However, the high-dose application of prostaglandins is associated with severe vasodilatation and hypotension. Moreover, there are no protocols elaborated for the dosing and monitoring of the prostaglandins as antiplatelet agents.

The GP IIb/IIIa inhibitors are among the most powerful inhibitors of platelet aggregation available and effectively inhibit HIT antibody-stimulated platelet aggregation in vitro [3, 4]. Tirofiban is a competitive nonpeptide GP IIb/IIIa receptor antagonist that specifically inhibits fibrinogen-dependent platelet aggregation. The elimination half-life is 2 hours and no cardiovascular side effects are known [8]. The efficiency of tirofiban has been investigated in large clinical trials (PRISM-PLUS, RESTORE, PRISM).

With the use of the RESTORE protocol, during the period of heparinization, the platelet aggregation was effectively inhibited as monitored by the 20-µmol ADP-stimulated platelet aggregation and the online PAF-accelerated HEMOSTATUS II platelet function assay.

Because of its ease in handling, this anticoagulation protocol appears to be not only suitable for patients with impaired renal function, but also for hospitals that are inexperienced with other alternative anticoagulation strategies for CPB.

However, no valid data are available concerning the pharmacodynamics of the heparin/platelet factor 4 antibody complexes. In consequence, despite the reversal of free heparin, after restoration of the platelet function or transfusion of platelets, the patient may be at a residual risk for developing a HIT II reaction. Therefore, the immediate postoperative initiation of a potent antithrombotic therapy that is able to inhibit the HIT II cascade, for example, recombinant hirudin [9], is an important integral part of the whole approach. In the present case, the immediate postoperative rise of the patient’s platelet count indicated that during this period no platelets were consumed in a HIT II-associated reaction. The moderate elevation of the D-dimers immediately postoperatively can be attributed to the extracorporeal circulation. However, the D-dimer levels 12 and 48 hours after surgery were within the normal range, which revealed a high predictive value for the exclusion of thromboembolism within this period. However, larger clinical investigations for further validation of this concept are necessary.

	References

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6. Despotis G.J., Levine V., Saleem R., Spitznagel E., Joist J.H. Use of point of care test for identification of patients who can benefit from desmopressin during cardiac surgery: a randomized controlled trial. Lancet 1999;354:106-110.[Medline]
7. Kraenzler E.J., Starr N.J. Heparin-induced thrombocytopenia: management of patients for open heart surgery. Case reports describing the use of iloprost. Anesthesiology 1988;69:964-967.[Medline]
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