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J Thorac Cardiovasc Surg 1995;110:265-267
© 1995 Mosby, Inc.

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Recombinant hirudin as a new anticoagulant during cardiac operations instead of heparin: Successful for aortic valve replacement in man

Hamburg and Bad Nauheim, Germany

Natural hirudin was isolated from the medicinal leech in the 1950s and characterized as a potent and specific thrombin inhibitor. Ever since recombinant hirudin (r-hirudin) was produced in sufficient quantities, the efficacy of this cofactor-independent anticoagulant has been shown in several studies and clinical investigations. ¹ Recent experiments in the dog and pig model have demonstrated that r-hirudin is a safe and efficient anticoagulant for cardiac operations in which cardiopulmonary bypass (CPB) is used. ^2,3 Furthermore, r-hirudin has already been effectively used as an anticoagulant during CPB in a patient with chronic pulmonary embolism. ⁴ As a result of the positive results gained from previous animal and clinical studies, the Behringwerke, Marburg, Germany, is conducting an investigation in which patients with a heparin-induced thrombocytopenia may be treated with r-hirudin. We report about one patient involved in this study, in whom r-hirudin was used as an anticoagulant during CPB.

A 72-year-old woman weighing 52 kg was admitted after cardiac decompensation resulting from valvular aortic stenosis ( pressure 71 mm Hg, aortic valve opening area 04 cm² ). Left ventricular function was compromised (ejection fraction 37%) and pulmonary vascular resistance was increased to 296 dyne · sec · cm^-5. After the diagnostic cardiac catheterization, while the standard heparin anticoagulation regimen was still being administered, deep pelvic vein thrombosis developed along with a decrease in platelet count from 343,000 to 14,000 x 10⁹/L. The suspected heparin-induced thrombocytopenia type II was confirmed by means of the heparin-induced platelet activation test. The only anticoagulant suitable for use during extracorporeal circulation proved to be r-hirudin HBW 023 (Behringwerke, Marburg, Germany), because all heparins and heparinoids caused platelet aggregation. The patient was transferred to our department for aortic valve replacement with r-hirudin used as the anticoagulant instead of heparin during CPB.

Anticoagulation with phenprocoumon (Marcumar) because of pelvic vein thrombosis was discontinued 3 days before the operation, and r-hirudin was simultaneously substituted. An initial bolus of 0.2 mg/kg body weight was administered intravenously followed by an infusion regimen with 0.1 mg/kg body weight per hour intravenously until the time of the operation to achieve a prolonged activated partial thromboplastin time (aPTT) within the range of 60 to 80 seconds. The resultant plasma concentration of r-hirudin was 1 to 1.5 µg/ml. Anesthesia was maintained with intravenous infusions of propofol and pancuronium bromide along with intermittent doses of fentanyl (up to 25 µg/kg body weight). The patient received a bolus of 9 mg of r-hirudin intravenously 10 minutes before the start of CPB. The heart-lung machine contained a capillary membrane oxygenator and was primed with 2000 ml of lactated Ringer's solution, 100 ml of mannitol solution (Osmofundin 15%), 50 ml of sodium bicarbonate, 750 ml of packed erythrocytes, and 5 mg of r-hirudin. The perfusion flow rate during normothermia was 3.9 L/min. The perfusion time was 83 minutes and the aortic crossclamp time, 60 minutes. Aortic valve replacement with a bioprosthesis was conducted with mild hypothermia up to 33 ° C. To monitor the anticoagulation during CPB, we measured the ecarin clotting time (ECT) ⁵ along with the aPTT in 10-minute intervals (Fig. 1). The aPTT was between 90 and 130 seconds and the ECT remained between 300 and 456 seconds. The plasma concentration of r-hirudin was kept within a range of 2.5 to 3.2 µg/ml throughout CPB. Four separate doses of r-hirudin (5, 5, 2.5, and 2.5 mg) were necessary to remain within this level. The half-life of r-hirudin depends on normal renal function. Therefore our patient showed a rapid fall of the r-hirudin concentration (documented by means of aPTT and ECT) toward the end of CPB. Throughout the CPB time the entire system remained free of clots. The pressure proximal to the oxygenator was constant during CPB. Bleeding and thromboembolic complications were not observed at any time during the operation or in the postoperative period. The total fluids from the chest drainage amounted to 240 ml. The entire postoperative course remained without sequel.

View larger version (54K): [in this window] [in a new window]   Fig. 1. Anticoagulation monitoring: Change of ECT (A) and aPPT (B) in correlation with r-hirudin plasma concentration before, during and after CPB.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Platelet function: Platelet aggregation induced by adenosine diphosphate (ADP) and by collagen before, during, and after CPB. Platelet counts were adjusted by dilution or centrifugation to 100,000 platelets µl-1 and aggregation was induced by addition of adenosine diphosphate (10 mmol/L) or collagen (4 µg/ml).

Footnotes

From the Department of Cardiac Surgery, Albertinen-Krankenhaus, Hamburg, Germany,^a and the Hemostasis Research Unit, Kerckhoff-Klinik, Max-Planck-Institut für physiologische und Klinische Forschung, Bad Nauheim, Germany.^b

J THORAC CARDIOVASC SURG 1995;110:265-7

References

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2. Walenga JM, Bakhos M, Messmore HL, Fareed J,Pifarré R. Potential use of recombinant hirudin as an anticoagulant in a cardiopulmonary bypass model. Ann Thorac Surg 1991;51:271-7.[Abstract]
   
3. Riess FC, Behr I, Pötzsch B, et al. Recombinant r-hirudin as a potential anticoagulant in open-heart surgery: studies in a pig model. Thromb Haemost 1993;69:A2728.
   
4. Pötzsch B, Iversen S, Riess FC, et al. Recombinant hirudin as an anticoagulant in open-heart surgery: a case report. Ann Hematol 1994;68:A53.
   
5. Nowak G, Bucha E. A new method for the therapeutical monitoring of hirudin. Thromb Haemost 1993;69:A2736.
   

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