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J Thorac Cardiovasc Surg 1996;112:1390-1392
© 1996 Mosby, Inc.

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CARDIOPULMONARY BYPASS FOR HEPARIN-INDUCED THROMBOCYTOPENIA: MANAGEMENT WITH A HEPARIN-BONDED CIRCUIT AND ENOXAPARIN

Milwaukee, Wis.

From St. Mary's Hospital, Milwaukee, Wis.

Received for publication March 19, 1996 Accepted for publication April 15, 1996. Address for reprints: W. Dudley Johnson. MD, 3300 South 16th St.. Milwaukee, W1 53215.

Heparin-induced thrombocytopenia (HIT) is a potentially dangerous condition in patients needing cardiac operation because the use of unfractionated, standard heparin for cardiopulmonary bypass (CPB) can cause severe bleeding, thromboembolism, and even death. Several strategies that avoid or modify the use of standard heparin have been tried in such situations but none has gained universal acceptance. We describe here the successful use of a heparin-bonded CPB circuit and enoxaparin, a low molecular weight heparin (LMWH), in a patient with HIT undergoing coronary artery bypass grafting.

Case report

A 70-year-old man with severe triple-vessel disease, unstable angina, and severe congestive heart failure was referred to us for coronary artery bypass grafting. At the previous hospital, HIT was suspected when the platelet count dropped from 313 x 10⁹/L to 77 x 10⁹/L after 6 days of heparin therapy and confirmed with positive platelet aggregation studies with standard heparin. Heparin administration was stopped immediately and the patient was given therapy with the LMWH enoxaparin (Lovenox, Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, Pa.) 30 mg every 12 hours, although separate aggregation tests were not done with this drug. The platelet count at hospital admission was 68 x 10⁹/L and varied from 92 x 10⁹/L to 172 x 10⁹/L over the next 4 days. Other coagulation parameters were within normal limits.

CPB was planned with a circuit coated with Carmeda Bioactive Surface (Medtronic, Anaheim, Calif.). The circuit included a Bio-Medicus vortex pump, a Maxima Plus membrane oxygenator, an MVR 1600 venous reservoir bag, an arterial line filter, and a cardiotomy reservoir, all manufactured by Medtronic; two 32F caval cannulas and an 8.0 aortic cannula (Sarns Inc., Ann Arbor, Mich.) and a 14F Argyle aortic root vent (Sherwood Medical, St. Louis, Mo.). For added anticoagulation intraoperatively, enoxaparin administration was continued using the manufacturer's recommended protocol. Twenty milligrams of enoxaparin was added to the prime, a further 80 mg/m² was given after sternotomy, and an infusion was maintained at a rate of 40 mg/m² per hour once CPB was instituted. Flow rates varied from 2 to 5 L/min, and intermittent ischemic fibrillatory arrest with mild hypothermia to 34º C was used. Activated clotting time was determined every 30 minutes with a Hemostasis Management Systems device (Medtronic) and ranged from 236 to 321 seconds. After about 4 hours of CPB, 130 minutes of total ischemic time, and completion of six vein grafts, the patient was removed from bypass with intraaortic balloon pump support.

For reversal of heparin, 500 mg of protamine sulphate was given. No evidence of visible thrombus, debris, or fibrin strands was found on close examination of the bypass circuit. The platelet counts remained higher than 98 x 10⁹/L throughout the operation. In the first 24 hours after operation, the patient lost 1.45 L of fluid, for which transfusions of platelets, fresh frozen plasma, and blood were given, after which the bleeding settled. Subsequent recovery was uneventful.

Discussion

Whereas some drop in platelet count is often seen after routine use of standard heparin, HIT is a more serious problem that occurs in about 3% of patients who receive the drug. ¹ It is characterized by thrombocytopenia, sometimes thrombosis, and the presence of an immunoglobulin G antibody causing complement C3–mediated platelet injury on exposure to standard heparin. Seen more often with bovine heparin than with other types, HIT typically occurs 7 to 10 days after the start of therapy. Decreasing serial platelet counts and laboratory platelet aggregation studies and serotonin release assays lead to the diagnosis. Treatment includes stopping heparin administration, giving platelet antiaggregation drugs, and, if needed, substituting other anticoagulants for heparin.

Kondo and associates ² have reviewed several options for cardiac operations in patients with HIT. These include deferring operation for a few weeks until the circulating platelet antibody levels come down; use of drugs such as aspirin, dipyridamole, and iloprost for modifying platelet activation in the presence of standard heparin; and using fibrinolytic agents and thrombin inhibitors such as ancrod, Hirudin, and Argatroban for anticoagulation. Substitution of standard heparin with heparinoids such as heparin sulphate and dermatan sulphate and LMWHs such as dalteparin (Fragmin), tedelaparin, and enoxaparin has also been reported. ^1,3 LMWHs are fragments cleaved from standard heparin that act mainly against clotting factor Xa and compared with standard heparin produce less bleeding for equivalent antithrombotic effect. Because crossreactivity with heparin is known, platelet aggregation tests are recommended to select the most appropriate LMWH. ³ We used enoxaparin because it was readily available and with it the platelet counts in our patient remained stable.

A major drawback of use of LMWHs is the need for frequent factor Xa assays for accurate monitoring of anticoagulation, which necessitates a specialized setup. However, a direct correlation between activated clotting time measurements and anti–factor Xa activity has been shown, and effective anticoagulation with LMWHs can be achieved at activated clotting time values lower than those usual for CPB with standard heparin. ⁴ Another problem with LMWHs is the inability to achieve complete reversal of anticoagulation at the end of CPB. Protamine only neutralizes their anti-IIa action, and the anti-Xa activity persists for longer. This may have partly contributed to the increased chest tube drainage in our patient.

A thromboresistant heparin-bonded perfusion circuit with its ability to eliminate the need for systemic heparinization during CPB ⁵ is an attractive option in cases of HIT. Of particular advantage with this is a circuit with covalently bonded endpoint-attached heparin (Carmeda) that prevents leaching of any heparin into blood. An added benefit of this circuit in patients with HIT could be the decreased complement activation (C3a and C5a) and hence less contribution to the cause of HIT. However, a major limitation of these circuits is that the anticoagulant effect is flow dependent and clotting may be induced at low or stagnant flow rates and additional anticoagulation may be required for safety. We combined the Carmeda circuit with enoxaparin and obtained satisfactory anticoagulation even at low activated clotting time levels.

Thus in patients with HIT, cardiac operations can be safely done with use of a Carmeda circuit with an appropriate LMWH such as enoxaparin, although further experience is needed to establish protocols for monitoring, dosing, and neutralization of LMWHs.

References

1. Wilhelm MJ, Schmid C, Kececioglu D, Mollhoff T, Ostermann H, Scheld HH. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996;61:920-4.[Abstract/Free Full Text]
   
2. Kondo NI, Maddi R, Ewenstein BM, Goldhaber SZ. Anticoagulation and hemostasis in cardiac surgical patients. J Card Surg 1994;9:443-61.[Medline]
   
3. Altés A, Martino R, Gari M, et al. Heparin induced thrombocytopenia and heart operation: management with tedelparin. Ann Thorac Surg 1995;59:508-9.[Abstract/Free Full Text]
   
4. Koza ML, Messmore HL, Wallock ME, Walenga JM, Pifarre ME. Evaluation of a low molecular weight heparin as an anticoagulant in a model of cardiopulmonary bypass surgery. Thromb Res 1993;70:67-76.[Medline]
   
5. Jones DR, Hill RC, Vasilakis A, et al. Safe use of heparin-coated bypass circuits incorporating a pump-oxygenator. Ann Thorac Surg 1994;57:815-9.[Abstract]
   

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