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Ann Thorac Surg 1997;64:1815-1817
© 1997 The Society of Thoracic Surgeons

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Case Report

Heparinoid Anticoagulation and Topical Fibrin Sealant in Heparin-Induced Thrombocytopenia

Department of Surgery, Walter Reed Army Medical Center, Washington, DC

Accepted for publication July 11, 1997.

	Abstract

Top Footnotes Abstract Introduction Comment References

 
The development of heparin-induced thrombocytopenia in patients who require systemic anticoagulation for cardiac and vascular operations poses a therapeutic dilemma because no alternative anticoagulants are generally available. Heparinoid (Org 10172) has been used as an alternative anticoagulant under protocol or on a compassionate use basis, and has recently been approved by the Food and Drug Administration. There is, however, no heparinoid antagonist to reverse the anticoagulation. This report describes the combined use of heparinoid anticoagulation and adjunctive fibrin sealant for topical hemostasis in a patient with heparin-induced thrombocytopenia. Recommendations for perioperative monitoring of heparinoid anticoagulation are provided.

	Introduction

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The need for parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT) poses a therapeutic dilemma. A potential alternative anticoagulant in this setting is the heparinoid lomoparan (Org 10172 or Orgaran; Organon Int, Oss, the Netherlands), which has been obtained in the United States for compassionate use from Organon, Inc, in West Orange, New Jersey. Lomoparan was recently approved by the Food and Drug Administration but is not yet widely available. Heparinoid presents several challenges for surgical use. Its anticoagulant activity, which is directed against factor Xa, has a half-life of 25 hours and cannot be neutralized by protamine sulfate. Furthermore, heparinoid does not prolong the activated clotting time (ACT) to a similar degree as unfractionated heparin and its anticoagulant activity is best defined by anti-factor Xa activity. Heparinoid was first used in a cardiopulmonary bypass operation in 1990 [1] and has since been administered to more than 20 patients. However, the outcome has been reported in only several individuals, and the dose, best method to monitor anticoagulation, and measures needed to prevent excessive bleeding have not been fully defined. Previous reports have described successful anticoagulation with concentrations of heparinoid that have been as high as 2.9 anti-factor Xa units/mL to as low as 0.7 U/mL [1–4]. In this report we describe successful anticoagulation with heparinoid during bypass with anti-factor Xa levels at 0.7 to 1.5 U/mL. Also described is the use of an investigational topical fibrin sealant (investigational new drug application held by Baxter-Hyland, Glendale, CA) prepared from virally inactivated purified human fibrinogen and thrombin. The outcome in this patient, combined with those in previous reports, suggests that strategies for anticoagulation with heparinoid can be developed for use during cardiac and vascular operations.

A 57-year-old man in whom HIT developed while he was being treated with unfractionated porcine heparin for deep venous thrombosis subsequently required coronary artery revascularization. The diagnosis of HIT was confirmed by an enzyme-linked immunosorbent assay for immunoglobulin G antibody to the complex of heparin/platelet factor 4. To prevent a recurrence of HIT and possible thrombosis, heparinoid was used instead of heparin during coronary artery bypass. Anticoagulant monitoring was performed during the procedure with the ACT (Hemachron; International Technidyne Co, Edison, NJ) and the anti-factor Xa activity (American Bioproducts, Parsippany, NJ).

Before bypass, 8,750 anti-Xa units of heparinoid was given intravenously with an additional 7,500 units to prime the extracorporeal circuit. The ACT increased from a baseline value of 128 seconds to 217 seconds with a corresponding anti-factor Xa activity of 1.55 U/mL. At 45 minutes the ACT was 181 seconds with an anti-Xa activity of 0.70 U/mL. At 2 hours, when fibrin strands were noted in the operative field and the cardiotomy reservoir, the ACT was 134 seconds, and an additional 1,500 units of heparinoid was then infused. The anti-factor Xa activity 3 minutes later was 0.56 U/mL.

Because heparinoid cannot be reversed with protamine sulfate and has a prolonged half-life, we also applied 30 mL of purified, virally inactivated human fibrin sealant to the proximal and distal anastomoses, the aortic cannulation site, and raw, oozing tissue surfaces in the mediastinum. There was no bleeding apparent from any of these areas after application of the fibrin sealant. Additionally, -aminocaproic acid was administered as a 10-g bolus at the beginning of the procedure and then its administration was continued at a rate of 10 mg • kg^-1 • h^-1 for 12 hours per our standard protocol.

Postoperatively, the chest tube output was 250 mL/h for the first 6 hours and then diminished to 50 mL/h by the next day, when the anti-Xa activity was 0.2 U/mL. Two units of autologous blood was transfused during the operation, and an additional 3 units of homologous blood was transfused on the first postoperative day. On the second postoperative day one chest tube was removed and warfarin administration was restarted. On the fourth postoperative day the remaining chest tube was removed. The patient's recovery was otherwise uneventful.

	Comment

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In an overview of the use of heparinoid in patients with HIT published in 1993, Magnini [5] stated that 19 patients had undergone cardiopulmonary bypass procedures with high-dose heparinoid and that 11 had bled excessively, with 3 having serious bleeding. In only 10 of the 19 patients were anti-factor Xa levels used to monitor therapy at the time of the operation. In addition to this review, which did not provide further details on dose or outcome, only several other reports are sufficiently detailed to provide a summary of the heparinoid dose and transfusion requirements (Table 1).

A major issue is how to best monitor anticoagulation during the bypass procedure. Usually anti-factor Xa activity assays cannot be performed as rapidly as an ACT. The ACT as well as the activated partial thromboplastin time may provide a satisfactory estimate of anticoagulation if the tests are first compared against known concentrations of anti-factor Xa activity in vitro. The goal for the ACT and activated partial thromboplastin time would be to establish upper and lower limits that would represent satisfactory anticoagulation (ie, anti-factor Xa activities of 0.7 to 1.2 U/mL). Other investigators have shown a dose-dependent ACT response to heparinoid as used as an anticoagulant during coronary artery bypass grafting as well as a linear response in the ACT versus anti-factor Xa activity [1, 3]. Our results suggest that the ACT can be used to monitor heparinoid anticoagulation during operation because it increases in a dose-dependent fashion and is sensitive to clinically important changes that indicate the need for additional anticoagulation or, at the termination of the procedure, predict surgical hemostasis. However, the dose range of heparinoid as measured by the ACT is lower and narrower compared with unfractionated heparin.

Low-molecular-weight heparin appears to be less immunogenic than unfractionated heparin [6] and has been used as an alternative anticoagulant in patients with HIT after negative aggregation testing for heparin-induced antibodies [7]. However, recently developed assays that are more sensitive than aggregation-based testing have shown that approximately 95% of patients with HIT have antibodies that cross-react with low-molecular-weight heparin, making this a poor alternative when continued anticoagulation is necessary. Given the presence of heparinlike substances in heparinoid, HIT patients can demonstrate antibody cross-reactivity, which has been shown to occur in about 9% of HIT cases [5]. The low molecular weight and lower degree of sulfation of heparinoid likely contribute to its weaker immunogenicity and cross-reactivity.

The clinical usefulness of heparinoid as an anticoagulant for cardiac and vascular operations is limited by the lack of a method of reversal and a long (25 hours) half-life. Others have reported significant postoperative bleeding when heparinoid was used for anticoagulation during cardiac operations [1, 4]. Administration of either protamine or fresh frozen plasma does not reverse the anticoagulant properties of heparinoid. We administered fibrin sealant to address the concerns of hemostasis. Although not presently approved by the Food and Drug Administration, fibrin sealant is being evaluated for hemostatic efficacy in clinical trials. We found the fibrin sealant easy to administer and effective in achieving hemostasis. Other investigators have reported effective hemostasis when fibrin sealant has been used during patients undergoing repeat cardiac bypass operations [8].

In conclusion, we report a case in which heparinoid and human fibrin sealant were used in combination during a cardiovascular operation in a patient with HIT. Our data support the use of the ACT to monitor heparinoid dosage during cardiovascular operations, recognizing that the target range is 170 to 217 seconds instead of the 480 seconds required for heparin. Our results suggest that heparinoid can be used safely for anticoagulation during cardiac and vascular operations in patients with HIT, and that fibrin sealant is a useful adjunct for hemostasis in this setting.

	Footnotes

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Address reprint requests to Dr Jackson, Division of Vascular Surgery, Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9157.

The opinions expressed herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.

	References

Top Footnotes Abstract Introduction Comment References

 

1. Doherty DC, Ortel TL, De Bruijn N, Greenberg CS, Van Trigt P. "Heparin-free" cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990;73:562–5.[Medline]
2. Wilhelm MJ, Schmid C, Kececioglu D, Möllhoff T, Ostermann H, Scheld HH. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996;61:920–4.
3. Gitlin SD, Deeb GM, Schmaier AH. Heart transplantation in a patient with heparin-associated thrombocytopenia [Abstract]. Blood 1995;86:871a.
4. Cannell PK, Herrman RP, Marshall L. Heparinoid during cardiopulmonary bypass [Abstract]. Aust NZ J Med 1991;21(Suppl)1:141.
5. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost 1993;70:554–61.[Medline]
6. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330–5.[Abstract/Free Full Text]
7. Slocum MM, Adams JG, Teel R, Spadone DP, Silver D. Use of enoxaparin in patients with heparin-induced thrombocytopenia syndrome. J Vasc Surg 1996;23:839–43.[Medline]
8. Rousou J, Levitsky S, Gonzalez-Lavin L, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. A multicenter study. J Thorac Cardiovasc Surg 1989;97:194–203.[Abstract]

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