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Ann Thorac Surg 1999;68:1076-1078
© 1999 The Society of Thoracic Surgeons

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Case Reports

Pediatric heparin-induced thrombocytopenia: management with Danaparoid (Orgaran)

^a Division of Haematology/Oncology, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
^b Division of Cardiac Surgery and Cardiovascular Perfusion, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada

Address reprint requests to Dr Black, Department of Cardiac Surgery, Lucile Packard Children’s Hospital, Stanford University School of Medicine, Stanford, CA 94305-5407
e-mail: michael.black{at}stanford.edu

	Abstract

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Heparin-induced thrombocytopenia is a rare and serious complication of anticoagulation therapy. There remains a paucity of information pertaining to alternative anticoagulation strategies for use during cardiopulmonary bypass concomitant with heparin-induced thrombocytopenia, especially in children. We report the successful treatment of heparin-induced thrombocytopenia and subsequent hemorrhagic complications postoperatively in a 2-year-old child with Danaparoid (orgaran). Emergent conduit revision with cardiopulmonary bypass was required for a thrombosed systemic-venous to pulmonary-arterial connection (completion modified Fontan procedure). Required doses of Danaparoid were consistently twofold that previously reported for adults.

	Introduction

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Heparin remains the most frequently used anticoagulant for pediatric cardiac surgery requiring cardiopulmonary bypass (CPB). Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy, associated with a high morbidity and mortality in adults [1, 2]. Danaparoid (Orgaran, NV Organon, The Netherlands) is a low-molecular-weight heparinoid that has low cross-reactivity (about 10%) with the antibody complex implicated in HIT [3, 4] and has been used previously in cases of HIT. There is, however, a limited experience with its use during cardiopulmonary bypass (CPB) [3, 5], particularly in children [6].

We report a child with HIT who required cardiopulmonary bypass, using Danaparoid as an anticoagulant, to expand the medical literature regarding Danaparoid dosing in the pediatric population.

A 2-year-old girl (body weight, 12 kg) with complex univentricular physiology was admitted for routine preoperative diagnostic cardiac catheterization 2 days before a completion Fontan (day 0). A completion Kawashima procedure using a 20-mm Gore-Tex (W.L. Gore & Assoc, Elkton, MD) conduit was planned. The preoperative platelet count was normal according to our hospital reference standards. She received unfractionated heparin (UH) for both the diagnostic and therapeutic procedures and had groin cannulation for arterial inflow. UH was initiated as per hospital protocol post-Fontan procedure (UH at 20 U/kg body weight hourly (U · kg^-1 · h^-1) by constant infusion but multiple dose reductions to 9 U · kg^-1 · h^-1 over the following 48 hours were required for a persistent and prolonged activated partial thromboplastin time (aPTT). Ultrasound studies for increasing left leg swelling on day 5 confirmed a venous thrombus extending from the left popliteal to the external iliac vein. The patient remained difficult to heparinize and became progressively thrombocytopenic (platelet count 55 x 10⁹/L). The fall in platelet count and the occurrence of thrombosis suggested HIT and the diagnosis was confirmed by enzyme-linked immunosorbent assay (Stago Diagnostica, Asnieres, France) and serotonin release assays as described previously [7]. A Danaparoid loading dose of 30 U/kg was administered followed by an infusion of 2 U · kg^-1 · h^-1.

Hepatomegaly and respiratory distress soon developed. Hepatic ultrasound, echocardiography, and cardiac catheterization (Figs 1 and 2) confirmed occlusive conduit thrombosis with subsequent hepatic venous stasis. Urgent conduit replacement was deemed necessary (M.D.B.), using a #16 aortic homograft and Danaparoid as an anticoagulant. Heparin-coated components for the cardiopulmonary bypass circuits were avoided. Serial intraoperative measurements of both anti-Xa levels and activated clotting time (ACT) were undertaken. The anti-Xa levels were calculated according to a standard curve established for enoxaparin sodium. The initial loading bolus of Danaparoid was 750 U (62.3 U/kg) with 4 U/mL in the prime, resulting in an anti-Xa level of 1.7 U/mL. The anti-Xa level declined to 0.7 within 40 minutes, a further 1500-U bolus was given, achieving an anti-Xa level of 2.5 U/mL. Due to the concomitant coagulopathy, the measured ACT, had only modest correlation with anti-Xa levels (r = 0.755, p = 0.14).

View larger version (110K): [in this window] [in a new window]   Fig 1. Cardiac catheterization displaying the occluded Gore-Tex (W.L. Gore & Assoc., Elkton, MD) conduit. The catheter is positioned in the left pulmonary artery via the superior vena cava. Dye demonstrates a thrombus at the caudad conduit anastomosis (juxtapposition to the hepatic veins).

View larger version (103K): [in this window] [in a new window]   Fig 2. Artistic interpretation of Figure 1.

	Comment

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This case demonstrates the typical time course for HIT, with thrombocytopenia and thrombotic complications occurring after an initial exposure and subsequent reexposure to heparin. There remains a lack of objective medical literature relating to HIT in the pediatric population. A limited number of adults [3, 4, 6] and a single adolescent [5] comprise current medical case reports pertaining to Danaparoid usage during CPB. At present there remains no reports of the use of Danaparoid in young children.

The initial reported doses of Danaparoid for CPB were a loading bolus of 8750 U plus 7500 U in the prime fluid for adults [3, 8]. Miller and colleagues [9] reported a bolus of 8750 U plus 3 U/mL in the prime fluid for adults weighing 55 to 90 kg and also the use of a 125-U/kg bolus. In our case, we initially used a smaller loading dose (62.3 U/kg) that needed to be repeated during the procedure to obtain an adequate intraoperative anti-Xa level. Postoperatively, due to liver disease, a serious coagulopathy developed. Alterations in Danaparoid dose did not correlate with severity of hemorrhage and Danaparoid was continued due to persistent thrombotic risk and the presence of a major life-threatening thrombus. The maintenance dose this child required to maintain an anti-Xa level of 0.4 to 0.8 U/mL was 4 to 6 U · kg^-1 · h^-1 by intravenous infusion even after her coagulopathy had fully resolved. Of note, hemodilution was likely partially responsible for the 60% decline in anti-Xa levels.

Previously reported intravenous treatment doses for thromboembolic disease in adults remains at 150 to 200 [3] and 200 to 400 U/h [8], which are lower than doses reported in this case. The higher dose of anticoagulation is not surprising based on previous pediatric experiences with heparin [10]. In the two cases reported by Wilhelm and colleagues [5], no correlation was found between ACT and anti-Xa levels. This result corresponds with the findings in our case.

This case report suggests Danaparoid’s potential to provide safe and effective anticoagulation during and after CPB surgery. Obviously a portion of excessive bleeding that occurred postoperatively must be attributed to Danaparoid. However one must remember that HIT in the adult population is an extremely thrombogenic state and the benefits of continuing anticoagulation through a bleeding episode far outweigh the risks. The maintenance dose of Danaparoid required was higher than reported in adults in similar circumstances (1.5 to 2.0 U/mL) [8]. When anticoagulation is indicated, postoperative hemorrhage should not preclude the use of Danaparoid. Studies are required to investigate the incidence of HIT in infants and children, optimal management of HIT, and pharmodynamic studies of Danaparoid.

	Acknowledgments

 
We would like to thank Mr Phil Dakin for his artistic talents (Fig 2 in the interpretation of Fig 1) and Dr Patti Massicotte for thoughtful suggestions.

	References

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1. King D.J., Kelton J.G. Heparin-associated thrombocytopenia. Ann Int Med 1984;100:533-540.
2. Chong B.H., Berndt M.C. Heparin-induced thrombocytopenia. Blut 1989;58:53-57.[Medline]
3. Magnani H.N. Heparin-induced thrombocytopenia (HIT). Thromb Haemost 1993;70:554-561.[Medline]
4. Chong B.H., Ismail F., Cade J., Gallus A.S., Gordon S., Chesterman C.N. Heparin-induced thrombocytopenia. Blood 1989;73:1592-1596.[Abstract/Free Full Text]
5. Wilhelm M.J., Schmid C., Kececioglu D., Mollhoff T., Ostermann H., Scheld H.H. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996;61:920-924.[Abstract/Free Full Text]
6. Doherty D.C., Ortel T.L., DeBruijn N., Greenberg C.S., Van Trigt P., III Heparin free cardiopulmonary bypass. Anesthesiology 1990;73:562-565.[Medline]
7. Sheridan D., Carter C., Kelton J.G. A diagnostic test fo rheparin-induced thrombocytopenia. Blood 1986;67:27-30.[Abstract/Free Full Text]
8. Chong B.H., Magnani H.N. Orgaran in heparin-induced thrombocytopenia. Haemostasis 1992;22:85-91.[Medline]
9. Miller L., Niecestro R., Magnani H. Successful cardiopulmonary bypass surgery with Orgaran in patients with heparin induced thrombocytopenia. Thromb Haemost 1997;78(Suppl):446.
10. Andrew M., Marzinotto V., Massicote P., et al. Heparin therapy in pediatric patients. Pediatr Res 1994;35:78-83.[Medline]

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