Use of fondaparinux (ARIXTRA®) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II

Michael Haase1, Rinaldo Bellomo4, Jens Rocktaeschel1, Sabine Ziemer2, Holger Kiesewetter3, Stanislao Morgera1 and Hans-H. Neumayer1

1 Departments of Nephrology and Anaesthesiology, University and Teaching Hospitals, 2 Department of Laboratory Medicine and Pathobiochemistry, 3 Department of Transfusion Medicine, Charité, Humboldt University of Berlin, Germany and 4 Department of Intensive Care, Austin and Repatriation Medical Centre, Melbourne, Australia

Correspondence and offprint requests to: M. Haase, MD, Universitätsklinikum Charité der Humboldt Universität zu Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie am CCM, Schumannstrasse 20/21, 10117 Berlin, Germany. Email: michael.haase{at}charite.de

Keywords: dialysis; fondaparinux; heparin-induced thrombocytopaenia type II



   Introduction
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 Introduction
 Case
 Discussion
 References
 
We report the successful use of fondaparinux in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II (HIT II). HIT II complicates the choice of an optimal anticoagulant in dialysis patients.

Two clinical entities of HIT can be distinguished—HIT I and HIT II. HIT I is a harmless pharmacological phenomenon that is seen when platelets fall in the 24–48 h after the start of heparinization. It never leads to thrombosis, and does not necessitate stopping heparins. HIT II is the most important and most frequent drug-induced immunologic thrombocytopaenia. The key mechanism leading to HIT II is the synthesis in predisposed patients of the heparin-platelet-factor-4-(PF4) complex that induces IgG or IgM antibodies. Antibody-heparin-PF4 complexes in turn bind to the cell membrane of thrombocytes and endothelial cells via their Fc fragments, leading to the activation of thrombocytes and their aggregation. The diagnosis of HIT II depends on the exclusion of a pseudo-thrombocytopaenia, the occurrence of thromboembolic events during anticoagulation with heparins and a significant fall of platelets, typically within 7–14 days after the start of heparinization. A rare condition exists: ‘early-responders’ who were pretreated with heparins in the preceding 3 months can develop an HIT II within 48 h after retreatment. Serological tests can prove the diagnosis, but if negative, these tests cannot rule out HIT II. In the face of HIT II, heparins must be stopped immediately and an alternative anticoagulant must be started.

For alternative anticoagulation in a dialysis patient, we chose fondaparinux, a synthetic selective inhibitor of activated factor X, because of the absence of the in vitro cross-reaction with HIT II-associated antibodies that is seen with danaparoid. In the past, we have also used lepirudine in patients with HIT II, but only in those without bleeding complications (which is why we rejected lepirudine in our patient with massive retroperitonal bleeding and haematoma).



   Case
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 Introduction
 Case
 Discussion
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A 52-year-old renal transplant patient (80 kg) presented to the emergency department (ED) of the Charité hospital with pain in his left lower abdomen and groin, and a weakness of his left leg. At admission, his blood pressure was 100/50 mmHg and heart rate 76 beats per minute. His blood tests showed normal leucocytes (10 000/µl) and CRP (0.12 mg/dl), whereas platelets (67 000/µl) and haemoglobin (7.4 g/dl) were low. His anti-factor Xa time was 62 seconds, INR 1.73 and serum creatinine 2.4 mg/dl. Until admission he had been in good health with stable renal graft function. Four days before admission, he was switched from long-term oral anticoagulation with phenprocoumon to low molecular weight heparin (5000 IE tinzaparin/day s.c.) in preparation for a biopsy of a breast lump of unknown origin.

His past medical history included renal transplantation in 1984 for end-stage renal disease due to chronic glomerulonephritis. Since transplantation, his immunosuppression has consisted of 60 mg cyclosporine b.i.d. and 4 mg of methylprednisolone per day. He required anticoagulation due to a deep vein thrombosis (DVT) which occurred 2 months before the current admission, and which was associated with activated C-protein resistance.

In the ED, L4-root compression, anaemia and thrombocytopaenia were diagnosed. A recurrent DVT was excluded. On the evening of his admission, the patient developed haemorrhagic shock. On questioning after stabilization, the patient denied any abdominal trauma. An ultrasound revealed a ruptured graft, which had to be removed immediately. Its pathological examination confirmed a small ruptured vein on the bottom of a laceration close to the hilum of the grafted kidney. The anuric patient was transferred to the intensive care unit, where his platelet count returned to normal values. Low-dose heparinization with unfractionated heparin (UFH) was started because of the increased risk of recurrent thrombosis. After 17 days, his platelets fell again to 55 000/µl (Figure 1). A new DVT was diagnosed and in addition, the blood inside the dialysis membrane clotted frequently. Cytomegalovirus infection, bleedings and sepsis were ruled out. Serological tests for HIT II were repeatedly negative. UFH was immediately discontinued because of the clinically diagnosed HIT II syndrome. As alternative anticoagulation, fondaparinux (ARIXTRA®, Sanofi-Syntelabo) was started, 2.5 mg instilled directly into the dialysis circuit on dialysis days only (in this patient, every second day). Because of the paucity of experience with the dosing of this drug in dialysis patients, we daily monitored the anti-factor Xa time, using RECALMIX (Amax-Accuclott Heptest, Trinity Biotech, USA) and factor Xa. We chose a reduced dosage, adjusted for renal insufficiency, for this patient. We strived for a therapeutic anticoagulation because of the symptomatic HIT II. The therapeutic range of the anti-factor Xa time—between 70 and 110 s—was reached during the next 10 weeks of dialysis. The platelet count rose to normal values and stayed stable during the following weeks (Figure 1). No further thromboembolisms, clotting of blood inside the haemodialysis membranes or bleeding occurred.



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Fig. 1. The course of platelet count before and after the administration of fondaparinux. 1, administration of unfractionated heparin (UFH); 2, platelet count 10 days after the administration of UFH; 3, discontinuation of UFH and initiation of 2.5 mg fondaparinux instilled into the dialysis circuit on dialysis days only (dialysis was done every second day).

 


   Discussion
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 Introduction
 Case
 Discussion
 References
 
The initial fall in platelets of our patient seemed to be related to renal graft rupture followed by haemorrhage. Unrecognized microtrauma and anticoagulation could have played a role in initiating this bleeding. However, it was repeated exposure to heparin that induced symptomatic HIT II. Such cases of antibody-negative HIT II syndrome are well documented in the literature [1]. The diagnosis of this entity is usually based on decreasing platelets and the occurrence of thromboembolic events during anticoagulation with heparin. In our patient, other conditions that could explain the drop of platelets, such as sepsis or bleeding with haematoma formation, could be ruled out. Thus, his heparinization had to be stopped, and we sought a new alternative anticoagulation. We rejected the standard alternative anticoagulants such as lepirudine and danaparoid. It is known that lepirudine accumulates in dialysis patients (because of a drastically prolonged half-life), putting patients at further risk of hemorrhages [2]. For danaparoid, an association with HIT II—by producing heparin-PF4 complex antibodies—has been shown in up to 30% of the patients [3]. We therefore initiated a new anticoagulation regimen with fondaparinux because of the absence of any in vitro cross-reactivity with heparin-PF4 complexes, documented in 25 patients with HIT [4]—though fondaparinux has no official approval for use in HIT II patients, yet. As there is approval for the use of fondaparinux as anticoagulant medication, we resorted to the ‘off-label’ use of fondaparinux in our HIT II patient. This required very frequent laboratory measurements and careful clinical observation.

A daily dose of ~2.5 mg of fondaparinux has the potential of preventing significantly thromboembolism in patients who have had elective total hip replacement and have normal renal function [5]. In these patients, ~50–75% overall of fondaparinux is eliminated by the kidneys. Because of the prolonged half-life of fondaparinux and its roughly five times lower plasma clearance in patients with a creatinine clearance <30 ml/min [6], we chose to give half of the normal dose of 2.5 mg every second day. This choice of dosage is similar to a case reported by Parody and colleagues [7]. They used 0.5 mg of fondaparinux daily in a dialysis patient with asymptomatic HIT II, administering a little less than half of the dose we used in our patient, and they reached prophylactic-range values for anti-factor Xa activity. However, because of our patient's symptomatic HIT II we wanted to and we did achieve a therapeutic target range of the anti-factor Xa time in him before the next scheduled dose. Presumably, because of fondaparinux's low molecular weight (1.7 kDa), it was eliminated in large amounts by the high-flux dialysis membrane (cut-off 35 kDa) we used.

Fondaparinux is a synthetic pentasaccharide whose biological activity is based on the selective inhibition of activated factor X, and it is known for its low immunogenicity. This may be because of its synthetic origin and short molecular structure. For this reason it is expected not to act as a potent protein binding hapten [8]. Therefore, it does not ineract with heparin-PF4 complexes, and the formation of a sensitizing complex resulting in an HIT II is not possible [8]. In severe bleeding under anticoagulation with fondaparinux, recombinant factor VIIa seems to be appropriate in reversing the anticoagulant effect of fondaparinux [9]. There also have been promising results with fondaparinux in recent clinical trials, which have found it to be a safe and effective medication in the initial treatment of pulmonary embolism [10].

To our knowledge, this is the first case that shows safe and effective anticoagulation with fondaparinux of a patient on maintenance haemodialysis. In this dialysis patient with clinically symptomatic HIT II, alternative standard anticoagulation could not be recommended. In total, fondaparinux was administered for 10 weeks without any side effects. Further studies are needed to establish fondaparinux as a new alternative anticoagulant in dialysis patients with HIT II.



   Acknowledgments
 
We extend our thanks to Anja Haase-Fielitz for corrections and advice, and to the members of our dialysis team for technical support.

Conflict of interest statement. None declared.



   References
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 Case
 Discussion
 References
 

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Received for publication: 25. 8.04
Accepted in revised form: 6. 9.04