Fondaparinux for the Treatment of Acute Heparin-Induced Thrombocytopenia: A Single-Center Experience

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1 Fondaparinux for the Treatment of Acute Heparin-Induced Thrombocytopenia: A Single-Center Experience Clinical and Applied Thrombosis/Hemostasis 16(6) ª The Author(s) 2010 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Elisavet Grouzi, MD, 1 Elias Kyriakou, MD, 1 Ioannis Panagou, MD, 1 and Ioanna Spiliotopoulou, MD 1 Abstract Heparin-induced thrombocytopenia (HIT) is a life-threatening immune response to heparin that is associated with a high risk of thromboembolic complications. The syndrome is caused by antibodies that are reactive against complexes of platelet factor 4/heparin (PF4/H). For patients with HIT, the discontinuation of heparin alone is not sufficient and the diagnosis necessitates the administration of an alternative anticoagulant. Fondaparinux is a synthetic pentasaccharide that binds to antithrombin and potentiates inhibition of factor Xa. Data have shown that fondaparinux is structurally too short to induce an antibody response and could be a useful agent to treat HIT. In our hospital, we retrospectively analyzed the use of fondaparinux in the treatment of 24 patients with acute HIT during unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) administration and compared the results to a similar population of 20 patients who were treated with lepirudin. The treated patients had a complete platelet count recovery, and none experienced a new thromboembolic complication or major bleeding. The development of limb gangrene (2 patients who received lepirudin and 1 who received fondaparinux) likely resulted from a delay in diagnosis and treatment initiation. Our data suggest that fondaparinux may be considered a safe and an effective alternative treatment in HIT complicated with or without thrombosis. Keywords heparin-induced thrombocytopenia, fondaparinux, direct thrombin inhibitors, venous thromboembolism Introduction Heparin-induced thrombocytopenia (HIT) is a life- and limbthreatening immune response to heparin that is associated with a high risk of thromboembolic complications. 1-3 It is caused by immunoglobulin G (IgG) antibodies against the platelet factor 4/heparin (PF4/H) complex, resulting both thrombocytopenia and a hypercoagulable state. Venous or arterial thromboembolic complications will develop in 30% to 75% of patients with HIT unless they are treated with an alternative anticoagulant. Current guidelines recommend the use of either direct thrombin inhibitors (direct thrombin inhibitors (DTIs), lepirudin, and argatroban) or heparinoids (danaparoid) for patients with suspected or confirmed HIT. 2,4 Unfortunately, the usefulness of the DTIs is limited mainly by the need for continuous intravenous infusions, frequent activated partial thromboplastin time (aptt) monitoring, and prolongation of the international normalized ratio (INR), which complicates transitioning patients to vitamin K antagonists. 5,6 Furthermore, among these agents, only lepirudin is available in Greece. Hence, other HIT treatment options are essential. Fondaparinux is a selective factor Xa inhibitor via the action of antithrombin that is administered once daily by the subcutaneous route for the prophylaxis and treatment in a number of thrombotic disorders (especially as thromboprophylaxis in orthopedic patients), without monitoring. Considering the published data and its properties, 7-10 fondaparinux provided to us a reasonable alternative anticoagulant to heparin. Moreover, fondaparinux received a level 2C recommendation for use in the treatment of HIT in the recent Consensus Conference of the American College of Chest Physicians evidence-based clinical practice guidelines (eighth edition). 2 In the current study, we report the successful use of fondaparinux in the treatment of 24 patients with acute HIT. Patients and Methods We retrospectively analyzed the use of fondaparinux for the treatment of 24 patients diagnosed with acute HIT during unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) administration between January 2003 and 1 Transfusion Medicine Department, KAT General Hospital, Athens, Greece Corresponding Author: Elisavet Grouzi, Doukissis Plakentias 30, 11523, Athens, Greece. egrouzi@otenet.gr 663

2 664 Clinical and Applied Thrombosis/Hemostasis 16(6) January 2008 in our hospital, also comparing this group of patients to a similar cohort of 20 HIT individuals treated with lepirudin at the same period. Analysis was performed with a retrospective chart review of total hospitalized patients to identify all HIT cases. Inpatients suspected to have HIT were referred to Haemostasis Blood Bank Integral Department, where we assessed HIT diagnosis via proper clinical and laboratory investigation and subsequently designated patients treatment and follow-up. Lepirudin was used mainly during the first 2 years of the study, when fondaparinux was available afterward. All patients fulfilled the diagnostic criteria of HIT as defined by Warkentin. 3 According to the criteria mentioned above, all patients had a decrease in platelet count by 50% compared to pretreatment values, between day 4 to day 14 of heparin administration, even if platelet count nadir remained greater than /L, with or without a new arterial or venous thromboembolic complication. No other cause of thrombocytopenia or platelet count fall was evident. Platelet count recovered within 3 to 8 days after heparin discontinuation. The end points for comparisons between the 2 groups were defined platelets count recovery, complication rates, and successful bridging to acenocoumarol. Complications were defined as death, limp amputation, new thromboembolic complications, venous limb gangrene, or major bleeding. Bleeding events were considered major if they were clinically overt and associated with a decrease of 2 g/dl or more in the hemoglobin level, led to the transfusion of 2 or more units of red cells or whole blood, were retroperitoneal or intracranial, occurred in a critical organ, or contributed to death. Other episodes of clinically overt bleeding were classified as minor. The laboratory diagnosis of HIT in all patients was serologically supported by the PF4/H complex enzyme-linked immunosorbent assay (PF4/H ELISA; Asserachrom, Stago, France) and by particle gel immunoassay ID-PF4/H-PaGIA (DiaMed, Switzerland), both run according to the manufacturer s specifications. A sample was considered ELISA positive if the optical density (OD) at 410 nm was greater than The ID-PF4/H-PaGIA is a semiquantitative, simple rapid test that detects PF4/H-antibodies. Quantitative variables are expressed as mean + standard deviation and were compared by Mann-Whitney test, while categorical variables were compared using the w 2 test (SPSS-14 for IBM PC; Chicago, Illinois). A 2-tailed P value of less than.05 was considered to indicate statistical significance. Results Tables 1 and 2 summarize the patients clinical data. In total, 18 of them were males and 26 females. The platelet count of all patients before heparin administration was normal in both groups. The mean platelet count nadir was /L in group of fondaparinux and /L in group of lepirudin. It is worthy of note that 2 patients treated with fondaparinux had essential thrombocythemia, and HIT was diagnosed in the absence of an absolute thrombocytopenia; if these 2 patients are excluded, the mean platelet count nadir of the remaining 22 patients treated with fondaparinux is /L. The average time of onset of thrombocytopenia was 7.3 days versus 7.1 after the commencement of heparin anticoagulation. The patients were taking UFH or LMWH for the treatment of venous thromboembolism and LMWH as thromboprophylaxis. In fondaparinux group, the majority of them had undergone various orthopedic operations or had multitrauma, while 3 of them were medical patients. The patients of lepirudin group were likewise diagnosed. New thromboembolic complications associated with HIT were identified in 14 patients in fondaparinux group versus 19 in the second group. In both the groups, the remaining patients had an initial thrombosis that led to heparin treatment. Thus, all 44 study patients had documented thrombosis either before beginning UFH or LMWH treatment (n ¼ 11) or as a complication of HIT (n ¼ 33). In all cases, UFH or LMWH was discontinued and patients were treated with daily subcutaneous injections of weight-based fondaparinux therapeutic regiment, or lepirudin as soon as the recognition of the syndrome was made. Given that none of our patients had renal impairment and all had thrombosis, fondaparinux was given once daily in 5 mg if body weight was less than 50 kg; 7.5 mg if body weight was between 50 and 100 kg or 10 mg if body weight was greater than 100 kg. In the second group, intravenous continuous lepirudin infusion was given in dose 0.15 mg/kg per hour adjusted according to aptt (maintaining aptt 2-3 times the baseline value), without a bolus. Additionally, intravenous immunoglobulin G (IVIgG) was given to 9 patients because of severe thrombocytopenia (mean platelet count nadir /L). Furthermore, lower limb amputation because of venous gangrene was required in 1 patient before the beginning of fondaparinux versus 2 in lepirudin group. The development of limb gangrene in both groups may have been a result of delayed recognition of HIT. Both PF4/H-ELISA and ID-PF4/H-PaGIA tests were positive in all the patients. Platelet factor 4/H-ELISA mean-od were in fondaparinux group versus in lepirudin group (P >.05). Furthermore, ID-PF4/H-PaGIA was strongly positive in all the cases. The laboratory diagnosis was made together with the clinical diagnosis in 32 patients and after the commencement of alternative anticoagulation in 12 patients. It is worth noting that the mean OD value (þsd) of the ELISA was significantly higher in those patients with a new HITassociated thrombosis versus the patients who only had documented thrombosis prior to starting heparin or LMWH ( [n ¼ 33] vs [n ¼ 11], P ¼.03). All patients responded with the platelet count normalizing between 1 and 9 days after initiation of fondaparinux versus 1 and 8 days after initiation of lepirudin. In all the patients, oral anticoagulation with acenocoumarol was initiated when the platelet count was > /L. Fondaparinux was discontinued when INR was 2.0 for 2 consecutive days. While platelet count had returned to normal, 1 patient of fondaparinux group and 2 patients of lepirudin group died from causes not related to HIT. The 41 surviving patients were being followed in the thrombosis clinic and took the long-term oral anticoagulation 664

3 Grouzi et al 665 Table 1. Baseline Characteristics of Patients With HIT Total (N ¼ 44) Lepirudin (N ¼ 20) Fondaparinux (N ¼ 24) P values Sex N % N % N % Male NS Female ND M/F ratio 1: :2 1:1.1 Age (years) Range NS Mean + SD Primary diagnosis N % N % N % Multiple trauma NS Hip fracture NS Fibular fracture ND Total hip replacement NS Total knee replacement NS Lumbar discectomy ND Femoral pseudarthrosis ND Infrainguinal bypass surgery ND Rectosigmoidectomy ND Meningioma ND DVT Acute pancreatitis ND Ischemic stroke NS Type of heparin received N % N % N % LMWH NS UFH NS UFH þ LMWH NS Reason for heparin administration N % N % N % Thromboprophylaxis NS DVT treatment PE treatment NS DVT þ PE treatment ND NOTES: DVT ¼ deep vein thrombosis; F ¼ female; HIT ¼ heparin-induced thrombocytopenia; LMWH ¼ low-molecular-weight heparin; M ¼ male; PE ¼ pulmonary embolism; UFH ¼ unfractionated heparin. (6-18 months or lifelong). There were no episodes of major bleeding or recurrent thrombosis during the mean follow-up period of 2 years. Discussion Although LMWH has continued to replace UFH over the years, HIT remains a common medical problem, because the absolute number of hospitalized patients exposed either to UFH or to LMWH is enormous. Mortality due to thromboembolic complications is from 18% to 50% without treatment. 2,11,12 Therefore, patients with HIT require a safe anticoagulant because the thrombotic process continues after the cessation of heparin. Although fondaparinux is identical in structure to the antithrombin-binding pentasaccharide domain of heparin, it does not bind to PF4 in such a way that promotes binding of HIT antibodies, that is, fondaparinux unlike UFH and LMWH does not usually cross-react with HIT antibodies using in vitro platelet activation assays or PF4-dependent immunoassays. 9,10 No episodes of HIT were reported in the large phase 2 and 3 clinical program, 7,8 which is consistent with the fact that, in vitro, fondaparinux did not cross-react with HIT antibodies. 9 It has also been shown not to stimulate platelets serotonin release or activate platelets in the presence of sera from patients with HIT. 10 Fondaparinux has an average halflife of 18 hours, making it suitable for once-daily administration. It has a linear, dose-dependent pharmacokinetic profile. The risk of major bleeding from fondaparinux was not found to be significantly higher than LMWH when used in prevention or treatment of venous thromboembolism (at 2.5 and 7.5 mg/d, respectively) in patients without renal impairment. In our study, all 24 patients with HIT who were treated with fondaparinux met our criteria for a successful outcome, that is, they had platelet count recovery without new or progressive thrombosis during a mean follow-up of 2 years. No hemorrhagic or other adverse effects were observed (although none of our patients had renal impairment). The overlapping use of acenocoumarol and fondaparinux did not result in major bleeding or venous limb gangrene (although 3 patients had venous limb gangrene prior to initiated fondaparinux or lepirudin). A limitation our study may be our reliance on the anti-pf4/h ELISA and ID-PF4/H-PaGIA to support the diagnosis of HIT, as there 665

4 666 Clinical and Applied Thrombosis/Hemostasis 16(6) Table 2. Laboratory and Clinical Characteristics of Patients With HIT Total (N ¼ 44) Lepirudin (N ¼ 20) Fondaparinux (N ¼ 24) P values Mean preheparin platelet count (10 9 /L) Range MV + SD NS Mean platelet count nadir (10 9 /L) Range MV + SD Days on heparin until hit screen Range MV + SD NS Thrombotic complications N % N % N % DVT NS PE NS PE þ DVT NS Cerebral vein thrombosis ND Arterial embolism ND Arterial thrombosis Skin necrosis Additional treatments N % N % N % IVIgG NS Lower limb amputation NS Embolectomy NS Vena cava filter ND Median days of platelet recovery Range MV + SD NS Outcome N % N % N % Successful outcome NS Death NS Death due to HIT NOTES: DVT ¼ deep vein thrombosis; HIT ¼ heparin-induced thrombocytopenia; IVIgG ¼ intravenous immunoglobulin G; MV ¼ mean OD value; PE ¼ pulmonary embolism. is a potential for overdiagnosis of HIT using these assays. However, most of our patients had relatively high OD values in the ELISA, and all had thrombosis (with the majority of patients developing new thrombosis in association with thrombocytopenia). These findings are consistent with the results reported by Zwicker et al 13 (who identified that higher ELISA OD values significantly correlate with thrombosis) and Warkentin et al 14 (who identified that the risk of HIT antibodies, defined as a strong-positive platelet serotonin-release assay [SRA] result (50% serotonin release) correlates with the magnitude of ELISA OD values), suggesting that at least a large majority if not all of our study patients likely had HIT. Furthermore, according to a recent study, 15 the combination of ID-PF4/H-PaGIA with the clinical score (thrombocytopenia, timing, thrombosis, other causes of thrombocytopenia not evident; 4T s) permits a safe a practical rapid HIT diagnosis. Our data, as well as few case reports, small case series, and a prospective pilot study from the literature suggest that fondaparinux may be considered a safe and effective alternative treatment in HIT complicated by active thrombosis. To our knowledge, this is the biggest case series of HIT patients treated successfully with fondaparinux. However, 1 case report of fondaparinux-related thrombocytopenia and thrombosis, 23 another of fondaparinux-associated thrombocytopenia in a previous LMWH-HIT patients, 24 and a third case of in vivo and in vitro cross-reactivity of HIT antibodies to fondaparinux, 25 highlight the fact that its safety needs to be further elucidated. Authors Note: The paper was presented orally at 19th International Congress on Thrombosis, Tel-Aviv, Israel, May 14-18, 2006 [10 patients were included, abstract at: Pathophysiology of Haemostasis and Thrombosis, 35(1-2), 2006] and at 20th International Congress on Thrombosis, Athens, Greece, June 25-28, 2008 [19 patients were included, abstract at: Pathophysiology of Haemostasis and Thrombosis, 36(Suppl 1), ] Declaration of Conflicting Interest The authors declared no conflicts of interest with respect to the authorship and/or publication of this article Funding The authors received no financial support for the research and/or authorship of this article. 666

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