Fondaparinux (Arixtra∗) hepatotoxicity in a 6 year-old child
Authors: Lupe Orostegui, Nadia Medejel, Isabelle Kone-Paut, Marie Dreyfus, Dan Benhamou
Journal: Journal of Hepatology (2012)

Fondaparinux (Arixtra∗) is a synthetic pentasaccharide, which selectively binds to antithrombin (AT) and causes a rapid and selective inhibition of Factor Xa [[1]Bergqvist D. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery.Vasc Health Risk Manag. 2006; 2: 365-370Crossref PubMed Scopus (22) Google Scholar]. Fondaparinux is effective at preventing [[1]Bergqvist D. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery.Vasc Health Risk Manag. 2006; 2: 365-370Crossref PubMed Scopus (22) Google Scholar] and treating [[2]Büller H.R. Davidson B.L. Decousus H. Gallus A. Gent M. Piovella F. et al.Matisse Investigators. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.Ann Intern Med. 2004; 140: 867-873Crossref PubMed Google Scholar] venous thrombosis and has a valuable place in the treatment of patients with acute coronary syndrome [[3]Mehta S.R. Boden W.E. Eikelboom J.W. Flather M. Steg P.G. Avezum A. et al.OASIS 5 and 6 investigators. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials.Circulation. 2008; 118: 2038-2046Crossref PubMed Scopus (92) Google Scholar]. Fondaparinux has been reported to be well tolerated and thrombocytopenia has only been reported as isolated occurrences [[4]Arixtra (fondaparinux sodium) injection. Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – August 2009. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm182229.htm [accessed 16.05.10].Google Scholar]. It does not undergo hepatic metabolism and does not interact with liver function [[5]Lieu C. Shi J. Donat F. Van Horn R. Brian W. Newton J. et al.Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs.Clin Pharmacokinet. 2002; 41: 19-26Crossref PubMed Scopus (34) Google Scholar]. Liver toxicity induced by fondaparinux has not yet been described. We report a case of acute hepatitis likely related to fondaparinux administration in a 5 year-old child who presented with a left-sided axillary veno-lymphatic malformation diagnosed at 9 days of life. A 5 year-old child weighing 12 kg was evaluated for persistent pain in the left upper limb probably related to thrombosis of the previously known vascular malformation. Treatment with low molecular weight heparin (enoxaparin, 100 IU/kg/d) was started, which effectively reduced pain. Plasma D-dimer concentration and anti Xa activity were 4000 μg/ml (normal range <400 μg/ml) and 0.67 IU/ml (normal therapeutic range value: 0.5–1.1 IU/ml), respectively. Five months later, the dose of enoxaparin had to be increased to 180 IU/kg/d and then to 200 IU/kg/d nearly one year later because of increase in pain intensity and enlargement of the malformation. Three days after the last increase in the dose of enoxaparin, clinical examination disclosed a growth of the left axillary tumor and occurrence of a superficial tuberous angioma. Moreover, the child temperature rose to 38.6 °C. The pain persisted and paracetamol (200 mg/day orally) and codein (0.6 ml/kg) were introduced. At that time, the liver function tests were within the reference ranges (Table 1). Because of the recurrence of pain, enoxaparin was replaced by fondaparinux (2 mg/day) while paracetamol and codein were maintained. Thirty hours after the start of fondaparinux administration, anti Xa activity was 1.21 μg/ml (normal therapeutic range value 0.6–1.5 μg/ml) and the child started to complain of nausea and vomiting. Severe toxic cytolytic hepatitis was evidenced with a 15-fold increase in alanine and aspartate aminotransferases (respectively, at ALT 509 and AST 720 IU/L, normal range: 5–40 IU/L) and a 5-fold increase in glutamyl transpeptidase (GGT 161 IU/L, normal range: <35 IU/L). Alkaline phosphatase (ALP 278, normal range: 100–400 IU/L) and bilirubin concentrations (Bil 10 μmol/L, normal range: <17 μmol/L) remained normal (Fig. 1).Table 1Timing of drug administration and results of liver function tests. Open table in a new tab Tests for hepatitis A, B, and C serology and viral titration for herpes, adenovirus, enterovirus, parvovirus B19, HHV6 and HHV8 were all negative. Ultrasound of the liver was normal, without hepatic thrombosis. Fondaparinux was immediately discontinued and enoxaparin was reintroduced (dose: 1700 IU/kg morning and 1500 IU/kg evening) with no modification of the associated treatment with codeine and paracetamol. Clinical and laboratory signs of liver injury resolved over the next 5 days with a return to baseline levels of AST and ALT. Fondaparinux was considered the probable cause of hepatotoxicity. This report describes a case of liver toxicity likely due to fondaparinux administered to a child. The injury was severe enough to cause both an increase in liver function tests and clinical signs of intolerance. The role of fondaparinux in this case is highly likely since signs occurred soon after fondaparinux introduction and disappeared rapidly after the drug was stopped. Other drugs had been used for months without problems and their use was not modified soon before the occurrence of liver toxicity became apparent. There was also no recent change in the child condition that could be linked to liver injury. We have not identified in the literature any previous similar case. The mechanism of fondaparinux-related hepatotoxicity is still debatable. Drug-induced hepatotoxicity is generally idiosyncratic in nature and diagnosis of drug-induced liver disease can be difficult to establish since other causes of liver injury cannot be easily excluded. A transient increase in aminotransferase plasma concentrations associated with the use of LMWH has already been described [5Lieu C. Shi J. Donat F. Van Horn R. Brian W. Newton J. et al.Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs.Clin Pharmacokinet. 2002; 41: 19-26Crossref PubMed Scopus (34) Google Scholar, 6Baker E.L. Loewenthal T. Salerno E. Baker W.L. Probable enoxaparin-induced hepatotoxicity.Am J Health Syst Pharm. 2009; 66: 638-641Crossref PubMed Scopus (16) Google Scholar, 7Capuano G. Rodino S. D'Agostino L. Budillon G. Evaluation of heparin toxicity in the isolated and perfused rat liver.Enzyme. 1986; 35: 77-81PubMed Google Scholar, 8Carlson M.K. Gleason P.P. Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparininduced hepatotoxicity.Pharmacotherapy. 2001; 21: 108-113Crossref PubMed Scopus (73) Google Scholar, 9Guevara A. Labarca J. Gonzalez-Martin G. Heparin-induced transaminase elevations: a prospective study.Int J Clin Pharmacol Ther Toxicol. 1993; 31: 137-141PubMed Google Scholar, 10Hui C.K. Yuen M.F. Ng I.O. Tsang K.W. Fong G.C. Lai C.L. Low molecular weight heparin-induced liver toxicity.J Clin Pharmacol. 2001; 41: 691-694Crossref PubMed Scopus (29) Google Scholar]. The heparin-induced effect on liver function appears to be rather benign [8Carlson M.K. Gleason P.P. Sen S. Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparininduced hepatotoxicity.Pharmacotherapy. 2001; 21: 108-113Crossref PubMed Scopus (73) Google Scholar, 10Hui C.K. Yuen M.F. Ng I.O. Tsang K.W. Fong G.C. Lai C.L. Low molecular weight heparin-induced liver toxicity.J Clin Pharmacol. 2001; 41: 691-694Crossref PubMed Scopus (29) Google Scholar] and the exact pathogenesis is so far unknown. Various trials in adult human subjects have reported that fondaparinux is well tolerated. Increase in serum aminotransferases has been a rare finding and variations in liver enzymes were comparable between fondaparinux and placebo groups or enoxaparin groups. The mechanism of fondaparinux hepatotoxicity may not be related to the drug metabolites since in physiological conditions, fondaparinux does not undergo hepatic metabolism, is recovered in the urine as the unchanged compound and does not interact with other drugs administered concomitantly [[4]Arixtra (fondaparinux sodium) injection. Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) – August 2009. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm182229.htm [accessed 16.05.10].Google Scholar]. One cannot exclude a direct toxicity of the parent drug in children whose tolerance to fondaparinux has not yet been evaluated. Moreover, in the present case, inflammatory mediators may have contributed to sensitize hepatocytes to injurious effects of an unknown compound. Because clinical experience of fondaparinux is limited in children, monitoring of liver function tests might be useful especially in the first days after drug introduction. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.