Development of factor VIII inhibitors in two patients with moderate haemophilia A

Abstract

IntroductionHaemophilia A is an X-linked disorder characterized by congenital deficiency of factor VIII (FVIII). The FVIII protein is secreted as a mixture of a single chain and heterodimer consisting of one heavy and one light chain. The heavy chain is comprised of the A1, A2 and B domains, whereas the light chain contains the activation peptide, A3, C1 and C2 domains [1]. Severe haemophilia A is defined by a FVIII activity level <1% of normal. Moderate and mild disease are defined by FVIII activity levels between 1% and 5%, and 5% and 40% of normal respectively [2]. Haemorrhage in severe haemophilia A may be spontaneous, whereas in mild and moderate disease, bleeding is usually a result of surgery or trauma. Patients are treated with either recombinant or plasma-derived FVIII concentrates which can induce the formation of inhibitory antibodies. The crude incidence of inhibitors in patients with severe haemophilia A is approximately 23%, whereas inhibitors in mild and moderate disease occur much less frequently [3]. When patients with mild and moderate haemophilia A (MMHA) develop inhibitors, antibodies are produced against the exogenous FVIII and occasionally against endogenous FVIII as well [4]. When both exogenous and endogenous FVIII are inhibited, the FVIII activity level falls to <1% which can increase the baseline bleeding frequency. Methods PatientsTwo adult patients with moderate haemophilia A seen at Vanderbilt University Haemostasis clinic who developed inhibitors were selected. Information on the clinical course during the presence of an inhibitor was obtained from the electronic medical record. Domain mapping ELISAPlasma specimens were available in the IRB approved inhibitor bank at The Emory University Haemophilia Treatment Center. Domainspecific anti-FVIII antibody mapping was carried out by direct ELISA in half-area 96-well plates using purified single human domain hybrid FVIII proteins as test antigens and B domain deleted (BDD) human FVIII and BDD porcine FVIII as positive control antigens. Patient plasma was diluted 1-20 in blocking buffer (0.15 M NaCl/ 20 mM HEPES/5 mM CaCl 2 /0.05% sodium azide/0.05% Tween-80/ 0.25% bovine serum albumin, pH 7.4) and then serially diluted down the ELISA plate. Domain specificity was evident by visual inspection of colour [5]. Cases Patient 1A 56-year-old man presented to establish care in comprehensive haemophilia clinic. He was diagnosed with FVIII deficiency in the 1980s and subsequently received factor replacement prior to invasive procedures. He had chronic hepatitis C infection presumed from blood product exposure. One month prior to presentation to clinic, he underwent a radical prostatectomy at another facility for a recently diagnosed prostate adenocarcinoma. Preoperative labs were significant for a prothrombin time (PT) of 16.4 s, INR 1.5 and partial thromboplastin time (PTT) of 63 s. He did not receive factor replacement prior to surgery. His postoperative course was complicated by hypovolemic shock felt secondary to mechanical bleeding. Following ...

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“…20 We reported inhibitors in moderate form of HA. This is not surprising as this has been reported by Wight et al and Paschal et al 21,22…”