Successful treatment of high titer inhibitors in mild hemophilia A with avoidance of factor VIII and immunosuppressive therapy

Abstract

We describe two patients with mild hemophilia A (MHA) who developed high titer inhibitor (HTI) following intensive recombinant factor VIII (rFVIII) concentrate replacement for surgery and trauma. Intranasal desmopressin was instituted shortly following immunosuppressive therapy (IST) and activated prothrombin complex concentrate (APCC) in one case, and following APCC alone in the second case. Avoidance of factor VIII (FVIII) coupled with intranasal desmopressin prophylaxis three times a week resulted in undetectable inhibitor levels. Both patients have had no further bleeding episodes and have been maintained on desmopressin prophylaxis prior to activity for the past 2 to 3 years. Recombinant factor VIIa (rFVIIa) was used successfully prior to a second surgery in one patient without complication. Am. J. Hematol. 68:184±188, 2001. ã 2001 Wiley-Liss, Inc.Key words: hemophilia; inhibitor; desmopressin; immune-suppression; factor VIII; factor VIIa One of the most serious complications in the treatment of hemophilia is the development of inhibitors. Inhibitor development in patients with MHA is rare and no consensus exists regarding the management of such patients. The incidence of inhibitors in severe hemophilia A (SHA) is reported to be as high as 20À35% [1], with certain FVIII gene mutations associated with the high frequency. In MHA, the incidence of inhibitors is estimated at 3À13% with some variance in frequency based on mutation [2]. Inhibitors in MHA arise later in life, often following intensive FVIII replacement for surgery or trauma and are accompanied by a fall in the basal level of FVIII coagulant activity (FVIIIC). Bleeding frequently is unrecognized leading to a delay in diagnosis and appropriate management resulting in considerable morbidity.The management of inhibitors in MHA patients remains controversial and has included replacement therapy with human, porcine and rFVIII, immune tolerance induction [1,3], IST [4,5,34], and bypassing therapy with APCC [6À8,35], rFVIIa [6,9,10,34] and episodic desmopressin [1,3,6,7,10,11]. Immune tolerance induction, routinely attempted in SHA with HTI, is expensive, and may be ineffective in MHA patients with inhibitors.To date, no prospective studies on the treatment of MHA with inhibitors have been reported. There is also very little data on the use of long-term use of intranasal desmopressin coupled with avoidance of FVIII concentrates in MHA with HTI. We describe two cases of MHA with HTI maintained on intranasal desmopressin prophylaxis. Their FVIII levels returned to the baseline value following the disappearance of the inhibitor. CASE REPORTS Case 1Case 1 was a 17-year-old white male with MHA and baseline FVIIIC of 11.5% (range 6À12%). On DNA analysis, he had a Ser535 to Gly mutation in the FVIII

Options for treating acute bleeds in addition to bypassing agents: extracorporeal immunoadsorption, FVIII/FIX, desmopressin and antifibrinolytics

“…In mild haemophilia complicated by an inhibitor, desmopressin may be effective, as released endogenous FVIII may be less reactive with the inhibitor, when compared with replacement FVIII. A tolerizing effect of treatment with desmopressin has also been reported in this specific patient group [14,15].…”

Continuous infusion of coagulation factors: current opinion

“…Our extended search for inhibitors in relation to continuous infusion of VIII in studies published between 2000 and 2006 revealed six additional case reports [18,[41][42][43][44][45] and three case series [19,20,21 ], comprising a total of 31 patients, aged 0.5-75 years (25 mild/six severe), who developed an inhibitor. All patients received intensive factor replacement for surgery or major bleeds; seven of nine authors reported use of rFVIII; most of the 25 patients with mild hemophilia received less than 30 exposure doses of FVIII before continuous infusion and four were previously untreated patients (PUPs).Table 3shows details of inhibitor development in patients with mild hemophilia in four well documented studies[16 ,18,20,45].…”

Eradication of factor viii inhibitors in patients with mild and moderate hemophilia A

“…The poor response rate to combination treatment most likely represents confounding by indication, i.e., patients with worse disease or a more persistent inhibitor, were more likely to have received several treatments either simultaneously or sequentially. Other single case reports or small case series have reported a positive experience with combination treatments that have included immune suppressive agents such as corticosteroids and/or cyclophosphamide, however, case reports are prone to reporting bias [5–7]. …”