The management of inhibitors in haemophilia A: introduction and systematic review of current practice

Abstract

Haemophilia is the commonest bleeding disorder in the UK, affecting approximately 5400 people, almost all of them male. In haemophiliacs, reduced levels, or absence, of factor VIII (FVIII) cause bleeding episodes, typically into joint spaces or muscles. Haemophilia is generally treated with exogenous FVIII. However, in some haemophiliacs, therapeutically administered FVIII comes to be recognized as a foreign protein, stimulating the production of antibodies (inhibitors), which react with FVIII to render it ineffective. Alternative treatment strategies then have to be used to manage bleeding episodes. In addition, strategies have been developed to attempt to abolish inhibitor production through the induction of immune tolerance. A systematic review was undertaken of current international practice for the clinical management of haemophilia A patients with inhibitors to FVIII, concentrating on literature published from 1995 onwards. Although it can be difficult to determine what constitutes current practice, current guidelines indicate that immune tolerance induction is seen as desirable, with the choice of regimen dependent on patient characteristics, familiarity with regimens and cost. Various approaches, based on similar factors, are used to control bleeding episodes.

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

“…In these patients, bleeding episodes may be managed by increased FVIII dosages (Fig 1). However, in patients with high-responding (HR) inhibitors (peak titre >5 BU/ml) by-passing agents [i.e., recombinant activated factor VII (rFVIIa), and activated prothrombin complex concentrates (aPCC)] are required to control bleeding (Fig 1;Paisley et al, 2003;Berntorp et al, 2006).…”

Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors

“…The main criteria of choice for the treatment of bleeding events in haemophilia patients with inhibitors are inhibitor characteristics (level and anamnestic response) and site and severity of the bleeding episode [1,3,5,21,24,25,[57][58][59][60][61][62][63][64][65][66][67][68] (grade B recommendation based on level III evidence) (Fig. 1).…”

“…This issue is made even more difficult by the almost complete absence of evidence-based guidelines, with the exception of the comprehensive UK Haemophilia Centre DoctorsÕ Organization guidelines [3][4][5]. The Italian Association of Haemophilia Centres (AICE) approved in November 2004, new Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors.…”

Quantitation of anti–factor VIII antibodies in human plasma

“…Low inhibitor profiles are classified as titers below 5 BU/mL and high titer inhibitors are above 5 BU/ mL. 25,26 Patients are categorized as low responders if their titer is below 5 BU/mL and do not show an immune response upon reexposure to fVIII. Some high responders with antibody titers above 5 BU/mL demonstrate an immune response upon reexposure and are considered for treatment with fVIII-bypassing therapy to control bleeds.…”