Inhibitor treatment in haemophilias A and B: summary statement for the 2006 international consensus conference

Abstract

Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enroll cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.

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).…”

Ten‐year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan

“…Bleeding is managed by FVIII or FIX replacement therapy, which can result in the production of alloantibodies (inhibitors) to the relevant coagulation factor [1]. Replacement therapy then becomes ineffective, and alternative methods of managing bleeding are required.…”

Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver

“…This is particularly relevant in hemophilia, where the risk of developing neutralizing antibodies to the transgene product (clinically termed inhibitors) is a serious concern. 19 In this regard, regimens containing sirolimus are of great interest, because the drug has been shown to promote the induction of regulatory T cells. [20][21][22] In this study, we used a nonhuman primate (NHP) model to assess the safety of IS regimens in AAV-mediated, liver-directed gene transfer.…”