The Reversal of Inhibitors in Congenital Hemophilia

Abstract

Hemophilias A and B are heritable bleeding disorders characterized by deficient baseline levels of factor VIII (fVIII) and factor IX (fIX), respectively. Standard treatment for acute bleeding events and for prophylaxis in patients with severe disease consists of recombinant fVIII and fIX infusions. The development of alloantibodies, or inhibitors, is a serious complication of congenital hemophilia that may impair the effectiveness of fVIII and fIX, leading to increased morbidity and cost of therapy. When inhibitors are present, bypassing agents such as recombinant activated factor VII and factor eight inhibitor bypass agent are available for treatment of bleeding events. Although usually effective, they are costly treatments. Immune-modulatory therapy may reverse inhibitors, allowing fVIII and fIX to be used again. Immune tolerance induction is the chief treatment option to decrease inhibitor levels, but about 20-30% of patients fail this treatment. Alternatively, multiple immune-modulating agents have been tried with limited success. Rituximab, an anti-CD20 monoclonal antibody, is one therapy that has been successful in reducing inhibitor titers in multiple case reports. Although current evidence is limited and questions regarding its use and place in therapy still exist, this agent shows promise for the future.

The 1.7 Å X-Ray Crystal Structure of the Porcine Factor VIII C2 Domain and Binding Analysis to Anti-Human C2 Domain Antibodies and Phospholipid Surfaces

“…Treatments for hemophilia A patients with inhibitor and acquired hemophilia patients have been fairly limited, and have consisted of fVIII bypass agents [ 36 ], immunosuppressive therapy [ 37 ], and the infusion of highly purified porcine fVIII (Hyate:C) [ 38 ]. Porcine factor VIII has been used historically for treating hemophilia A patients with inhibitors due to its low cross-reactivity with anti-human fVIII antibodies, which results in a higher level of activity in comparison with human fVIII [ 39 – 41 ].…”

Rituximab as first‐line treatment for the management of adult patients with non‐severe hemophilia A and inhibitors

“…Our results are consistent with the finding of Kempton et al showing that rituximab use alone in six patients (three of whom were from our institution, and included in this case series) was significantly associated with an increased likelihood of inhibitor clearance (hazard ratio 4.4 [95% confidence interval 1.06-20.03]) [8]. Furthermore, given that none of our patients required concomitant ITI therapy for inhibitor eradication, the potential cost savings were enormous ($15 480 for a 4-week regimen of rituximab alone vs. $247 260 for a 4-week regimen of rituximab and concomitant FVIII 50 IU kg À1 daily), and our patients were spared the inconvenience and associated risks of daily factor infusions [17].…”

Practical guidance on immunogenicity to biologic agents used in the treatment of psoriasis: What can be learnt from other diseases?

“…Detection of inhibitors is therefore essential in tailoring the treatment of haemophilia A to the individual patient and impacts the treatment of acute bleeding and prevention of bleeding in haemophiliacs with inhibitors. Immune tolerance induction is used to decrease inhibitor levels, but it is unsuccessful in 20-30% of patients; rituximab has shown some promise in reducing inhibitor titres (49). Multiple protocols have been developed to induce immune tolerance, including the use of high-dose factor replacement, low-dose factor replacement, immunomodulation and various combinations of these therapies; however, it is currently unknown which dosing regimen is superior (49).…”