Properties of Anti-Factor VIII Inhibitor Antibodies in Hemophilia A Patients

Abstract

Blood coagulation factor VIII functions in the intrinsic pathway of blood coagulation as a cofactor by enhancing the assembly of its complex with factors IX and X on the surface of activated platelets. This requires factor VIII interaction with these two proteins, von Willebrand factor (vWF), and phospholipids on the platelet surface. Once factor VIII and factor IX are activated by proteolytic cleavage, the complex is able to activate factor X to factor Xa by proteolysis. In hemophilia A patients with severe factor VIII deficiency, about 30% respond to factor VIII infusion therapy immunologically to produce antibodies that inactivate the infused factor VIII and others that are noninhibitory. An assay that measures only the inhibitor antibodies demonstrated that the factor VIII A2, A3, and C2 domains are the most immunogenic, and domains A1 and B are poorly immunogenic or not immunogenic. The specific antibody responses to A2, A3, and C2 vary considerably among individuals, and epitopes for inhibitor antibodies have been determined for all three. The anti-C2 inhibitors prevent factor VIII binding to phospholipids and vWF, and anti-A3 inhibitors prevent binding to factor IX (IXa). An inhibitor binding site for factor X has been localized to the A1 domain acidic region, leading to inhibition of factor VIII/factor X binding by antibodies. This inhibitor mechanism is rare. Because a second binding site for factor IX was localized to the factor VIII A2 domain, it is likely but not proven that prevention of factor IX binding to factor VIII is the inhibitor mechanism for this epitope.

Phenotypic correction of murine hemophilia A using an iPS cell-based therapy

“…Treatment for hemophilia generally includes either fixed-dose prophylaxis or factor replacement therapy on an as-needed basis. With either approach, neutralizing antibodies to the replacement protein have been reported and present a unique problem when treating hemophiliacs (4,19). The monogenic nature of hemophilia makes it an ideal target for gene therapy.…”

Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies

“…Even the development of an inhibitor titer of 2-5 BU/ml presents a difficult and often expensive challenge to clinical care. This strategy has the potential to offer therapeutic benefit both for hereditary hemophilia A patients with inhibitors and for nonhemophilia A patients with acquired inhibitory antibodies (3,47,48) who also have major life-threatening clinical bleeding. As demonstrated in Figure 4A, 100% of FVIII null mice infused to as little as 0.02 U/ml rhBDDFVIII in plasma survived tail clipping.…”

“…Currently, hemophilia A is treated by infusion of recombinant or plasma-derived FVIII (2). However, 25-30% of patients develop antibodies (FVIII inhibitors) that selectively inactivate the clotting activity of FVIII and negate its therapeutic efficacy (3). Hemophilia A is considered a strong candidate for gene therapy because the therapeutic window is broad and even a minimal plasma level of plasma FVIII is clinically advantageous.…”

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

“…2 Although FVIII replacement markedly improves the life expectancy of patients with hemophilia, up to 30% of patients with severe hemophilia A develop antibodies after FVIII replacement therapy. [3][4][5][6][7] These antibodies cause the clinical failure of treatment in response to routine replacement therapy for bleeding episodes and therefore are referred to as FVIII inhibitors. [8][9][10] Clinically, inhibitor titers greater than 5 Bethesda units (BU)/mL are considered untreatable using routine FVIII replacement.…”