Hemophilia A affects about 1/5000 males, is typically inherited, and is normally treated with factor VIII (F8) replacement therapy. However, factor replacement therapy has a major side effect-inhibitors occur in approximately 25% of those with severe hemophilia A, and are a direct result of factor replacement therapy. Inhibitors are antibodies that neutralize the function of F8, which means that the F8 replacement that is being used to treat bleeding episodes (to stop the bleeding or prevent the bleeding) isn’t effective (and so the bleeding doesn’t stop)!
Why do inhibitors develop in hemophilia?
Severe hemophilia is the result of a mutation in the F8 gene that renders the protein useless. Some mutations result in the complete loss of the protein (large deletions and nonsense mutations) whereas others result in a protein that isn’t functional (missense mutations and splice site mutations). If a mutation results in complete loss of the F8 protein, then when F8 is introduced as part of replacement therapy, the protein is foreign to the body!
So, what about the immunology?
First, not all antibodies to F8 are inhibitors (they aren’t all dangerous). Actually, about 15% of healthy blood donors have non-pathogenic F8 antibodies. CD4+ T-cells play a role in anti-F8 antibody synthesis. Like any other protein, F8 is processed into peptides by an antigen-presenting cell, presented with MHC class II to a CD4+ T-cell, and, with a proper CD4+ T-cell receptor and with costimulation, the CD4+ cell directs B cells to make antibodies. Both Th1 and Th2 cells contribute to the production of anti-F8 antibodies, and the proportion of the Th1/Th2 response is unique to the individual. In addition, it appears that the pathogenic immune response to F8 is the result of failure to activate regulatory CD4+ cells specific for certain F8 sequences.
Why does it matter?
Inhibitor development, especially if the inhibitor develops at a high titer, can be devastating for those with severe hemophilia. In extreme cases, where factor replacement therapies don’t work, some patients turn to “immune tolerance therapy,” in which the patient is exposed to high doses of F8 daily for weeks and even years, sometimes in conjunction with immunosuppressive drugs. The idea is to tolerize the body to the F8 (teach the body not to mount an immune response to the F8), and according to the National Hemophilia Foundation, works about 60-80% of the time. Interestingly, patients who respond successfully to immune tolerance or immunosuppressive therapies tend to have a predominance of Th1-driven antibodies, whereas those who fail to respond to these therapies tend to have a Th2-driven response.
References
National Hemophilia Foundation (http://www.hemophilia.org/)
M.T. Reding, “Immunological aspects of inhibitor development,” Haemophilia, 12 (Suppl. 6) 30-36, 2006.
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3 comments:
A common treatment that is used while a patient has an inhibitor is FVIIa. This induces clotting through the extrinsic clotting pathway bypassing the intrinsic clotting pathway which includes FVIII. FVIIa is used to end a bleeding episode or prepare a FVIII inhibitor patient for surgery. The downsides to FVIIa are its cost and its short half-life. Patients using FVIIa generally have to recieve treatments every two hours while bleeding is occuring and single doses can cost around $10,000.
Another option is FEIBA which is another bypass agent. It contains several activated clotting factors and is used to stabilize clotting. This is more convenient then FVIIa because it is used twice a day but not as effective in an active bleed.
Immunosuppression is not used for active bleeding but is used in an attempt to eliminate an inhibitor.
I find it very interesting that about 15% of healthy blood donors have non-pathogenic FVIII antibodies! That combined with the fact that FVIII inhibitors are so common in severe hemophilia A patients, while FIX inhibitors are much more rare (about 3%) in severe hemophilia B patients - do you think there is something about the actual FVIII molecule that makes it more immunologically active?
I recently attended an interesting research talk by Dr. Meeks, a physician from Emory, related to this topic. She presented her research that focused on the C2 domain of fVIII, one of two locations where the majority of inhibitory fVIII antibodies are directed. The C2 domain also contributes to the binding of fVIII to von Willebrand factor (VWF), thrombin, and factor Xa. Her research analyzed the diversity of fVII C2 domain antibody epitopes using a competition ELISA technique. She discovered 5 groups of structural epitopes and 2 groups of functional epitopes that inhibit binding of fVIII to phospholipid and von Willebrand factor. I appreciated the emphasis on both the structural influence of the antibody related to the response as well as the influence of the functional complexity of the anti-C2 domain to the antibody response.
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