Since we talked about HIV/AIDS a couple weeks ago in class, I wanted to remind everyone about HIV infection of hemophilia patients in the 80's. Patients with hemophilia often require frequent transfusions of clotting factors to control bleeding. This plasma-derived factor is made from pooled factor from many blood donors, which greatly increased the risk of HIV contamination in the 80s, when HIV screening of blood donors was not in place (and for some time they didn't even know about HIV). HIV transmission has not occurred from factor products since 1986, when they started viral inactivating blood products.
Unfortunately, about half of the hemophilia patients in the late 1970s and early 1980s in the United States were infected with HIV via blood products, and many have developed AIDS. Currently, 10-15% of the hemophilia population is HIV positive.
I think there is an important lesson from this story-even though we believe the blood supply is safe, it is only safe with respect to the infections we know about and can/do test for.
Showing posts with label hemophilia. Show all posts
Showing posts with label hemophilia. Show all posts
30 October 2008
29 September 2008
Inhibitors in Hemophilia: A Potentially Devastating Problem
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.
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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