Summer 1996 - Factor Nine News

The immune system recognizes all of the body’s own molecules and does not attack them. Early on in a baby’s development the immune system learns what the body’s own molecules looks like and programs itself not to make antibodies to them. Probably what happens in the development of Factor IX inhibitors is that if a child with hemophilia has no Factor IX in his body, the immune system never learns to recognize it as a “good” protein, one that is supposed to be there. Then when the boy is given Factor IX injections the immune system sees the Factor IX protein as a foreign substance and attacks it. However, as with most biological systems the story is not quite that simple since only a few hemophiliacs develop inhibitors. No one knows why that is but a lot of research is going on to figure it out.

Researchers have recently gotten some clues that could help explain why some patients develop inhibitors and some do not. To understand this we need to review a little about what goes wrong with the Factor IX in a hemophiliac’s body. Factor IX like all of the other proteins in the body is made according to the recipe in our genes. A person with hemophilia B has a defective factor IX gene so his body makes Factor IX incorrectly. There are a number of ways that can happen. Some hemophiliacs have Factor IX genes that only have a tiny mistake in them. Their bodies make Factor IX molecules that look very similar to normal Factor IX but do not work quite right. Other hemophiliacs have a Factor IX gene that has a completely confused recipe. Their bodies either make a protein that is nothing like normal Factor IX or the gene might be so confused that they do not make anything. Finally, the third major type of gene defect is one in which the gene is either partly or completely missing. These patients also make either an unrecognizable protein in place of Factor IX, or they make nothing at all. Recent research has shown that most inhibitor patients fall into the last two categories. They make either totally unrecognizable Factor IX or no Factor IX at all so their immune systems have never been programmed to recognize Factor IX as a normal body protein. Hemophiliacs who make a Factor IX that basically looks like the normal molecule even though it is ineffective tend to not produce inhibitors.

Most current research on the inhibitor problem focuses on treatment of patients with inhibitors. Hemophiliacs with low levels of inhibitors can simply be given larger doses of Factor IX. Basically the patients are given enough Factor IX that even after the inhibitors have bound up all of the Factor IX they can, there is still some left over to restore clotting. However, that only works for a little while because in the same way the body will produce more and more antibodies to eventually overcome a virus infection, it will also produce more and more inhibitor antibodies to overcome the additional Factor IX.

The most common method used to treat bleeding episodes in both Hemophilia A and B patients with inhibitors is to use high doses of Factor IX complex or of a special activated Factor IX Complex. Factor IX Complex is the older, less pure form of Factor IX that also contains several other clotting factors. In an earlier issue we discussed that one of the problems in routinely treating hemophilia B patients with factor IX Complex is that in large doses it can cause potentially dangerous, unwanted clotting. This may be a clue to how it works in treating inhibitor patients. Factor IX Complex may leave the blood just on the verge of clotting. In an area where there is bleeding there are a number of natural processes trying to activate the clotting system and these might be enough to push the blood over the verge and cause it to clot. This therapy is risky, however, and must be used with caution. It is just as easy to end up with a clot in a dangerous place like the lungs, heart, or brain. A genetically engineered, activated Factor VII product is being developed in Europe that probably works in a similar fashion, but may have fewer side effects. Other experimental methods have looked at the possibility of removing the inhibitor antibodies from the bloodstream. While these have shown some limited success, they have their own problems.

The most promising technique being studied to treat inhibitor patients is called Immune Tolerance. It is not really understood why this works, but patients are given large daily doses of Factor IX for several months. As expected, early on in this treatment the body responds by producing more and more inhibitor antibodies. However, after a while the number of inhibitor molecules starts to decrease. It eventually falls off to zero and stays there. This usually takes several months. While this is an expensive therapy because of the large amount of Factor IX used, it does seem to be a permanent “cure” for the inhibitor problem. Also over the long run it appears to be less expensive because of the high cost of treating inhibitor patients by other methods. As this method becomes more widely used and understood, it may represent the final solution to the inhibitor problem.

A SPECIAL THANKS TO…

THE AMERICAN RED CROSS

FOR THEIR KIND DONATION WHICH HELPS US TO HELP KEEP YOU BETTER INFORMED!!