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New Treatments for Immune Hemolytic Anemias

Immune hemolytic anemia in adults is the most common cause of acquired hemolytic anemia.Immune hemolytic anemia is, by its very nature, characterized by antibodies and there are three subclasses of antibodies which are involved; IgM, IgG and IgA. IgA antibody autoimmune problems are probably very rare, and in fact are exceedingly uncommon, so most of all we will be focusing on the IgM antibodies and immune hemolytic anemia.

The diagnosis of immune hemolytic anemia but I want to point out some things that I think are worthwhile reiterating. In the first place, direct agglutination is a very poor way of detecting it because normal IgG, the IgG cells because they donít deglutinate. Whereas the IgM cells do. So if we relied upon agglutination as they did in the days before the Coombs test was invented, they were very seldom diagnosed. In IgG mediated hemolysis agglutination almost never occurs. On the other hand, with the findings of the direct Coombs test, more than 99% of patients with immune hemolytic anemia will have a positive test. The reason that IgG cells donít agglutinate.

Acrocyanosis is the condition in which the areas of the skin that have become chilled for some reason - sometimes simply walking around in cold air - results in agglutination of the blood within the vessels and the patient gets very purple. So the digits, the nose, the ears become very purple and then, as they are warmed, clear without a reaction. Now some patients may also have Raynaudís phenomenon but this is not Raynaudís phenomenon. Raynaudís phenomenon, as you recall, is white - is a vascular phenomenon - white during the arterial closure.

If the reticulated endothelial system has been worn out for some reason by immune complexes and is not able to bind to the IgG, the amount of hemolysis that one sees will be diminished. But by and large the titer and the characteristics of the antibody are what determine the characteristics. In cold agglutinin disease the same thing is true. And the titer of the antibody is important. Very rarely will an antibody with a titer of less than 1:1000 cause clinical problems. Very often your blood bank may report back to you, "Cold agglutinin detected."

Cold agglutinins have a characteristic which we call thermal amplitude, which is to say, what is the highest temperature at which that antibody will react with red cells? Some antibodies react almost at body temperature, and you can imagine then that those would be more destructive simply because they would have been in contact, they would have been able to react with the red cells even during circulation into the core body temperature. In fact that is the only time when the titer of the antibody may be quite low, say 1:500 or so, and the act of hemolysis.

The fixation of complement. Some antibodies are much better at fixing complement than others. I have several patients who have very high titers of antibody but their antibodies are relatively unable to fix complement. The reason for it is that in all those cases where weíve seen that the antibody is not only a cold agglutinin - that is, agglutinates in the cold - but is also a cryoprotein. That is, it precipitates in the cold. And I think what happens is that as it cools down it binds to the red cells, but in so doing it loses the ability to bind the complement.

Finally, something that we just discovered, and that is; we usually think of IgM molecules as being five sub-units. However, in cold agglutinin disease some patients have a considerable percentage of their antibody molecules that are hexamers; six instead of five sub-units. Weíve been able to separate those out and been able to show that those hexamers are

There are two other things I want to talk about before we get into treatment and one is the drug-induced immune hemolysis and this I think is well-recognized. That there are two types; one is autoimmune in which the drug appears to change the face of the cell. Antibodies are formed to that change and therefore hemolytic anemia occurs. The protein that is changed

Now the important thing about the Aldomet, the autoimmune form, is that the indirect Coombs test does not require the drug to detect the antibody. Thatís because the drug is not part of the antigen. The drug has created the antigen but it is not part of the antigen and therefore the Coombs test is negative. This type of a reaction, the Aldomet - and there are several others like it Ö incidentally, I just had a patient who took chromium for energy or

Now the other syndrome that I wanted to mention, because it is vastly under-diagnosed I think, that is paroxysmal cold hemoglobinuria. This was first known because of the fact that it was a complication of lues syphilis, tertiary syphilis. In fact it was the first autoimmune hemolytic anemia ever defined as such, in the middle of the 19th century. Nowadays we almost never see it, as a result of lues, because syphilis is almost gone but it is still a relatively common form of autoimmune hemolytic anemia. The problem that we have is in diagnosing it. The antibody is IgG but it is cold reacting. So it does not cause - even in the cold agglutinin test - it does not cause agglutination because of the fact that there is IgG. The direct Coombs test is

If you use PNH cells instead of normal cells you increase it because they are more sensitive to the hemolytic action of complement. You can increase the chances of making the diagnosis by the Donath-Landsteiner test by maybe 50 or 60%. They are now working on ways in which what is called the cold Coombs test, cold indirect Coombs test, which depends upon detecting IgG at zero degrees but not at 37 degrees. With that test we are able to detect - I donít know if we are detecting them all - but we certainly detect a large number of patients who have PCH, who do not test positive with the Donath-Landsteiner. So if you get a negative Donath-Landsteiner test, take it for what it is. Unlikely to be very helpful. Nowadays itís most

Letís talk for a few minutes about the therapy in autoimmune hemolytic anemia. There are several objectives. One is the reduction in the production of antibody. Second is reduction of available antibody, and third is reduction in the mechanisms of destruction by antibody. This is the general chart which we will referring to several times. Each of these has an application to either IgG or IgM depending. The first one we are going to be talking about is the reduction in antibody production by prednisone. Because if prednisone is going to be effective, the

How are they used? They are used in the following way, at least that is that when the patient first appears with warm agglutinin and hemolytic anemia, the severity is assessed. If it is markedly severe then you have to pull out everything at once. Most patients present with moderate severity, that is; requiring treatment but not emergent treatment. Some patients, many patients, may have evidences of immune hemolytic anemia but it may be minimal and may be watched with safety. Prednisone is usually begun with prednisone of 1 mg/kg per day, which is maintained for a period of two to three weeks at a maximum. That is important because - some