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New Treatments for Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura is a diagnosis of exclusion. Patients with immune thrombocytopenic purpura are typically otherwise well, that have an isolated hematologic defect, namely lower than normal platelet count. In eliminating other possibilities, you need to rule out the presence of a viral infection, including HIV. In 2006 if somebody presents with a new diagnosis of thrombocytopenia, at the very least we need to screen the patient to see if he or she is at risk for HIV disease. Have to do a careful history and perhaps even some serological testing if there is suspicious history for other autoimmune diseases, perhaps most commonly immune thrombocytopenic purpura.

ITP is caused by autoantibodies that are directed to platelet membrane antigens, primarily 2B and 3A, and to a lesser extent, 1B and glycoprotein 9. The prevalence is about 1-1.3 per 100,000. Interestingly there has really been no long term longitudinal study of ITP patients to get a sense of how many have what complications. About 5% of adults have spontaneous remissions as opposed to 90% in children. Of course the biggest risk is intracranial hemorrhage which fortunately doesn’t happen too often.

Typical characteristics or findings in ITP patients include, obviously, thrombocytopenia. When we do a bone marrow examination we would expect to find morphologically normal megakaryocytes and we would expect to see megakaryocytes present in normal to usually increased numbers. We have thought historically that the problem is associated with increased levels of platelet-associated IgG which in turn results in an increased rate of platelet destruction. Platelet survival time being significantly less than the normal 8-10 days that platelets typically live.

So we know for a fact that many patients with ITP suffer from the very rapid destruction of platelets. We also know now that there seems to be suppression of thrombopoiesis. In order to have ITP we also need to have an intact reticuloendothelial system. Patients that have reticuloendothelial systems such as terminal HIV patients tend not to have thrombocytopenia as a consequence.

Impaired lymphocyte capping has been shown in several articles published, dating back to the 1970’s. A Blood article in 1988, T lymphocytes were depressed in ITP and specifically blastogenesis to T cell mitogens, response to T cell-dependent B cell mitogens and the helper inducer cells all were depressed in ITP patients. So it’s more complicated than just a clone of B lymphocytes making antibody in renegade fashion against platelet antigens. The platelet associated antibodies are increased in 90% of ITP patients.

Now among children who develop acute ITP the peak age is in this area of maybe 2-5, 2-6. By the way, among children there is no predilection between boys or girls. Among adults there is a 3:1 increased incidence among women, and the typical time that we see increased incidence is in the 25-40 age groups and mirrors what we see in other autoimmune diseases. Now it’s important to appreciate other differences between acute ITP seen in children and chronic ITP seen in adults. We mentioned that there is no sexual predilection among children. The sensitizing event in children is usually obvious. The classic situation for a child is infection with a virus.

When we are evaluating patients with ITP, in addition to getting a good history - particularly a good drug history - on doing a physical exam, also need to look for evidence of other autoimmune diseases. Chemistries. Platelet-associated IgG, which was a standard test as of 10 and 15 years ago - as you’ll see later when I review the American Society of Hematology guidelines -is not considered mandatory to obtain in order to make a diagnosis of ITP.

In making the diagnosis of ITP, again, history, physical exam, CBC, examination of the peripheral blood smear. In the absence of atypical findings, and in the absence of any suggestion of other diagnoses, no additional studies are warranted. And specifically what’s not included here are bone marrow aspirate and biopsy. What’s also included here is FANA or other testing for autoimmune diseases and finally platelet- associated IgG. These are all the items that are missing from this list from this position paper and this is something that you need to know for testing because it’s been out long enough that I would expect.

In terms of therapies; there’s a whole range of treatments to choose from. None that are particularly new, and we are going to renew these in order. Prednisone is usually given at a dose of 1 mg/kg per day, sometimes in divided doses. If prednisone is going to work, it usually works within 2-3 days, although the patient really needs to be on the drug for two weeks in order to say that he or she is not responding. It seems to allow increased production of platelets.

The anti-D therapy has become more prominent in the past ten years. The usual product used is WinRho. This is a study that was published in 2006 in Blood by Scaradavou, in a study of 272 patients. The platelet count increased in 70% of Rh positive patients with intact spleens. The effect lasted at least 21 days in about 50% of the responders. One important rule in thinking about anti-D therapy is that patients who have had splenectomy should not be treated simply because it doesn’t seem to work in people who have previously undergone splenectomy.

Another standard approach to treating ITP is the use of IV IG. The mechanism initially was thought to be reticuloendothelial blockade. More recently people have thought that while that may be part of it, the IV IG also seems to serve as an anti-idiotype type process. The advantage of IV IG is that it really has very low toxicity and it’s effective in patients who have the standard, the classic kind of ITP with short platelet survival and very rapid platelet turnover. The use of IV IG seems to be very effective. The obvious disadvantages are that it is a temporary effect.

Splenic irradiation can be utilized if surgery simply isn’t an option and the patient really needs to have a splenectomy. Just one small point there. For refractory patients, people who aren’t responding to splenectomy or have and then relapse.