Hematology
Chronic Immune Thrombocytopenia
Mechanisms Contributing to the Pathophysiology of Immune Thrombocytopenia
Overview
Although the subject of multiple scientific studies and despite the emergence of novel treatment options that might help understand it, the pathogenesis of immune thrombocytopenia (ITP) remains poorly understood. Two major mechanisms known to be involved in the development of ITP are increased platelet destruction and insufficient platelet production. An insufficient level of thrombopoietin and impaired function of megakaryocytes are factors associated with decreased platelet production. Thrombopoietin is the main regulator of the process of new platelets being formed from megakaryocytes. Therefore, the superior efficacy of thrombopoietin receptor agonists in increasing platelet counts in patients with ITP supports the idea that platelet production is also insufficient in these patients.
Q: What mechanisms contribute to the pathophysiology of ITP?
Howard A. Liebman, MD
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“ITP is a very heterogeneous disease. The heterogeneity of the disease is very complex, and it cannot be predicted.”
ITP is a very heterogeneous disease. The heterogeneity of the disease is very complex, and it cannot be predicted. In some patients, the antibodies themselves can induce apoptosis in megakaryocytes in culture, yet other patients’ antibodies that bind the same receptors, either IIVIIIA or the IB-IX, do not have an effect. It has been proven that there are T-cell–mediated events involved that can lyse platelets, and they respond to the same antigens that are in megakaryocytes. There are older patients whom I have seen fail treatment with corticosteroids, then respond to cyclosporine, and then experience remission on cyclosporine. The mechanisms are related to a loss of immune tolerance, and it is usually peripheral immune tolerance for the majority of cases. It has been shown that the best responders to anti-CD20 therapy, which kills the B cell lymphocyte, were individuals who reset the T cell repertoire. So, there is this concept of the B cells talking to the T cells in a backward manner, and those patients were the individuals who experienced the complete responses. It also showed increases in T regulatory cells, yet the vast majority of patients do not experience long-term remissions or that great of a treatment response to anti-CD20 therapy.
Terry B. Gernsheimer, MD
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“I think that the best you can say about the mechanisms that are associated with the pathophysiology of ITP is that it is a loss of immune tolerance and that there is a production and a destructive defect. That is probably where you have to stop before you start speculating.”
I think that it is loss of immune tolerance, but there are a lot of reasons for a loss of immune tolerance. Years ago, people always thought that ITP was a disease of platelet destruction alone, that peripheral platelet destruction was responsible for this disease. Therefore, it was thought that what you had to do was to stop the peripheral platelet destruction. What we have proven over the last 20 to 30 years is that there is also a production defect. Now, it is likely due to the same mechanism because I think that the megakaryocytes probably do, indeed, have the same targets as the platelets. So, we are talking about a disease that has a production defect and a destructive side to it. I think that the best you can say about the mechanisms that are associated with the pathophysiology of ITP is that it is a loss of immune tolerance and that there is a production and a destructive defect. That is probably where you have to stop before you start speculating.
Adam Cuker, MD, MS
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“I believe that we are moving toward an ability to understand the pathophysiologic mechanisms operating in an individual patient and toward being able to match treatments to those mechanisms to enhance response rates. We are not there yet, but I do think that we are moving in that direction.”
We are learning that the answer is ͞”multiple mechanisms.” The traditional viewpoint about ITP was that it was a disease of accelerated platelet clearance, and the clearance was due to immunoglobulin G antibodies against antigens on the platelet surface that lead to their clearance in the spleen. That is clearly an important mechanism in ITP, but it is not the only mechanism and it is also more nuanced than that. We now know that antibodies in ITP are heterogeneous. There are antibodies to the glycoprotein IIBIIIA complex that do behave generally in that way, but then there are also antibodies to the glycoprotein IB-IX-V complex that seem to have a different pathophysiology. There is some new medical literature to suggest that when those antibodies bind to platelets, the antibody-coated platelets are cleared in the liver rather than the spleen. Therefore, we would not expect those patients to respond, for example, to splenectomy, corticosteroids, or anti-D. As far as cellular immunity, T cells are important in ITP, potentially as a means of platelet destruction, and the T cells can also attack the megakaryocytes and interfere with platelet production. What we are really learning is that ITP is a complicated disease. It is probably more than 1 disease, and the pathophysiologic mechanisms that operate in 1 patient may not be the same as those that operate in another patient. I believe that we are moving toward an ability to understand the pathophysiologic mechanisms operating in an individual patient and toward being able to match treatments to those mechanisms to enhance response rates. We are not there yet, but I do think that we are moving in that direction.
References
Bakchoul T, Sachs UJ. Platelet destruction in immune thrombocytopenia. Understanding the mechanisms. Hamostaseologie. 2016;36(3): 187-194.
Khan AM, Mydra H, Nevarez A. Clinical practice updates in the management of immune thrombocytopenia. P T. 2017;42(12):756-763.
Nugent D, McMillan R, Nichol JL, Slichter SJ. Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production. Br J Haematol. 2009;146(6):585-596.
Toltl LJ, Arnold DM. Pathophysiology and management of chronic immune thrombocytopenia: focusing on what matters. Br J Haematol. 2011;152(1):52-60.