Each month, PDSA highlights research and clinical advances being made to better understand ITP and how to treat patients more effectively. In this issue, we share two presentations given at this year’s annual International Society on Thrombosis and Haemostasis (ISTH) Congress that was held in Montreal, Canada in June, and attended by PDSA staff and medical advisors.
At this year’s ISTH conference, Hanny Al-Samkari, MD, shared a presentation on a condition called Persistent Isolated Mild Thrombocytopenia (PIMT), defined as a platelet count between 100,000 and 149,000. Although this platelet count does not meet current commonly employed criteria to diagnose ITP, it is nonetheless a condition with slightly reduced platelet counts that hematologists encounter quite often. Currently, PIMT is not well understood, so treatment plans can vary. Therefore, the goal of this presentation was to share what researchers know about PIMT and ultimately create standardized guidelines to assess it.
Dr. Al-Samkari began his presentation by explaining that a platelet count of less than 100,000 is often used as part of the diagnostic criteria for ITP even though platelet counts in healthy individuals are typically between 150,000 and 450,000. One justification of using 100,000 is that many apparently healthy individuals have platelet counts between 100,000 to 149,000. Another reason is that slight reductions in platelet counts often occur during healthy pregnancies.
However, one study published in 2006 followed 191 otherwise healthy individuals with PIMT (platelet counts between 100,000 and 150,000). They found that within 10 years, a small number (7%) of such individuals developed ITP and 12% developed a different autoimmune condition.
Dr. Al-Samkari then shared results of a 2022 study looking at what happens in those with PIMT when followed for more than 10 years. This study compared 91 patients with PIMT to 364 healthy individuals over approximately 21 years. They found that in the PIMT group, about one third (~33%) of participants developed a blood disorder (such as ITP or a blood cancer). This was more than the number of blood disorders that developed in the healthy control group (2%).
This study also found that 26% of those with PIMT had bleeding events, whereas only 2% in the control group did. Furthermore, 13% in the PIMT group developed a different autoimmune disease, compared to only 3% in the healthy control group. Dr. Al-Samkari concluded that although there is much to learn, PIMT should not go unnoticed and there is a need to create guidelines to follow patients in this setting.
Comments from PDSA Medical Advisors
The presented studies demonstrate that adults with persistent isolated mild thrombocytopenia should be followed over time to anticipate the potential development of a hematologic condition. The indicated diagnostic workup of PIMT and frequency of longitudinal lab monitoring are not clear and so there is wide variability between patients currently. Guidelines would help to create consistency in the approach to care of individuals with PIMT given that the outcomes are not common and develop over years.
Paolo Gresele, MD, PhD, gave a talk at ISTH on how cells called megakaryocytes are affected in immune thrombocytopenia (ITP).
ITP was initially known to be a condition where platelets in the blood are destroyed at a faster rate than normal. Research confirmed this by showing that patients produced antibodies that attacked their own platelets, causing low platelet counts. If this was the full story, it would be expected that platelet turnover – a measure of how fast platelets are produced – would be increased in ITP patients. Initially, this was universally accepted, but then technologically improved studies showed that though this is true for some, many patients have either normal or even decreased platelet turnover. This indicated that platelet destruction is not the only cause for low platelet counts in ITP.
Researchers (PDSA medical advisors) then showed that antibodies from ITP patients not only interacted with platelets, but also with megakaryocytes. These are cells that live in the bone marrow and give rise to platelets – they are the platelet precursor cell. Furthermore, when samples from the bone marrow were analyzed, antibodies against platelet proteins (called GPIIb/IIIa and GPIb/IX) were found attached to megakaryocytes in some patients. These are the same antibodies in the blood that destroy platelets in ITP. This research showed that megakaryocytes, in addition to platelets, can be affected in ITP.
Megakaryocytes undergo several developmental steps in order to give rise to platelets. Megakaryocytes in each of these stages of development may be affected by the immune system in patients with ITP. For example, megakaryocyte movement and ability to form normal-shaped platelets can be affected by ITP antibodies. It is clear through these studies that the immune attack on megakaryocytes significantly contributes to the low platelet count in patients with ITP. Interestingly, one study showed that the ITP therapies eltrombopag and romiplostim were able to restore the formation of proper platelet shapes.
Comments from PDSA Medical Advisors
Megakaryocytes are targeted by the immune system in patients with ITP. This combined with platelet destruction causes the combination of both poor platelet production and increased platelet clearance which can result in particularly severe thrombocytopenia. The thrombopoietic agents (romiplostim, eltrombopag and avatrombopag) emerged as a result of these findings. Through a greater understanding of the complex effects of the immune system on megakaryocytes, ITP-directed therapies have expanded over time. Continued further research on the effect of ITP on megakaryocytes may lead to new ITP treatment approaches in the future.