Editor's Note: The 2025 European Hematology Association (EHA) Annual Meeting was grandly held both online and in-person, gathering top experts and scholars from the global hematology community. During the highly anticipated Presidential Symposium, Professor Nicola Cooper, an immune-hematologist from Imperial College London, delivered a keynote speech on "Immune Thrombocytopenia (ITP): From Biology to Targeted Therapy." She systematically reviewed the century-long evolution of ITP from its initial recognition to modern treatment, and by focusing on cutting-edge research, she outlined a clear roadmap for the future of personalized, precision therapy.

Since its first description by Werlhof in 1735, the understanding and treatment strategies for Immune Thrombocytopenia (ITP) have undergone a long evolution. As Professor Nicola Cooper cited at the beginning of her presentation, pioneers like Harrington and his colleagues had already foreseen in the 1950s that ITP might not be a single disease but rather a syndrome with multiple pathogenic mechanisms. Now, in 2025, this view is profoundly confirmed by modern medical research. Professor Cooper pointed out that the diagnosis of ITP still relies on the principle of exclusion, lacking a gold standard. Its clinical presentation, disease course, and response to treatment all exhibit significant individual variability, highlighting the urgent need for a deeper investigation into its biological nature.

Beyond “Counts”: A New Perspective on ITP Disease Burden and Clinical Heterogeneity

For a long time, the clinical focus on ITP has been primarily on platelet counts and bleeding risk. However, Professor Cooper’s team has revealed a much heavier burden associated with the disease. Data show that over 50% of ITP patients suffer from fatigue, which is often their most debilitating symptom. At the same time, up to 50% of patients exhibit cognitive impairment, affecting their concentration and ability to perform tasks, which in turn hinders their academic and professional lives. More alarmingly, about 40% of patients experience symptoms of depression, an issue often overlooked in clinical practice.

A study on pediatric ITP (the KIT score) shared by Professor Cooper further confirmed that the disease significantly impacts the entire family, with many parents restricting their work and social activities as a result. These findings emphasize that the treatment goal for ITP should not solely be to increase platelet counts but also to improve the patient’s overall quality of life. When patients enter remission, their health-related quality of life improves significantly, suggesting that pursuing a “cure” or “deep remission” may be a more ideal treatment strategy for the future.

Furthermore, the clinical heterogeneity of ITP is also manifested in the paradoxical coexistence of bleeding and thrombosis. Studies have found that 43% of adult ITP patients have cerebral microbleeds associated with long-term low platelet counts. Concurrently, the risk of thrombosis in ITP patients is also significantly increased. The latest research from Professor Cooper’s team found that platelets in ITP patients also show significant heterogeneity in size and function; some patients have hyperreactive platelets, while others have hyporesponsive ones, which may partially explain the differences in bleeding and thrombosis risks among patients.

A New Landscape in Targeted Therapy: From TPO-RAs to Precise Intervention in the B-Cell Pathway

On the treatment level, Thrombopoietin receptor agonists (TPO-RAs), which stimulate the bone marrow to produce platelets, have become the mainstream second-line treatment choice for most ITP patients. Although TPO-RAs have brought hope to many, about one-third of patients still respond poorly or experience significant fluctuations in their platelet counts, indicating a need to intervene at the immunological root of the disease.

Targeting B-cell-mediated antibody production is another core strategy in ITP treatment. The Spleen tyrosine kinase (Syk) inhibitor, Fostamatinib, has shown response rates of 20% to 43% in clinical trials by inhibiting macrophage-mediated phagocytosis and destruction of platelets. As a new-generation targeted drug, the Bruton’s tyrosine kinase (BTK) inhibitor, Rilzabrutinib, not only acts on macrophages but also inhibits B-cell proliferation, reducing the production of pathogenic antibodies at the source. A pivotal Phase III clinical study confirmed that Rilzabrutinib significantly increases platelet counts in patients. More groundbreaking is the finding that Rilzabrutinib improves fatigue and quality of life regardless of whether the patient’s platelet count increases. This discovery suggests for the first time that targeting immune cells like B-cells or macrophages may directly alleviate systemic symptoms caused by immune dysregulation, providing a new dimension to treatment that goes beyond “platelet elevation.”

An Alternative Approach: Unveiling the Key Role of T-Cells in Refractory ITP

Why do a large number of patients still respond poorly to B-cell targeted therapies? Professor Cooper’s team turned their attention to another key component of the immune system—T-cells. They found a large number of highly activated cytotoxic T-cells in patients with refractory ITP. Through deep T-cell receptor sequencing, the researchers confirmed that the T-cell diversity in these patients was significantly reduced due to the abnormal expansion of specific T-cell clones, which “occupied” a large amount of immune space.

These expanded T-cell clones are closely related to disease activity: when the patient’s platelet count drops, these clones expand rapidly; when the condition improves, their numbers decrease accordingly. Gene expression profiling further revealed that these expanded clones have typical cytotoxic characteristics and are in a state of activated TCR signaling, indicating that they are actively attacking target cells and are directly involved in the pathological process of ITP. This series of findings provides a completely new pathological explanation for ITP, especially refractory ITP, suggesting that it may be a T-cell-driven disease. Interestingly, the research also preliminarily found that the TPO-RA drug Eltrombopag may exert an immunomodulatory function by inhibiting T-cell over-proliferation through its iron-chelating properties.

Expert Outlook: The Future of Personalized ITP Treatment Guided by Genomics

Synthesizing the evidence above, the heterogeneous nature of ITP is abundantly clear. Professor Cooper concluded by emphasizing that the future breakthrough lies in achieving personalized treatment. A study by her team performed genetic sequencing on 80 patients clinically diagnosed with ITP and found that as many as 10% carried definitive pathogenic gene variants. This means their “ITP” was actually a misdiagnosis for other conditions such as hereditary thrombocytopenia or B-cell dysregulation disorders.

This finding opens the door to precision diagnosis and treatment for ITP. Professor Cooper envisions a future where, through multi-omics technologies like single-cell sequencing, clinicians can identify the core pathogenic pathway for each patient before treatment—whether it is B-cell driven, T-cell driven, or due to macrophage dysfunction. This would allow them to “tailor” the most appropriate targeted drug, avoiding wasted time on ineffective treatment plans.

In summary, Professor Nicola Cooper’s presentation systematically demonstrated the deepening of ITP research from macroscopic clinical phenomena to microscopic cellular and molecular mechanisms. This not only provides key clues for deciphering the complexity of ITP but also points the way for developing safer and more effective T-cell targeted therapies and providing comprehensive psychological support. In the spirit of collaboration and innovation promoted by the EHA Annual Meeting, the in-depth exploration of ITP’s pathobiology is guiding the treatment of this ancient disease into a new era of greater precision and humanization.