Novel insights on immune thrombocytopenia purpura with platelet contraction cytometry

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PROJECT SUMMARY/ABSTRACT Defined by a low platelet count in the absence of any other cause, immune thrombocytopenic purpura (ITP) affects over 4,000 US children and 8,000 adults each year. While the majority of ITP cases resolve themselves, patients with ITP have an enhanced risk of bleeding, with 10% experiencing major bleeding, and 0.5% of experiencing life-threatening intracranial hemorrhage. Currently, there is no accurate biomarker or diagnostic test that assesses the bleeding risk in ITP and all therapies potentially cause significant side effects. This leaves clinicians with a significant dilemma in deciding whether or not to treat. Patients who are ultimately at high risk may not receive treatment until serious bleeding occurs, and low risk patients may be exposed to unnecessary treatment side effects. The research objective of this proposal is to investigate a novel hypothesis, namely, that the contractile force of individual platelets correlates with bleeding phenotype in ITP, independent of traditionally used biological markers or assays of hematological function. Using a technique developed by our lab, a high-throughput platelet contraction cytometer (PCC), to measure platelet contractile forces at the single cell level, our latest results of a study of pediatric patients with primary ITP suggests that platelet forces 1) vary significantly from healthy controls, 2) strongly correlate with bleeding and 3) change over time in the same patient. Aim 1 builds on this preliminary data and proposes a rigorous investigation into the relationship between contractile force, platelet characteristics, and clinical endpoints by studying a cohort of newly enrolled ITP patients at a single time point and prospectively for 12 months. We will specifically see if platelet contractile force correlates with bleeding score, immature platelet fraction, platelet activation, platelet morphology, patient demographics, and treatments. The PCC also offers a unique opportunity to gain new insights into the function of platelets from patients with ITP and mechanistic underpinnings of low force. Previous studies were hindered as traditional tools of platelet function such as aggregometry, platelet functional analyzers, or thromboelastography are confounded by the low platelet count in ITP. We will use the PCC to test our hypothesis that both intrinsic platelet changes and extrinsic plasma factors modify platelet contractile force. From an extrinsic perspective, our data has shown that the presence of anti-platelet IgG antibodies correlates with more severe bleeding and lower contractile forces. From an intrinsic perspective, we have found that patients with low mean platelet volume have lower platelet force and increased bleeding symptoms. As the mechanistic underpinnings are unclear, Aim 2 seeks to perform systematic, unbiased investigation into both the intrinsic and extrinsic factors that may modulate platelet function. This F31-diversity predoctoral training grant will allow me to push forward and satisfy my learning and career objectives, while simultaneously enhancing my training in diverse technical, computational and medical topics, that will only contribute to my development as a physician scientist devoted to Hematology in both medicine and research as I plan to pursue a career in academic medicine.