Novel insights on immune thrombocytopenia purpura with platelet contraction cytometry

血小板收缩细胞术对免疫性血小板减少性紫癜的新见解

• 批准号: 10677532
• 负责人: Oluwamayokun Oshinowo
• 金额: $ 5.18万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2026-08-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677532
• 关键词: Actins; Address; Adult; Adverse effects; Affect; Antibodies; Architecture; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Biomedical Research; Biophysics; Blood; Blood Coagulation Disorders; Blood Platelets; Cells; Characteristics; Child; Clinical; Clinical Data; Contusions; Cytometry; Data; Data Set; Development; Diagnosis; Diagnostic tests; Disease; Engineering; Enrollment; Exposure to; Fibrin; Flow Cytometry; Foundations; Goals; Grant; Hematological Disease; Hematology; Hemorrhage; Immature Platelet; Immune; Immune system; Immunofluorescence Immunologic; Immunoglobulin G; Impairment; Individual; Intracranial Hemorrhages; Intrinsic factor; Investigation; Lead; Learning; Life; Life Experience; Measurement; Measures; Medical; Medicine; Microfluidics; Monitor; Morphology; Myosin ATPase; Nature; PAC1 phosphatase; Patient Care; Patient risk; Patient-Focused Outcomes; Patients; Pediatric cohort; Phenotype; Physicians; Plasma; Platelet Activation; Platelet Count measurement; Platelet Function Tests; Purpura; RNA; Research; Resolution; Risk; Sampling; Scientist; Severities; Signal Pathway; Stains; Symptoms; System; Techniques; Technology; Testing; Thrombelastography; Thrombocytopenia; Thrombocytopenic Purpura; Time; Training; Treatment Side Effects; base; biophysical analysis; biophysical properties; career; clinical diagnostics; cohort; demographics; diagnostic biomarker; experience; high risk; improved; insight; medical attention; microdevice; novel; pediatric patients; platelet function; pre-doctoral; prospective; receptor; side effect; skills; thiazole orange; tool; treatment strategy; unnecessary treatment

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.

项目总结/摘要 免疫性血小板减少性紫癜是指在没有任何其他原因的情况下血小板计数降低， (ITP)每年影响超过4,000名美国儿童和8,000名成年人。虽然大多数ITP病例都能解决 ITP患者本身出血风险增加，10%的患者发生大出血， 0.5%发生危及生命的颅内出血。目前，没有准确的生物标志物或 评估ITP出血风险的诊断测试和所有治疗都可能导致显著的副作用。 这使得临床医生在决定是否治疗时陷入了一个重大的困境。 高风险患者可能在发生严重出血后才接受治疗，低风险患者可能暴露于 不必要的治疗副作用。本提案的研究目标是调查一个新的假设， 也就是说，单个血小板的收缩力与ITP的出血表型相关， 传统上使用的生物标记或血液功能测定。利用我们的科学家开发的技术， 实验室，高通量血小板收缩细胞仪（PCC），以测量血小板收缩力在单一的 在细胞水平上，我们对患有原发性ITP的儿科患者进行的最新研究结果表明，血小板的作用力1） 与健康对照组显著不同，2）与出血密切相关，3）随着时间的推移， 病人目标1建立在这些初步数据的基础上，并提出了一个严格的调查， 通过研究一个新入组的ITP队列，研究收缩力、血小板特征和临床终点 患者在单个时间点和前瞻性12个月。我们将特别观察血小板收缩力 与出血评分、未成熟血小板分数、血小板活化、血小板形态、患者 人口统计学和治疗。PCC还提供了一个独特的机会，以获得新的见解的职能 ITP患者的血小板和低力的机械基础。以前的研究受到阻碍 作为血小板功能的传统工具，如聚集测定法、血小板功能分析仪，或 血小板弹性描记术被ITP中的低血小板计数混淆。我们将使用PCC来检验我们的假设 内源性血小板变化和外源性血浆因子均能改变血小板收缩力。从一个外在的 从这个角度来看，我们的数据表明，抗血小板IgG抗体的存在与更严重的 出血和收缩力降低。从内在的角度来看，我们发现平均值低的患者 血小板体积降低，血小板力降低，出血症状增加。作为机械的基础， 目标2旨在对内在和外在因素进行系统的、无偏见的调查 可以调节血小板功能这个F31多样性博士前培训补助金将使我能够推动 满足我的学习和职业目标，同时加强我在各种技术， 计算和医学主题，这将只有助于我的发展，作为一个医生科学家致力于 我计划在医学和研究领域从事血液学研究，因为我计划从事学术医学职业。