Leveraging platelet contraction cytometry for immune thrombocytopenia

利用血小板收缩细胞术治疗免疫性血小板减少症

基本信息

批准号：
10327638
负责人：
David Richard Myers
金额：
$ 38.55万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327638
关键词：
Actins Adult Affect Basic Science Biological Assay Biological Markers Blood Coagulation Disorders Blood Platelets Cells Characteristics Child Clinical Clinical Data Cytometry Data Development Diagnostic Disease remission Enrollment Exposure to Fractionation Genetic Transcription Goals Hematology Hemorrhage Immature Platelet Immune Immunoglobulin G Immunologic Markers Impairment Incubated Individual Intracranial Hemorrhages Investigation Lead Life Life Experience Longitudinal Studies Measures Monitor Morphology Myosin ATPase Nature Outcome Outcome Study PAC1 phosphatase Patient Care Patient risk Patients Phenotype Physicians Plasma Platelet Activation Platelet Count measurement Platelet Function Tests Platelet Transfusion Platelet aggregation Process Proteomics Publishing Quality of Care Research Resolution Risk Sampling Series Specificity Structure Symptoms Techniques Testing Thrombelastography Thrombocytopenia Thrombocytopenic Purpura Time Treatment Side Effects Validation Visit Work base clinical practice cohort demographics diagnostic tool droplet sequencing experience high risk improved insight novel pediatric patients platelet function prospective side effect tool unnecessary treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Defined by 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. There is no biomarker for ITP or much less, bleeding risk, and all treatments involve 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 newly developed high-throughput platelet contraction cytometer (PCC) to measure single platelet contractile forces in parallel, 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 (n=49 patients) and 3) change over time in the same patient (n=7). Using an average force cutoff value of 26nN, we found that low forces identified bleeding in ITP with 100% sensitivity and 89.4% specificity, with a specificity improvement to 94% when only considering patients with a platelet count <40,000 uL. Aim 1 builds on this preliminary data and proposes a rigorous investigation into the relationship between contractile force, platelet characteristics, clinical characteristics, and outcomes by studying a cohort of newly enrolled ITP patients (n=100) 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, treatments, and time to resolution. 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 IgG correlates with more severe bleeding and lower contractile forces, and furthermore that incubating platelets in non-autologous plasma leads to lower contractile forces. From an intrinsic perspective, we have found that patients with low mean platelet volume have lower platelet force and increased bleeding. As the mechanistic underpinnings are unclear, Aim 2 seeks to perform systemic, unbiased investigation into both the intrinsic and extrinsic factors that may modulate platelet function.

项目摘要/摘要在没有任何其他原因的情况下，由低血小板计数定义，免疫血小板减少紫癜（ITP）每年影响4,000多名美国儿童和8,000名成年人。而大多数ITP案例解决 ITP患者本身的出血风险增加，有10％的患者出血，并且 0.5％的经历威胁生命的颅内出血。 ITP没有生物标志物或更少的生物标志物，出血风险，所有治疗均涉及重大副作用。这给临床医生留下了重大的决定是否治疗时的困境。最终处于高风险的患者可能无法接受治疗直到发生严重出血之前，低风险患者可能会暴露于不必要的治疗副作用。该提议的研究目的是研究一个新的假设，即单个血小板与ITP中的出血表型相关，与传统使用的生物学无关标记或血液学功能的测定。使用新开发的高通量血小板收缩细胞仪（PCC）并行测量单个血小板收缩力，这是我们研究的最新结果原发性ITP的儿科患者表明血小板力1）与健康对照组有显着差异， 2）与出血（n = 49例）和3）在同一患者中随时间变化（n = 7）密切相关。使用一个平均力截止值为26nn，我们发现低力在ITP中识别出100％灵敏度的出血和89.4％的特异性，特异性提高到94％，仅考虑血小板患者计数<40,000 ul。 AIM 1建立在此初步数据的基础上，并提出了对该数据的严格调查收缩力，血小板特征，临床特征和结果之间的关系在一个时间点研究一组新入学的ITP患者（n = 100），并前瞻性12个月。我们将明确查看血小板收缩力是否与出血得分相关，未成熟的血小板分数，血小板激活，血小板形态，患者人口统计学，治疗和分辨时间。 PCC还提供了一个独特的机会，可以从患者的患者中获得有关血小板功能的新见解。低力的ITP和机械基础。以前的研究被阻碍为血小板的传统工具诸如聚集，血小板功能分析仪或血栓射击之类的功能被混淆 ITP中的低血小板计数。我们将使用PCC测试我们的假设，即固有血小板都会改变和外部等离子体因子修饰血小板收缩力。从外部的角度来看，我们的数据已显示 IgG与更严重的出血和较低的收缩力相关，此外还可以孵化非自动血浆中的血小板导致较低的收缩力。从内在的角度来看，我们有发现平均血小板体积低的患者的血小板力较低，出血增加。作为机械基础尚不清楚，AIM 2试图对两者进行系统性，无偏见的研究可能调节血小板功能的固有和外在因素。