Novel Assays Predicting Phenotypic Heterogeneity in Severe Hemophilia

预测严重血友病表型异质性的新方法

• 批准号: 8464235
• 负责人: John S. Lollar
• 金额: $ 49.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464235
• 关键词: Age; Age of Onset; Anticoagulants; Binding; Biochemistry; Biological; Biological Assay; Biomedical Engineering; Blood Coagulation Factor; Blood Platelets; Charge; Child; Clinical; Clinical Research; Coagulation Process; Data Collection; Defect; Development; Endothelium; Environment; Frequencies; Gene Mutation; Generations; Healthcare; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Heterogeneity; In Vitro; Individual; Individual Differences; Instruction; Investigation; Investigational Therapies; Joints; Knowledge; Liquid substance; Methods; Microfluidics; Modeling; Morbidity - disease rate; Multienzyme Complexes; Pathway interactions; Patients; Pattern; Phenotype; Phospholipids; Platelet Activation; Process; Proteins; Regulation; Replacement Therapy; Risk; Sample Size; Series; Stratification; Subgroup; Surface; System; Testing; Thrombin; Time; Translational Research; Universities; Variant; Whole Blood; base; clinical phenotype; cohort; cost; experience; insight; mutant; novel; prophylactic; prospective; receptor; research study; tool; treatment center

PROJECT SUMMARY (See instructions): The clinical phenotype of patients with severe hemophilia varies widely despite similarly low factor levels (<1% of normal activity). Even in individuals with the same causative genetic mutation and factor levels, there are significant differences in joint bleed frequencies, age of onset of joint bleeding, and requirements for factor Vlll (fVIII). The biological determinants that drive these different bleeding patterns in patients with severe hemophilia are largely unknown. This lack of knowledge considerably hampers the clinician's ability to individualize treatment decisions In patients with severe hemophilia. Development of a method that distinguished severe hemophilia patients with mild and severe clinical phenotypes would have multiple clinical benefits. Examples Include the potential to adjust the start or cessation of prophylactic therapy based on an individualized assessment of bleeding risk, and the identification of patient subgroups that would be most likely to benefit from experimental therapies. Novel concepts and assays are proposed that will allow the stratification of severe hemophilia A patients according to bleeding risk. The central hypothesis is that platelet phenotype contributes to bleeding phenotype in patients with hemophilia A, and hemostatic assays that incorporate platelet function will allow prospective determination of bleeding phenotype in patients with severe hemophilia A. Two complementary pathways of investigation are proposed; the first focused on platelet procoagulant activity and the regulation of platelet-fVIII interactions, the second on the assessment of hemostatic plug formation in a dynamic fluid environment. Aim 1 will test the hypothesis that individual differences in platelet procoagulant activity contribute to the variability in bleeding phenotype observed in patients with severe hemophilia A and investigate the mechanisms regulating the binding of procoagulant proteins to activated platelets. Aim 2 will test the hypothesis that differences in bleeding phenotype can be prospectively identified by assessment of hemostatic potential in a novel endothelialized microfluidics model. A systematic series of experiments examine the impact of variations in platelet phenotype and coagulation factor concentrations on hemostatic plug formation In PRP and whole blood in this novel system.

项目摘要（请参阅说明）： 尽管因子水平相似（占正常活性的1％），但患有严重血友病患者的临床表型也有很大变化。即使在具有相同因果关系突变和因子水平的个体中，关节出血频率，关节出血年龄以及因子VLLL（FVIII）的要求也存在显着差异。在患者中驱动这些不同出血模式的生物决定因素 严重的血友病在很大程度上是未知的。这种知识的缺乏极大地阻碍了临床医生在严重血友病患者中个性化治疗决策的能力。开发一种方法，即具有轻度和严重临床表型的严重血友病患者将具有多种临床益处。例子包括调整基于预防治疗的开始或停止的潜力 在对出血风险的个性化评估中，以及最有可能受益于实验疗法的患者亚组的鉴定。提出了新的概念和测定法，该测定将允许根据出血风险对严重的血友病患者分层。中心假设是血小板表型有助于血友病患者的出血表型和止血测定 纳入血小板功能将允许在严重的血友病患者中前瞻性测定出血表型。提出了两种互补的研究途径。第一个侧重于血小板凝聚活性和血小板-FVIII相互作用的调节，第二个是评估 在动态流体环境中止血塞形成的形成。 AIM 1将检验以下假设：血小板突发性活性的个体差异有助于严重血友病患者观察到的出血表型的可变性，并研究了调节procagulant蛋白与活化型血浆结合的机制。 AIM 2将检验以下假设：出血表型的差异可能是 在新型的内皮化微流体模型中，通过评估止血潜力的预测鉴定。 一系列系统的实验研究了该新型系统中PRP和全血的血小板表型和凝结因子浓度对止血塞形成的变化的影响。