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（参见说明）： 尽管因子水平相似（<正常活动的 1%），但严重血友病患者的临床表型差异很大。即使在具有相同致病基因突变和因子水平的个体中，关节出血频率、关节出血发病年龄以及因子 VIII (fVIII) 的需求也存在显着差异。导致患者出现这些不同出血模式的生物学决定因素 严重的血友病很大程度上是未知的。这种知识的缺乏极大地妨碍了临床医生对严重血友病患者进行个体化治疗决策的能力。开发一种区分严重血友病患者轻度和重度临床表型的方法将具有多种临床益处。示例 包括调整预防性治疗的开始或停止的可能性 对出血风险进行个体化评估，并确定最有可能从实验疗法中受益的患者亚组。提出的新概念和检测方法将允许根据出血风险对严重甲型血友病患者进行分层。中心假设是血小板表型导致 A 型血友病患者的出血表型，并且止血检测 结合血小板功能将能够前瞻性地确定严重甲型血友病患者的出血表型。提出了两种互补的研究途径；第一个侧重于血小板促凝血活性和血小板-fVIII 相互作用的调节，第二个侧重于评估 动态流体环境中止血塞形成的研究。目标 1 将检验以下假设：血小板促凝血活性的个体差异导致严重甲型血友病患者观察到的出血表型变异，并研究调节促凝血蛋白与活化血小板结合的机制。目标 2 将检验以下假设：出血表型的差异可以通过 通过评估新型内皮化微流体模型中的止血潜力来前瞻性地鉴定。 一系列系统的实验研究了血小板表型和凝血因子浓度的变化对这个新系统中 PRP 和全血中止血栓形成的影响。