Molecular Studies of Hemolytic Thrombosis
溶血性血栓形成的分子研究
基本信息
- 批准号:10685734
- 负责人:
- 金额:$ 3.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAdsorptionAntibodiesBindingBiochemicalBlood PlateletsCirculationComplicationDevelopmentDevicesExposure toFibrinFibrinogenFibrinolytic AgentsFormalinFoundationsGlycoproteinsHemoglobinHemoglobin concentration resultHemolysisHemorrhageMediatingMolecularMolecular ConformationOrganPathologyPatientsPlasmaReportingRoleSurfaceTestingTherapeutic InterventionThrombosisThrombusWhole BloodWorkenhancing factormechanical circulatory supportshear stresssurface coatingtargeted agenttargeted treatmentvon Willebrand Diseasevon Willebrand Factor
项目摘要
A major complication of mechanical circulatory support devices (MCSD) for multi-organ
support is the dichotomous pathology of thrombosis and bleeding. Intravascular
hemolysis associated with MCSD produces free hemoglobin (fHb). Adsorption of
fibrinogen and von Willebrand factor (VWF) onto non-biological surfaces captures
platelets that may aggregate. We reported that high levels of fHb increased VWF-
mediated platelet adhesion and thrombus formation on fibrin(ogen)-coated surfaces at
high shear stress. Importantly, fHb increased the flow-dependent adhesion of formalin
fixed platelets to a VWF coated surface, suggesting that fHb directly enhances the VWF-
glycoprotein (GP)Ib interaction. VWF deficiency or antibodies against GPIb block the
enhancement of platelet adhesion by fHb, validating the role of VWF. Lastly, our
identification of ultra large VWF (ULVWF) in whole blood exposed to fHb and high shear
rates suggests that platelet derived ULVWF may contribute to the pathology of thrombosis
in the presence of high levels of fHb. Together, these findings provide the first evidence
that high levels of fHb are critical for VWF-mediated thrombosis on surfaces coated with
fibrin(ogen), and that ULVWF multimers from shear-activated platelets may enhance
thrombosis more robustly than plasma VWF in the presence of fHb. Our overarching
hypothesis is that fHb targets VWF, including the platelet-derived VWF, to promote
platelet adhesion via GPIb, and potentiate fibrin formation by facilitating the binding of
VWF to fibrinogen. We propose molecular, biochemical, and structural studies to
investigate the mechanisms by which fHb dysregulates the interactions between VWF,
fibrin(ogen), and platelets. Aim 1 will investigate the contributions of platelet VWF vs.
plasma VWF to thrombosis. We will test the hypotheses that fHb interaction with platelet
VWF enhances platelet adhesion to fibrin(ogen) and potentiates fibrin formation more
robustly than plasma VWF. Aim 2 will test the hypothesis that fHb-bound VWF has a
conformation that favors platelet adhesion. Aim 3 will determine the mechanism by which
fHb dysregulate VWF-fibrin(ogen) interaction. We will test the hypotheses that fHb
promotes VWF-fibrin(ogen) association and modulates the VWF-mediated fibrin
formation. These studies will describe new mechanisms related to thrombosis in patients
on MCSD and identify new, potential targets for therapeutic interventions in fHb-induced
thrombosis.
多器官机械循环支持装置(MCSD)的主要并发症
支持的是血栓和出血的二分病理学。血管内
与 MCSD 相关的溶血会产生游离血红蛋白 (fHb)。吸附
将纤维蛋白原和血管性血友病因子 (VWF) 捕获到非生物表面
可能聚集的血小板。我们报道高水平的 fHb 会增加 VWF-
介导血小板粘附和纤维蛋白(原)涂层表面上的血栓形成
高剪切应力。重要的是,fHb 增加了福尔马林的流动依赖性粘附
将血小板固定到 VWF 涂层表面,表明 fHb 直接增强 VWF-
糖蛋白 (GP)Ib 相互作用。 VWF 缺乏或 GPIb 抗体会阻断
fHb 增强血小板粘附,验证 VWF 的作用。最后,我们的
暴露于 fHb 和高剪切的全血中超大 VWF (ULVWF) 的鉴定
率表明血小板衍生的 ULVWF 可能导致血栓形成的病理学
在存在高水平 fHb 的情况下。这些发现共同提供了第一个证据
高水平的 fHb 对于 VWF 介导的表面血栓形成至关重要
纤维蛋白(原),并且来自剪切激活血小板的 ULVWF 多聚体可能增强
在 fHb 存在的情况下,血栓形成比血浆 VWF 更强烈。我们的首要任务
假设是 fHb 靶向 VWF,包括血小板衍生的 VWF,以促进
通过 GPIb 促进血小板粘附,并通过促进结合来增强纤维蛋白形成
VWF 转为纤维蛋白原。我们提出分子、生物化学和结构研究
研究 fHb 失调 VWF 之间相互作用的机制,
纤维蛋白(原)和血小板。目标 1 将研究血小板 VWF 与血小板 VWF 的贡献。
血浆VWF导致血栓形成。我们将检验 fHb 与血小板相互作用的假设
VWF 增强血小板对纤维蛋白(原)的粘附并增强纤维蛋白形成
比等离子 VWF 更稳定。目标 2 将检验以下假设:fHb 结合的 VWF 具有
有利于血小板粘附的构象。目标 3 将确定机制
fHb 失调 VWF-纤维蛋白(原)相互作用。我们将检验以下假设:fHb
促进 VWF-纤维蛋白(原)结合并调节 VWF 介导的纤维蛋白
形成。这些研究将描述与患者血栓形成相关的新机制
MCSD 并确定新的、潜在的治疗干预靶点
血栓形成。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Miguel Angel Cruz其他文献
Miguel Angel Cruz的其他文献
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{{ truncateString('Miguel Angel Cruz', 18)}}的其他基金
Collaborative Research Training in Thrombosis and Inflammation
血栓和炎症合作研究培训
- 批准号:
10451533 - 财政年份:2018
- 资助金额:
$ 3.03万 - 项目类别:
Collaborative Research Training in Thrombosis and Inflammation
血栓和炎症合作研究培训
- 批准号:
9750797 - 财政年份:2018
- 资助金额:
$ 3.03万 - 项目类别:
Collaborative Research Training in Thrombosis and Inflammation
血栓和炎症合作研究培训
- 批准号:
10219340 - 财政年份:2018
- 资助金额:
$ 3.03万 - 项目类别:
Collaborative Research Training in Thrombosis and Inflammation
血栓和炎症合作研究培训
- 批准号:
9983169 - 财政年份:2018
- 资助金额:
$ 3.03万 - 项目类别:
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