Molecular Studies of Hemolytic Thrombosis
溶血性血栓形成的分子研究
基本信息
- 批准号:10874054
- 负责人:
- 金额:$ 6.87万
- 依托单位:
- 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:2021-06-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAdsorptionAntibodiesAnticoagulationAvidityBindingBiochemicalBloodBlood PlateletsCirculationCoagulation ProcessComplexComplicationCryoelectron MicroscopyDevelopmentDevicesEnvironmentExposure toExtracorporeal Membrane OxygenationFibrinFibrinogenFibrinolytic AgentsFormalinFoundationsGlycoproteinsHemoglobinHemoglobin AHemoglobin concentration resultHemolysisHemolysis InductionHemorrhageHemostatic AgentsHemostatic functionInterventionInvestigationMeasuresMediatingMolecularMolecular ConformationMonitorMusOrganOutcomePathologyPatientsPlasmaProcessProteinsPublishingReactionRecombinant ProteinsReportingRiskRisk FactorsRoleSurfaceTestingTherapeuticTherapeutic InterventionThrombosisThrombusVariantVisualizationWhole BloodWorkage groupenhancing factormechanical circulatory supportmortalitynovel therapeutic interventionshear stresssurface coatingtargeted agenttargeted treatmentthromboticthrombotic complicationsventricular assist devicevon Willebrand Diseasevon Willebrand Factorvon Willebrand factor receptor
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
支持是血栓形成和出血的两种病理。血管内
与MCSD相关的溶血可产生游离血红蛋白(FHb)。吸附剂的吸附
纤维蛋白原和血管性血友病因子(VWF)在非生物表面捕获
可能聚集的血小板。我们报告说,高水平的FHb会增加VWF-
介导的血小板黏附和血栓在纤维蛋白涂层表面的形成
高剪应力。重要的是,FHB增加了福尔马林的流动依赖性黏附
将血小板固定在VWF涂层表面,表明FHb直接增强VWF-
糖蛋白(GP)Ib相互作用。血管性血友病因子缺乏或抗GPIB抗体阻断
FHB增强血小板粘附性,验证VWF的作用。最后,我们的
FHB和高切暴露全血中超大VWF的鉴定
RATES提示,血小板来源的ULVWF可能参与血栓形成的病理过程
在高水平的FHB存在的情况下。总而言之,这些发现提供了第一个证据
高水平的FHb对VWF介导的表面血栓形成至关重要
纤维蛋白(原)和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。我们最重要的是
假设FHB靶向VWF,包括血小板衍生的VWF,以促进
通过GPIB黏附血小板,并通过促进结合促进纤维蛋白的形成
VWF转化为纤维蛋白原。我们建议进行分子、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。目的1将研究血小板VWF与VWF的关系。
血浆VWF与血栓形成的关系。我们将检验FHb与血小板相互作用的假说
VWF增强血小板与纤维蛋白原的粘附性,进一步促进纤维蛋白的形成
比等离子体VWF更强劲。目标2将检验与FHb结合的VWF具有
有利于血小板黏附的构象。目标3将决定通过什么机制
FHB失调VWF-纤维蛋白(原)相互作用。我们将检验FHB的假设
促进VWF-纤维蛋白原结合并调节VWF介导的纤维蛋白
队形。这些研究将描述与患者血栓形成相关的新机制。
关于MCSD和寻找新的潜在靶点治疗FHB诱导的
血栓形成。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
High levels of von Willebrand factor with reduced specific activities in hospitalized patients with or without COVID-19.
- DOI:10.1007/s11239-022-02679-5
- 发表时间:2022-08
- 期刊:
- 影响因子:4
- 作者:Bray, Monica;Guzel, Melda A.;Lam, Fong;Yee, Andrew;Cruz, Miguel A.;Rumbaut, Rolando E.
- 通讯作者:Rumbaut, Rolando E.
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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:
$ 6.87万 - 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:
$ 6.87万 - 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:
$ 6.87万 - 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:
$ 6.87万 - 项目类别:
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