Platelet FcGammaRIIa and Risk of Venous Thromboembolism in Cancer

血小板 FcGammaRIIa 与癌症中静脉血栓栓塞的风险

• 批准号: 10351077
• 负责人: Chris Elaine Holmes
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351077
• 关键词: Acute; Affinity; Agonist; Ambulatory Care; Biological Markers; Blood Platelets; Cancer Center; Cancer Patient; Case Fatality Rates; Cause of Death; Cessation of life; Clinic; Clinical; Clinical Research; Collaborations; Consensus; Data; Enrollment; Event; Fc Receptor; Goals; Growth; Guidelines; Hemorrhage; Immunoglobulin Fragments; Immunoglobulin G; Incidence; Link; Malignant Neoplasms; Mediator of activation protein; Methods; Morbidity - disease rate; Myocardial Infarction; Neoplasm Metastasis; Outcome; Outpatients; Participant; Pathogenesis; Patient Care; Patients; Pilot Projects; Platelet Activation; Prevention; Principal Investigator; Prophylactic treatment; Prospective cohort study; Recurrence; Research; Risk; Sampling; Stroke; Surface; Thromboembolism; Thrombosis; Time; Tumor Cell Invasion; Universities; Vascularization; Vermont; cancer risk; clinical risk; experience; high risk; improved; improved outcome; mortality; neoplastic cell; novel; novel marker; platelet function; programs; skills; success; therapy design; therapy outcome; thrombotic; thrombotic complications; tool; tumor; tumor growth; tumor progression; venous thromboembolism

Thrombosis is common and contributes significantly to morbidity and mortality in patients with cancer. At least 20% of patients with cancer develop venous thromboembolism (VTE) and another 5% will experience acute arterial thromboembolism (ATE) due to cancer and its treatment. Current guidelines recommend VTE thromboprophylaxis in high-risk outpatients. Thromboprophylaxis strategies are inadequate as 50% of high- risk patients on prophylaxis still develop a VTE, the rate of recurrent VTE is ~24% with a case fatality rate of 14.8%, and the incidence of major bleeding is ~13% with a case fatality rate of 8.9%. We and others have implicated platelets in both the pathogenesis of VTE as well as cancer growth and metastasis. To investigate a new biomarker of risk in patients with cancer, we propose a pilot study to determine whether quantification of platelet FcɣRIIa expression can discriminate risk of VTE and cancer progression. We chose platelet FcɣRIIa expression because we have found that quantifying platelet surface expression of FcγRIIa identifies patients at high and low risk of thrombotic arterial events. Thus, we hypothesize that elevated platelet expression of FcγRIIa will identify patients with cancer who are greater risk of VTE as well as cancer progression. The proposed studies leverage a clinical research program that was established in 2015 at the University of Vermont Cancer Center (Venous Thromboembolism Prevention in the Ambulatory Care Clinic [VTEPACC]) and will allow simultaneous access to research samples, thrombosis complications and cancer outcomes in order to achieve the following specific aims: 1) To determine whether platelet expression of FcγRIIa identifies cancer patients at high and low risk of VTE, and 2) To determine whether increased platelet expression of FcγRIIa is associated with a) advanced stage cancer at the time of enrollment and b) greater progression of cancer. Platelet reactivity is increased in patients with cancer and has been associated with VTE risk. Platelet expression of FcγRIIa can increase the risk of thrombosis by both increasing platelet reactivity and by promoting the procoagulant potential of platelets. In addition, platelets promote cancer by facilitating tumor vascularization, growth, and metastasis. FcγRIIa has been shown to be a key mediator of platelet secretion and cross-talk between platelets and tumor cells. Thus, we propose that increased platelet FcγRIIa expression will be linked to enhanced tumor growth and metastasis by facilitating cancer-tumor cell cross-talk and thereby the activation of platelets that leads to the release of platelet products. Identification of a biomarker capable of discriminating high and low risk of VTE will provide an important precision tool that could be combined with existing tools to guide therapy and improve outcomes. Results from aim 2 will provide key preliminary data in support of novel antiplatelet treatments to limit cancer progression.

血栓形成是常见的，并且显著地导致癌症患者的发病率和死亡率。至少 20%的癌症患者会发生静脉血栓栓塞（VTE），另外5%的患者会发生急性血栓栓塞。 动脉血栓栓塞（ATE）由于癌症和治疗。当前指南建议VTE 高危门诊患者的血栓预防。血栓预防策略是不够的，因为50%的高- 预防性治疗的风险患者仍发生VTE，复发率约为24%，病死率为 大出血的发生率约为13%，病死率为8.9%。我们和其他人已经 血小板与静脉血栓栓塞的发病机制以及癌症的生长和转移有关。调查一个 癌症患者风险的新生物标志物，我们提出了一项试点研究，以确定是否量化 血小板Fc γ RIIa表达可以区分VTE和癌症进展的风险。我们选择血小板Fc γ RIIa 表达，因为我们发现定量血小板表面FcγRIIa表达可鉴定出 血栓性动脉事件的高风险和低风险。因此，我们假设，血小板表达升高， FcγRIIa将识别出VTE和癌症进展风险更高的癌症患者。的 拟议的研究利用了2015年在纽约大学建立的临床研究项目， 佛蒙特州癌症中心（门诊护理诊所静脉血栓栓塞预防[VTEPACC]） 并将允许同时访问研究样本，血栓并发症和癌症结果， 为了达到以下具体目的：1）确定血小板表达FcγRIIa是否鉴定 在VTE的高风险和低风险的癌症患者中，和2）为了确定血小板表达增加是否与血小板聚集有关， FcγRIIa与a）入组时的晚期癌症和B） 癌癌症患者的血小板反应性增加，并与VTE风险相关。血小板 FcγRIIa的表达可以通过增加血小板反应性和增加血栓形成的风险， 促进血小板的促凝血潜能。此外，血小板通过促进肿瘤的发生而促进癌症的发生。 血管形成、生长和转移。已证明FcγRIIa是血小板分泌的关键介质 以及血小板和肿瘤细胞之间的相互作用。因此，我们认为血小板FcγRIIa表达增加 将通过促进癌症-肿瘤细胞的相互作用而与增强的肿瘤生长和转移相关联， 血小板的活化导致血小板产物的释放。鉴定能够 区分VTE的高风险和低风险将提供一个重要的精确工具， 现有的工具来指导治疗和改善结果。目标2的结果将提供关键的初步数据， 支持新型抗血小板治疗以限制癌症进展。