ADAMTS13 and Late Neurologic Morbidity after Thrombotic Thrombocytopenic Purpura

ADAMTS13 和血栓性血小板减少性紫癜后的晚期神经系统发病率

基本信息

批准号：
9883453
负责人：
Shruti Chaturvedi
金额：
$ 21.33万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883453
关键词：
Acute Adult African American Age Animals Anticoagulation Autoimmune Diseases Autoimmune Process Award Binding Biological Biological Markers Blood Platelets Blood specimen Brain Cerebral Infarction Cerebrovascular Disorders Cerebrum Cleaved cell Clinical Clinical Data Cognitive Cohort Studies Collaborations Coupled Data Development Diabetes Mellitus Disease Disease remission Dose Enrollment Epidemiology Evaluation Event Factor VIII-Related Antigen Funding Future General Population Genes Goals Health Hematological Disease Hematology Hospitals Hypertension Immune Impaired cognition Incidence Individual Infarction Intervention Studies Lesion Life Longterm Follow-up Magnetic Resonance Imaging Mentors Morbidity - disease rate Neurocognitive Neurocognitive Deficit Neurologic Neurologic Examination Neurologic Symptoms Non-Malignant Obesity Outcome Patient Outcomes Assessments Patients Peptide Hydrolases Pilot Projects Plasma Exchange Population Population Control Preparation Prevalence Prospective cohort Publishing Rare Diseases Recovery Registries Relapse Research Research Personnel Risk Factors Role Smoking Specimen Stroke Survivors Testing Thrombosis Thrombotic Thrombocytopenic Purpura Thrombus Time Training United States National Institutes of Health Variant Woman cardiovascular risk factor cerebrovascular clinical risk cohort experience gene complementation genetic epidemiology genetic risk factor genetic variant high risk improved investigator training ischemic lesion modifiable risk mortality neurocognitive test neurovascular organ injury post stroke pre-clinical prospective rare variant sex skills stroke incidence stroke risk von Willebrand Factor

项目摘要

PROJECT SUMMARY/ABSTRACT Acquired autoimmune thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder characterized by acute episodes of systemic microvascular thrombosis caused by deficiency of ADAMTS13, a von Willebrand factor cleaving protease. TTP is more common in women and African Americans. Plasma exchange has improved survival of acute TTP from <10% to 80-90%; however, long-term adverse health outcomes in adults following recovery from TTP are under recognized. Recent data indicate that TTP survivors have higher mortality than age and sex matched controls and over 60% of TTP survivors demonstrate neurocognitive impairment. In a cohort of 157 TTP survivors at Johns Hopkins Hospital, we found a high rate of incident stroke unrelated to an acute TTP relapse during long-term follow up.Intriguingly, over 50% of TTP survivors did not recover ADAMTS13 activity in remission and low ADAMTS13 activity in remission was associated with a higher risk of stroke. Silent cerebral infarcts are ischemic lesions seen on MRI in patients without neurologic symptoms, which are associated with future stroke and cognitive impairment in the general population. Currently, there are no published studies evaluating the prevalence of silent infarcts in TTP survivors, and their association with future stroke and cognitive impairment. The association of ADAMTS13 in remission with ischemic cerebral events (silent infarct and stroke) is also unknown. Dr. Chaturvedi has established a large prospective cohort of patients with TTP, generated compelling preliminary data regarding the risk of stroke in TTP survivors, and established collaborations throughout Johns Hopkins Hospital to answer these questions. We will use the existing Johns Hopkins Thrombotic Microangiopathy Registry to test the hypothesis that silent cerebral infarcts more common in TTP survivors than an age and sex-matched control population, and are a risk factor for stroke and cognitive impairment (Aim 1). We will evaluate whether low ADAMTS13 activity during TTP remission is associated with cerebral ischemic events (silent infarcts and stroke) (Aim 2). Finally, we will evaluate the association of traditional cardiovascular risk factors and germline variants in ADAMTS13 and complement genes with silent infarcts and stroke (Aim 3). Understanding the epidemiology and risk factors for cerebrovascular and cognitive sequelae of TTP will lead to a pilot study of an intervention (low dose anticoagulation or antiplatelet therapy) to reduce the incidence of silent cerebral infarcts and stroke in high-risk TTP patients and has implications for understanding the role of ADAMTS13 in cerebrovascular disease in other populations. Dr. Chaturvedi's mentors, Dr. Robert Brodsky and Dr. Michael DeBaun, have extensive expertise in thrombotic microangiopathies, rare disease research, and evaluation of cerebrovascular disease. Her additional training proposed will enable her to transition to an independent NIH-funded investigator training and experience in cohort studies in rare disease, genetic epidemiology, and cerebrovascular disease research in hematology.

项目摘要/摘要获得的自身免疫性血栓性血小板减少紫癜（TTP）是一种罕见的，威胁生命的疾病特征是由ADAMTS13缺乏引起的全身微血管血栓形成急性发作 von Willebrand因子切割蛋白酶。 TTP在妇女和非裔美国人中更为普遍。等离子体急性TTP的生存率从<10％提高到80-90％；但是，长期不良健康从TTP恢复后，成年人的结果已得到认可。最近的数据表明TTP幸存者具有高于年龄和性匹配的对照的死亡率高，超过60％的TTP幸存者证明神经认知障碍。在约翰·霍普金斯医院的157个TTP幸存者队列中，我们发现长期随访期间与急性TTP复发无关的事件中风。幸存者在缓解中没有恢复ADAMTS13活性，而ADAMTS13的缓解活性较低为与较高的中风风险相关。无声的脑梗塞是患者MRI的缺血性病变没有神经系统症状，这与一般中的中风和认知障碍有关人口。目前，尚无公开的研究评估TTP中无声梗塞的流行幸存者，以及他们与未来中风和认知障碍的联系。 Adamts13协会脑缺血性脑事件（无声梗塞和中风）的缓解也未知。 Chaturvedi博士已经建立了大量的TTP患者，产生了引人注目有关TTP幸存者中风风险的初步数据，并在Johns建立了合作霍普金斯医院回答这些问题。我们将使用现有的约翰·霍普金斯（John Hopkins）血栓形成微血管病注册表以检验以下假设：静音脑梗塞在TTP幸存者中更为常见比年龄和性别匹配的对照人群，是中风和认知障碍的危险因素（目标 1）。我们将评估TTP缓解期间低的ADAMTS13活性是否与脑有关缺血事件（无声梗塞和中风）（目标2）。最后，我们将评估传统的协会 ADAMTS13中的心血管危险因素和种系变异，并与无声梗塞相辅相成中风（目标3）。了解脑血管和认知后遗症的流行病学和危险因素 TTP将导致对干预措施（低剂量抗凝或抗血小板疗法）的试点研究，以减少高危TTP患者中无声脑梗塞和中风的发生率，对理解有影响 ADAMTS13在其他人群中脑血管疾病中的作用。 Chaturvedi博士的导师Robert博士 Brodsky和Michael Debaun博士，在血栓形成微型病毒，罕见病中拥有广泛的专业知识研究和评估脑血管疾病。她提出的其他培训将使她能够过渡到独立的NIH资助的研究者培训和在稀有疾病研究中的经验，遗传流行病学和血液学脑血管疾病研究。