ADAMTS13 and Late Neurologic Morbidity after Thrombotic Thrombocytopenic Purpura

项目总结/摘要 获得性自身免疫性血栓性血小板减少性紫癜（TTP）是一种罕见的，危及生命的疾病 其特征在于由ADAMTS 13缺乏引起的全身性微血管血栓形成的急性发作， 血管性血友病因子裂解蛋白酶。TTP在女性和非裔美国人中更常见。血浆 交换使急性TTP的存活率从<10%提高到80-90%;然而， 成人TTP恢复后的结局未得到充分认识。最近的数据表明TTP幸存者 死亡率高于年龄和性别匹配的对照组，超过60%的TTP幸存者表现出 神经认知障碍在约翰霍普金斯医院的157名TTP幸存者队列中，我们发现 在长期随访中，与急性TTP复发无关的卒中事件。有趣的是，超过50%的TTP 存活者在缓解期没有恢复ADAMTS 13活性，缓解期的低ADAMTS 13活性是 与中风的高风险相关。无症状性脑梗死是MRI上发现的缺血性病变， 没有神经系统症状，这些症状与未来的中风和认知障碍有关， 人口目前，尚无已发表的研究评估TTP中无症状性梗死的患病率 幸存者，以及他们与未来中风和认知障碍的关系。ADAMTS 13与 缺血性脑事件（无症状梗塞和中风）的缓解也是未知的。 Chaturvedi博士已经建立了一个大型的TTP患者前瞻性队列， 关于TTP幸存者中风风险的初步数据，并在约翰 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血栓 微血管病登记研究旨在检验无症状性脑梗死在TTP幸存者中更常见的假设 与年龄和性别匹配的对照人群相比，是中风和认知障碍的危险因素（Aim 1）。我们将评估TTP缓解期ADAMTS 13活性降低是否与脑梗死相关。 缺血性事件（无症状性梗死和卒中）（目的2）。最后，我们将评估传统的 心血管危险因素和ADAMTS 13和补体基因的种系变异与无症状性梗死， 中风（目标3）。了解脑血管病和认知后遗症的流行病学和危险因素 TTP将导致一项干预（低剂量抗凝或抗血小板治疗）的初步研究，以减少 高风险TTP患者中无症状性脑梗死和卒中的发生率， ADAMTS 13在其他人群脑血管疾病中的作用。查图维迪博士的导师罗伯特博士 Brodsky和Michael DeBaun博士在血栓性微血管病、罕见疾病 脑血管疾病的研究和评价。她建议的额外培训将使她能够 过渡到独立的NIH资助的研究者培训和罕见疾病队列研究的经验， 遗传流行病学和血液学中的脑血管疾病研究。

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.