ADAMTS13 and Late Neurologic Morbidity after Thrombotic Thrombocytopenic Purpura

项目摘要/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 以ADAMTS13缺乏引起的全身微血管血栓形成的急性发作为特征 Von Willebrand因子裂解酶。TTP在女性和非裔美国人中更常见。电浆 Exchange已将急性TTP的存活率从10%提高到80%-90%；然而，长期的不利健康 成人从TTP恢复后的结果没有得到充分的认识。最近的数据表明，TTP幸存者 比年龄和性别匹配的对照组死亡率更高，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幸存者中，我们发现有很高的比率 在长期随访中，卒中事件与急性TTP复发无关。 存活者缓解期ADAMTS13活性未恢复，缓解期ADAMTS13活性低 与较高的中风风险相关。无症状性脑梗塞是患者在MRI上可见的缺血性病变 没有神经系统症状，这些症状通常与未来的中风和认知障碍有关 人口。目前，还没有公开的研究评估无症状性脑梗塞在TTP中的患病率。 幸存者，以及他们与未来中风和认知障碍的关系。中的ADAMTS13协会 缺血性脑事件(静止性脑梗塞和中风)的缓解也是未知的。 Chaturvedi博士已经建立了一大批TTP患者的预期队列，产生了令人信服的 关于TTP幸存者卒中风险的初步数据，以及在整个约翰斯建立的合作 霍普金斯医院回答了这些问题。我们将使用现有的约翰·霍普金斯大学的血栓药 微血管病登记处测试无症状性脑梗塞在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(目的 1)。我们将评估TTP缓解期间ADAMTS13活性降低是否与脑部相关 缺血事件(静止性脑梗塞和中风)(目标2)。最后，我们将对传统的协会进行评估 无症状性脑梗塞患者ADAMTS13和补体基因的心血管危险因素和生殖系变异 笔划(目标3)。了解脑血管及认知后遗症的流行病学及危险因素 TTP将导致一项干预措施(低剂量抗凝或抗血小板治疗)的试点研究，以减少 无症状性脑梗塞和卒中在高危TTP患者中的发生率及其对理解的意义 ADAMTS13在其他人群脑血管疾病中的作用查图尔韦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变、罕见疾病方面拥有丰富的专业知识 脑血管疾病的研究和评估。她提议的额外培训将使她能够 过渡到由美国国立卫生研究院资助的独立研究人员培训和罕见疾病队列研究经验， 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.