Pathophysiology and Treatment of Thrombotic Microangiopathy

血栓性微血管病的病理生理学和治疗

基本信息

批准号：
8464253
负责人：
J Evan Sadler
金额：
$ 26.61万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464253
关键词：
Active Sites Address Adjuvant Adult Autoantibodies Autoimmune Process Binding Biochemical Biological Assay Blood Platelets Cell surface Cleaved cell Clinical DNA Detection Diagnostic Disease Dose Endothelial Cells Enrollment Evaluation Functional disorder Genomics Goals Growth Hemolytic Anemia Infection Innovative Therapy Kidney Location Malignant Hypertension Malignant Neoplasms Metalloproteases Methods Minor Modeling Molecular Conformation Neurologic Organ Transplantation Outcome Pathogenesis Patients Peptide Hydrolases Pharmaceutical Preparations Plasma Plasma Exchange Pre-Eclampsia Prospective Studies Proteins Recurrent disease Relapse Sampling Site Solutions Specificity Speed Stress Structure Subgroup Symptoms Syndrome Testing Thrombocytopenia Thrombosis Thrombotic Thrombocytopenic Purpura Thrombus Tissues base biobank clinical application clinical phenotype improved in vivo inhibitor/antagonist mortality novel patient oriented research prevent prognostic prospective rituximab

项目摘要

Thrombotic microangiopathy is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and tissue damage caused by microvascular thrombosis. Clinical manifestations of thrombotic microangiopathy vary considerably, depending in part on predisposing conditions such as infections, cancer, organ transplantation, malignant hypertension, toxemia of pregnancy, and a variety of drugs. When thrombotic microangiopathy occurs in adults without a secondary cause, in most cases renal damage is a minor feature and neurological symptoms are prominent; this syndrome is called idiopathic thrombotic thrombocytopenic purpura (idiopathic TTP) and usually is due to acquired, autoimmune deficiency of ADAMTS13, a metalloprotease that cleaves von Willetjrand factor (VWF) and inhibits the growth of platelet thrombi. In some clinically similar cases, ADAMTS13 levels are normal and the cause of TTP almost always is unknown. Patients with severe ADAMTS13 deficiency usually respond to plasma exchange and the mortality for this subgroup is v15%, although a high titer of inhibitory autoantibody correlates with high likelihood of relapsing disease. In contrast, patients with detectable ADAMTS13 activity almost never relapse, and whether plasma exchange improves their survival is uncertain. Several studies suggest that ADAMTS13 activity and inhibitor assays provide useful prognostic information, but current tests have significant shortcomings in terms of speed and sensitivity, especially for inhibitor detection.

血栓性微血管病的特征是微血管病性溶血性贫血、血小板减少以及微血管血栓形成引起的组织损伤。血栓性微血管病的临床表现差异很大，部分取决于感染、癌症、器官移植、恶性高血压、妊娠毒血症和各种药物等诱发因素。当血栓形成时微血管病发生在成人身上，没有继发性原因，在大多数情况下，肾损害是次要特征，神经系统症状是突出的；这种综合征称为特发性血栓性血小板减少性紫癜（特发性 TTP），通常是由于 ADAMTS13 的获得性自身免疫缺陷所致，ADAMTS13 是一种金属蛋白酶，可裂解 von Willetjrand 因子 (VWF) 并抑制血小板血栓的生长。在一些临床类似病例中，ADAMTS13 水平正常，TTP 的病因几乎总是未知。严重 ADAMTS13 缺乏的患者通常对血浆置换有反应，该亚组的死亡率为 15%，尽管高滴度的抑制性自身抗体与疾病复发的高可能性相关。相比之下，具有可检测到的 ADAMTS13 活性的患者几乎不会复发，并且血浆置换是否能提高他们的生存率尚不确定。多项研究表明 ADAMTS13 活性和抑制剂检测提供了有用的预后信息，但目前的检测在速度和灵敏度方面存在显着缺陷，特别是对于抑制剂检测。