Role of ADAMTS13 in Maternal Complications of Preeclampsia

ADAMTS13 在先兆子痫孕产妇并发症中的作用

• 批准号: 9119325
• 负责人: S. Ananth Karumanchi
• 金额: $ 27.98万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119325
• 关键词: ADAMTS; Acute Kidney Failure; Adhesions; Affect; Anemia; Angiogenic Factor; Biological; Biology; Blood; Blood Platelets; Blood coagulation; Brain; Chemotherapy-Oncologic Procedure; Cleaved cell; Clinical; Cohort Studies; Complement; Development; Disease; Disintegrins; Enzymes; Exhibits; Fetal Growth Retardation; Fetus; Genetic; HELLP Syndrome; Hemolysis; Hemolytic Anemia; Human; Hypertension; Injury; Kidney; Knockout Mice; Laboratories; Lead; Life; Link; Liver; Measurement; Measures; Metalloproteases; Mus; Organ; Pathogenesis; Pathology; Pathway interactions; Pilot Projects; Placental Growth Factor; Plasma; Platelet Count measurement; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Premature Birth; Proteins; Proteinuria; Recombinants; Renal function; Risk Factors; Rodent; Role; Symptoms; Syndrome; Therapeutic; Third Pregnancy Trimester; Thrombocytopenia; Thrombosis; Toxic effect; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Viscera; Woman; Zinc; adverse outcome; fetal; inhibitor/antagonist; member; modifiable risk; mouse model; novel therapeutics; overexpression; public health relevance; von Willebrand Disease; von Willebrand Factor

 DESCRIPTION (provided by applicant): Thrombotic microangiopathies (TMAs) are a heterogeneous group of life-threatening disorders characterized by thrombocytopenia, schistocytosis, hemolytic anemia, microvascular thrombosis and end-organ damage affecting the kidney and brain. During pregnancy, TMAs may present as preeclampsia (PE), characterized by hypertension and proteinuria with glomerular endotheliosis (a form of thrombotic microangiopathy), or as part of the HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelet count) which is typically classified as a severe form of PE. Recent studies suggest that at least among preterm PE (<34 weeks), angiogenic imbalance as a result of excessive circulating anti-angiogenic factors plays a role in the development of PE pathology. While there a number of placental derived anti-angiogenic factors, our laboratory has characterized the role of soluble fms like tyrosine kinase 1 (sFlt1), a circulating vascular endothelial growth factor inhibitor in the pathogenesis of preeclampsia. Rodent studies suggest that excess sFlt1 is sufficient to induce the maternal syndrome of PE. Humans receiving VEGF inhibitors as part of cancer chemotherapy also get PE-like state and rarely develop full blow thrombotic microangiopathy that resembles HELLP syndrome. In this proposal, we hypothesize that deficiency of the VWF-cleaving enzyme ADAMTS13, a protein that has been linked to the genetic forms of thrombotic microangiopathies contributes to the development of severe preeclampsia and HELLP syndrome. ADAMTS13 is a zinc containing metalloprotease enzyme that cleaves von Willebrand factor (VWF), a large protein involved in blood clotting. In humans, both ADAMTS13 and VWF levels are critical determinants for the development of various TMAs. In pilot studies, ADAMTS13-/- mice overexpressing sFlt1 in the non-pregnant state developed severe hypertension, thrombocytopenia, schistocytosis, anemia and microthrombi in multiple organs. We will therefore first evaluate whether deficiency of ADAMTS13 contributes to the development of HELLP syndrome in a mouse model of PE characterized by high circulating sFlt1. We will also perform initial proof-of-concept studies to evaluate whether recombinant ADAMTS13 will rescue features of severe PE in our mouse model without overt adverse consequences to the fetus. Finally, we will measure ADAMTS13 and its target VWF during third trimester of pregnancy in blood among women with normal and PE pregnancies and will correlate alternations in these hematological factors with PE- related adverse maternal/fetal adverse outcomes (elevated liver enzymes, low platelets, very preterm delivery or fetal growth restriction). These studies may have broader relevance to other forms of TMAs.