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.
Using genetically modified mice that are deficient in ADAMTS13, we will evaluate the biological role of ADAMTS13 and VWF in the maternal complications of preeclampsia. Using complementary studies in humans, we will evaluate whether ADAMTS13 and VWF are critical determinants of maternal complications of preeclampsia such as the HELLP syndrome.
|Gray, Kathryn J; Saxena, Richa; Karumanchi, S Ananth (2018) Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis. Am J Obstet Gynecol 218:211-218|