In silico features of ADAMTS13 contributing to plasmatic ADAMTS13 levels in neonates with congenital heart disease. Issue 193 (September 2020)

• Record Type: Journal Article
• Authors: Katneni, Upendra K.; Holcomb, David D.; Hernandez, Nancy E.; Hamasaki-Katagiri, Nobuko; Hunt, Ryan C.; Bar, Haim; Ibla, Juan C.; Kimchi-Sarfaty, Chava
• Is Part Of: Thrombosis research. Issue 193(2020)
• Page Start: 66
• Page End: 76
• Publication Date: 2020-09
• Subjects: Congenital heart disease (CHD) -- Thrombosis -- ADAMTS13 -- Genetic variants -- In silico assessment; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2020.05.042
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Introduction: Risk factors contributing to heightened thrombosis in pediatric congenital heart disease (CHD) patients are not fully understood. Among the neonatal CHD population, those presenting with single ventricular physiology are at the highest risk for perioperative thrombosis. The von Willebrand factor and ADAMTS13 interactions have emerged as causative risk factors for pediatric stroke and could contribute to heightened thrombosis in CHD neonates. Methods: This study investigates a cohort of children with single ventricle physiology and undergoing cardiac surgery, during which some patients developed thrombosis. In this cohort, we analyzed the relationship of several molecular features of ADAMTS13 with the plasma and activity levels in patients at risk of thrombosis. Additionally, in light of the natural antithrombotic activity of ADAMTS13, we have sequenced the ADAMTS13 gene for each patient and evaluated the role of genetic variants in determining the plasma ADAMTS13 levels using a series of in silico tools including Hidden Markov Models, EVmutation, and Rosetta. Results: Lower ADAMTS13 levels were found in patients that developed thrombosis. A novel in silico analysis to assess haplotype effect of co-occurring variants identified alterations in relative surface area and solvation energy as important contributors. Our analysis suggested that beneficial or deleterious effect of a variant can be reasonably predicted by comprehensive analysis of in silico assessment and in vitro and/or in vivo data. Conclusion: Findings from this study add to our understanding the role of genetic features of ADAMTS13 in patients at high risk of thrombosis related to an imbalanced relation between VWF and ADAMTS13. Highlights: Dataset of neonatal congenital heart disease patients, including ADAMTS13 variants Low ADAMTS13 levels in patients presenting with thrombosis during cardiac surgery Novel in silico prediction of haplotype effect of co-occurring variants Change in protein surface area is a notable contributor to variant effects. Beneficial or deleterious variant effects predicted by comprehensive analysis