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Investigation of new pathophysiological mechanisms of hypercoagulability in sickle cell disease

Grant number: 15/24666-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2016
Effective date (End): February 29, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Erich Vinicius de Paula
Grantee:Bidossessi Wilfried Hounkpe
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches, AP.TEM


Sickle cell disease (SCD) is a condition characterized by chronic inflammation and increased thrombotic risk in both arterial and venous beds. In the last decades, important advances were achieved in understanding the pathophysiology of hypercoagulability in these patients. However, several new mediators of coagulation activation have been recently described in other pathological contexts, opening new avenues for the research about hypercoagulability in SCD. Among these new mediators, Neutrophil Extracellular Traps (NETs) and free heme can be considered the most promising targets. In this project, we aim to use different experimental strategies to explore the role of these elements in the pathophysiology of SCD. The role of NETs will be explored by specific assays of NETosis, and by the evaluation of the expression of a key regulatory checkpoint of NET formation, which is the protein PAD4 in patients with SCD. These results will also be correlated with classic biomarkers of coagulation activation to question the association of these two processes. We will also use an in vitro model of NET formation induced by free heme (one of the pivotal factors of hypercoagulability in SCD), to evaluate: (i) the participation of PAD4 in heme-induced NETosis, (ii) the effect of PAD4 inhibitors in this process, and (iii) the profile of post-transcriptional modification of histones (a key step of NET formation) induced by heme. As a second strategy, we will validate the results of a recently published meta-analysis of gene expression studies involving heme-stimulated endothelial cells and patients with SCD performed by our group, in which we identified two candidate genes (IFI27 and SYK) associated with innate immunity activation. The project is part of a broader effort, started a few years ago in the Hematology and Hemotherapy Center of Unicamp, which aim to evaluate the pro-thrombotic mechanisms of SCD and the pathways activated by the free heme in this process.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE SOUZA, GLEICE REGINA; HOUNKPE, BIDOSSESSI WILFRIED; LUZ FIUSA, MAIARA MARX; COLELLA, MARINA PEREIRA; ANNICHINO-BIZZACCHI, JOYCE M.; TRAINA, FABIOLA; COSTA, FERNANDO FERREIRA; DE PAULA, ERICH VINICIUS. Tissue factor-dependent coagulation activation by heme: A thromboelastometry study. PLoS One, v. 12, n. 4 APR 24 2017. Web of Science Citations: 1.

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