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Evaluation of “The role of platelets ín sickle cell disease

Grant number: 15/18369-6
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2016
Effective date (End): September 30, 2019
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Nicola Amanda Conran Zorzetto
Grantee:Hanan Chweih
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

Abstract

Hemoglobinopathies are diseases that result from mutations in genes coding the globin chains of hemoglobin (Hb). Sickle cell anemia (SCA), caused by the homozygous hemoglobin SS (HbSS) genotype, is characterized by chronic hemolytic anemia, painful vaso-occlusive crisis and target organ damage. Thus, SCA is often associated with a chronic inflammatory state that plays a key role in the activation of endothelial and blood cells, especially leukocytes. SCA patients have high leukocyte counts, and these cells have a major role in the pathophysiology of sickle cell disease. There is evidence that leukocytes are involved in both the initiation and the propagation of vaso-occlusive processes as these cells are relatively large and rigid, and their recruitment to the endothelium of blood vessels of the microcirculation may decrease blood flow through these vessels. Additionally, platelets of SCA patients circulate in an activated state and present inflammatory properties, since they release high levels of potent inflammatory mediators, including the LIGHT and CD40L cytokines. The roles of platelets in SCA and in the vaso-occlusive process are little understood, although platelet activation is known to occur in SCA as well as an important cross talk between the "hypercoaguability" state and the inflammatory state. Previous findings suggest that platelets can play a role in the "propagation" of the vaso-occlusive process, however is still necessary establish the role of platelets in the vaso-occlusive process and in the inflammatory state to stimulate approaches to minimize platelets activation in SCA and determine their contribution to the pathophysiology of the disease. Therefore, this project aims to (i) investigate the role of platelets in the vaso-occlusive process using a SCA animal model (mice) and an intravital microscopy technique, (ii) analyze whether the treatment of mice with SCA using a platelet aggregation inhibitor drug (Prasugrel®) changes the parameters associated with vaso-occlusion and (iii) investigate the role of platelets and the signaling pathways involved in the formation of heterocellular aggregates between erythrocytes and/or leukocytes,using blood from patients with SCA, by imaging flow cytometry (Amnis) and evaluate changes in heterocellulares interactions between leukocytes and platelets after in vitro treatment with Prasugrel®.