Evaluation of the Role of Immunothrombosis in the Pathophysiology of Tissue Injury in Sepsis in Patients with Febrile Neutropenia.

• Grant number: 25/04429-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2025
• End date: May 31, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Alexander Leonardo Silva Junior
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 22/13216-0 - Crosstalk between hemostasis and innate immunity (Immunothrombosis): pathogenic, diagnostic and therapeutic implications in infectious and inflammatory diseases, AP.TEM

Abstract

Recent data showed that the role of neutrophils in the response to pathogens goes beyond phagocytosis and includes the generation of neutrophil extracellular traps (NETs) and activation of hemostasis, contributing to immunothrombosis. Platelets also participate in this process beyond their hemostatic functions. However, it is also known that both cell types contribute to the tissue damage observed in sepsis. Patients with febrile neutropenia (FN) following chemotherapy for hematologic malignancies generally present with severe neutropenia and thrombocytopenia, with neutrophil counts often dropping below 100 cells/mm³. These patients are at higher risk of progressing to severe sepsis and death, although the influence of neutrophil count on this unfavorable outcome remains controversial. Thus, the objective of this project is to explore the cellular and molecular mechanisms of tissue injury in sepsis and septic shock in FN patients. Given the complexity of this process, we propose an exploratory phase based on proteomics, which has been useful in other complex contexts such as sepsis itself. Additionally, we aim to perform a comparative analysis of the biomarker profile related to tissue injury and immunothrombosis in plasma and/or serum samples from the following cohort groups: (1) neutropenic patients, (2) FN patients, (3) FN patients with sepsis, (4) patients with sepsis but without FN, and (5) healthy individuals. This project is already underway, and the initial findings will be relevant for identifying potential new biologically significant pathways. This new proposal seeks to ensure the continuity of the current project while complementing it with functional analyses focused on other cellular components involved in immunothrombosis, such as monocytes and extracellular vesicles (EVs), as well as elements identified in the ongoing screening phase. These investigations aim to provide insights into underexplored pathways in sepsis that may be linked to clinical outcomes. (AU)