Crosstalk between hemostasis and innate immunity (Immunothrombosis): pathogenic, diagnostic and therapeutic implications in infectious and inflammatory diseases

• Grant number: 22/13216-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2024
• End date: August 31, 2029
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Erich Vinicius de Paula
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Fernanda Loureiro de Andrade Orsi
• Associated researchers: Antonio Roberto Lucena de Araújo ; Beatriz de Moraes Martinelli ; Bruna de Moraes Mazetto Fonseca ; Bruno Deltreggia Benites ; Eduardo Magalhães Rego ; Fabio Trindade Maranhão Costa ; Fabíola Taufic Monica Iglesias ; Fabíola Traina ; Jason Knight ; Jéssica Rafaela dos Santos Alves ; Joyce Maria Annichino-Bizzacchi ; Letícia Queiroz da Silva Justo ; Marina Pereira Colella ; Murilo Vieira Geraldo ; Nigel Key ; Paula Ribeiro Villaça ; Rodrigo Nogueira Angerami ; Sara Teresinha Olalla Saad ; Thiago Martins Santos ; Tiago Dias Martins
• Associated scholarship(s): 25/11091-4 - Purinergic signaling pathways in platelet activation in antiphospholipid syndrome: modulation of platelet-leukocyte interaction in APS and possible mechanisms of inhibition., BP.PD; 25/06564-0 - Evaluation of the role of isotype IgM antiphospholipid antibodies in the clinical manifestations of thrombotic antiphospholipid syndrome, BP.IC; 25/07064-1 - Assessment of the clinical relevance of isolated aPTT-LA positivity in the diagnosis of Antiphospholipid Syndrome., BP.IC; 25/04429-9 - Evaluation of the Role of Immunothrombosis in the Pathophysiology of Tissue Injury in Sepsis in Patients with Febrile Neutropenia., BP.PD

Abstract

Hemostasis and innate immunity are closely linked processes that contribute to containing the progression of infectious agents, thus constituting an effector mechanism of host defense, which is conventionally called "immunothrombosis". However, unregulated and excessive activation of this process causes secondary tissue injury and micro and macrovascular thrombosis. Although initially described in infectious diseases, the interaction between hemostasis and innate immunity is also seen in the host response to sterile inflammatory processes. The mechanisms of hemostasis activation in immunothrombosis are distinct from classical hemostasis, and are based on a vicious circle of activation of innate immune cells, pro-inflammatory cytokines, complement system, platelets, release of neutrophil extracellular traps (NETs), extracellular vesicles and activation of tissue factor and of the intrinsic coagulation pathway. Although the fundamental mechanisms triggered by the joint activation of inflammation and hemostasis may be similar, it is possible that the pathophysiology of tissue damage has particularities depending on the infectious agent or inflammatory stimulus. Therefore, the identification of these mechanisms in several current and emerging inflammatory and infectious diseases has the potential to direct diagnostic strategies and therapeutic measures for these conditions. In this context, the objective of this project is to investigate the participation of pathways that act at the interface between hemostasis and innate immunity in the pathophysiology of infectious and inflammatory diseases characterized by changes in hemostasis. The proposal can be subdivided into two fronts. In the first, we will use three model diseases (sickle cell disease, sepsis and antiphospholipid syndrome) in which hypercoagulability is recognized as a relevant pathophysiological element, to explore the participation, prognostic relevance and activation mechanisms of emerging immunothrombotic pathways related to platelet activation, endothelial activation and coagulation activation. On a second parallel front, we will explore three clinical conditions that can also lead to deregulated activation of hemostasis, but which have as a peculiarity the presence of cytopenias involving neutrophils and platelets: febrile neutropenia (NF) associated with sepsis, acute promyelocytic leukemia (APL) and immune thrombocytopenia (ITP). The interest in these conditions derives from the fact that neutrophils and platelets are central cells in immunothrombosis, making it interesting to study the mechanisms of hemostasis activation in contexts in which there is a dramatic reduction of these cells. With the development of the subprojects that are part of these fronts, we hope to expand knowledge of the clinical relevance of immunothrombosis in infectious and inflammatory conditions that will be used as a model, describe new pathways responsible for hypercoagulability in these conditions, identify biomarkers capable of refining the diagnosis and prognosis of these diseases , identify potential therapeutic targets, and lay the foundations for intervention studies aimed at modulating hypercoagulability in inflammatory diseases. (AU)

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)

JACINTHO-ROBISON, BRUNA CARDOSO; OLIVEIRA, JOSE DIOGO; CESPED, LUCAS MATHEUS BISPO; DE SOUZA, CRISTIANE MARIA; BARION, BARBARA GOMES; VAZ, CAMILA DE OLIVEIRA; MAZETTO, BRUNA DE MORAES; ORSI, FERNANDA ANDRADE. Association between extracellular vesicles (EVs) and thrombosis in antiphospholipid syndrome. Lupus, v. 34, n. 5, p. 11-pg., 2025-03-23. (22/13216-0, 20/13956-9, 23/07899-0, 20/12630-2)