Purinergic signaling pathways in platelet activation in antiphospholipid syndrome: modulation of platelet-leukocyte interaction in APS and possible mechanisms of inhibition.

• Grant number: 25/11091-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernanda Loureiro de Andrade Orsi
• Grantee: José Diogo Oliveira
• 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

Antiphospholipid syndrome (APS) is one of the main acquired causes of thrombosis and pregnancy loss. To date, lifelong anticoagulation remains the only recommended treatment for thrombotic complications in APS. Despite anticoagulation, recurrence rates are high, and prevention of arterial and microvascular disease, which leads to organ damage, is insufficient. On the other hand, treatments to address manifestations that are resistant to anticoagulants have not yet been established. Our group has recently demonstrated evidence of enhanced purinergic signaling in platelets of patients with APS, supported by hyperreactivity to ADP, overexpression of the P2Y12 receptor, and reduced intracellular levels of cAMP and cGMP. In a collaborative study, we also observed that ATP hydrolysis is reduced in neutrophils and platelets from APS patients. It is well known that activated or senescent cells release purine nucleotides such as ATP and ADP, which bind to surface receptors on cells such as neutrophils and platelets, triggering an inflammatory response. The interaction between neutrophils and platelets has the potential to perpetuate the cycle of inflammation and thrombosis and is associated with a higher risk of thrombotic complications in cardiovascular diseases. Adenosine inhibits platelet activation by stimulating its surface receptors (A2a and A2b), thereby increasing intracellular cAMP. Our hypothesis is that in APS, there is resistance to adenosine-mediated inhibitory mechanisms in platelets, or impaired degradation of ATP and ADP mediated by endothelial CD39/CD73 receptors. This resistance could lead to platelet hyperactivation and consequent platelets-leukocytes aggregation. In this context, the aim of this study is to characterize the role of the adenosine signaling pathway in platelet-leukocyte aggregation in patients with primary thrombotic APS, through functional and biochemical assays. As a secondary objective, we will assess whether the presence of antiphospholipid antibodies (aPL) alters the expression of the ectonucleotidases CD39 and CD73 in platelets and neutrophils. With this, we aim to provide new insights into the role of purinergic signaling in leukocyte and platelet activation and in the thrombotic events affecting APS patients. We also hope to identify more promising pathways and potential therapeutic targets that may be evaluated in clinical trials. (AU)