EXPLORATION OF PURINERGIC SIGNALING PATHWAYS AS A PLATELET ACTIVATION MECHANISM IN ANTIPHOSPHOLIPID SYNDROME

• Grant number: 23/07899-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): December 01, 2023
• Effective date (End): January 31, 2027
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Fernanda Loureiro de Andrade Orsi
• Grantee: Bruna Cardoso Robison
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Antiphospholipid syndrome (APS) is a major acquired cause of thrombosis and gestational loss. To date, definitive anticoagulant therapy is the only recommended treatment for thrombotic complications of APS. Despite anticoagulation, the recurrence rate is high, and the prevention of microvascular diseases, which lead to target organ deterioration, insufficient. However, complementary treatments to combat the anticoagulant-resistant manifestations are undetermined. Our group recently demonstrated that there are signs of stimulated purinergic signaling in platelets from APS patients, supported by hyper-reactivity to ADP, overexpression of the P2Y12 receptor, and decreased intracellular levels of cAMP and cGMP. Activated or senescent cells are known to release purine nucleotides, such as ATP and ADP, which bind to cell surface receptors to trigger inflammation and platelet activation. As a counterpoint, endothelial cells express the surface ectonucleotidases CD39 and CD73, which catalyze the degradation of ATP to adenosine, thus creating an anti-inflammatory and antithrombotic "halo" around the cell. Adenosine restricts platelet activation by activating its surface receptors (A2A) and thus increasing intracellular cAMP. Our hypothesis is, in APS, there is resistance to adenosine-mediated inhibitory mechanisms in platelets or inactivation of ATP and ADP degradation mediated by endothelial CD39/CD73 receptors. In this context, the aim of the current study is to evaluate the action of adenosine receptors on platelet aggregation in patients with primary thrombotic APS (SAF-t) and to characterize, by means of functional and biochemical assays, the activation and inhibition pathways of purinergic and cyclic nucleotide signaling. As a secondary objective we will evaluate whether the presence of aPL alters the expression of CD39 and CD73 ectonucleotidases in endothelial cells. By doing so, we hope to provide new insight into the role that purinergic signaling plays in platelet activation and thrombotic events that afflict APS patients. We also hope to be able to identify more promising pathways (and, possible therapies) that merit clinical testing in patients.