Investigation of the role of PDPN in the pathophysiology of coagulopathy in acute promyelocytic leukemia

• Grant number: 23/03765-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2024
• End date: April 30, 2027
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Erich Vinicius de Paula
• Grantee: Carla Roberta Peachazepi de Moraes
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/21801-2 - Predictors of severity and new treatments for bone marrow neoplasias, AP.TEM

Abstract

Acute promyelocytic leukemia (APL) is part of the group of acute myeloid leukemias and is characterized by having the best long-term prognosis. On the other hand, its initial treatment is characterized by high morbidity and early mortality. The occurrence of a severe hemorrhagic syndrome at the time of diagnosis, in a significant number of patients, results in the most relevant aspect of ALI and one of the most frequent reasons for early death. The pathophysiology of coagulopathy associated with ALI is complex and has not been fully elucidated, however, being caused directly or indirectly by the interaction of leukemic cells with hemostasis, with marked activation of platelets and the coagulation cascade. Recently, the anomalous expression of podoplanin (PDPN), a protein that promotes platelet activation in inflammatory contexts, was described as relevant to this syndrome. Furthermore, in other neoplasms associated with the activation of coagulation, it has been demonstrated that PDPN can be carried by exosomes. In this project we intend to explore some of these mechanisms in a cohort of patients with ALI and other forms of AML, through: (i) characterization of laboratory parameters of hemostasis (ii) quantification of PDPN expression in leukemic cells and plasma; (iii) Characterization and quantification of PDPN expression in EVs from patients with ALI; (iv) Determination of the effect of EVs from patients with ALI on the activation of hemostasis through functional tests; (v) Reproduction of platelet activation induced by PDPN in blasts and (vi) Assessment of the therapeutic potential of inhibition of the PDPN-dependent platelet activation pathway. Furthermore, these results will be correlated with clinical outcomes of mortality and major bleeding.