Investigation of the pathophysiological aspects and novel therapeutic approaches for thromboembolic disorders

Abstract

Thromboembolic disorders represent a major culprit for morbidity-mortality in Brazil and the World. The Hemocentro at Unicamp has a scientifically recognized research group, with over 100 highly cited publications in this field. We have revealed the roles of FVIII, VWF and of ADAMTS13 in Deep Venous Thrombosis (DVT) and severe Post-Thrombotic Syndrome (PTS); the association between hypercoagulability, inflammation and neutrophils; circulating endothelial cells and repairing processes; protein expression in venous thrombus in animals exposed arterial risk factors; platelet proteins differentially expressed and in vitro studies supporting these results. Analyze the images of residual thrombi using the Grayscale Median (GSM) suggested clinical applicability for rethrombosis. We have demonstrated immature platelet fraction and generation of thrombin in acute inflammatory process such as sepsis and SIRS. We investigated gene therapy using VEGF in peripheral arterial occlusive model in rats, and we are evaluating fat stromal cells or Platelet Rich Plasma (PRP) in murine models. All these studies demonstrated that many issues remain open and the continuity of our investigations. Hemocentro at Unicamp has a bioterium with models for arterial and vein thrombosis, imaging methods like laser doppler perfusion imager and doppler ultrasound, and transgenic models available at the animal facility center of the University, CEMIB. Our outpatient clinic has over 500 patients followed for 5 years, and patients diagnosed with DVT at the Unicamp Hospital School are currently referred to our service. Patients with Antiphospholipid Syndrome and thrombotic manifestations constitute a fruitful cohort for investigation. In this thematic project, the focus will be maintained on the pathophysiological mechanisms in DVT and investigation of novel therapies to the prevention of atherosclerosis and treatment of peripheral arterial disease. The collaboration established with the professors of renowned research groups (Paolo Simmioni, University of Padua, Italy; Leonardo Brandão, Hospital for Sick Children, Toronto, Canadá; Ricardo Forastieiro, Favaloro University, Buenos Aires, Argentina; Jose Diaz, University of Michigan, Ann Arbor, EUA) will be of great support for the development of cutting-edge research. Our research strategy will be divided into five main branches: 1) DVT - Evaluate Neutrophil Extracellular Traps (NETs), hypercoagulability and inflammation correlating them with the development of PTS and recurrence. Analyze prospectively residual thrombi using GSM and validate their association with rethrombosis. Determine DVT prevalence in a pediatric registry. Analyse mathematically DVT recurrence using artificial neural nets and fuzzy logic. Investigate the endothelium contribution to DVT development; 2) Cancer - Explore NETs in patients with Polycythemia Vera and Essential Thrombocythemia. Evaluate the mechanisms associated to cardiovascular events in patients with Chronic Myeloid Leukemia treated with tyrosine kinase inhibitor. Investigate in a Brazilian multicenter study DVT risk factors in cancer patients; 3) Antiphospholipid Syndrome - Evaluate the pathophysiology of thrombotic events, risk factors and novel therapeutic approaches; 4) Inflammation and thrombosis - explore the association between inflammation and hemostasis activation, focusing the interfaces between innate immune system and hypercoagulability of acute and chronic disorders; 5) Novel therapeutic approaches - evaluate PRP upon angiogenesis in patients with Peripheral Arterial Occlusive Disease (PAOD); PRP and Mesenchymal Cells (MSCs), in the healing process of ulcers in animal models; the use of low doses of rivaroxaban and dabigatran and development of atherosclerosis in LDL or apoE deficient murine model. (AU)