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

Grant number: 16/14172-6
Support type:Research Projects - Thematic Grants
Duration: May 01, 2017 - April 30, 2022
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Joyce Maria Annichino-Bizzacchi
Grantee:Joyce Maria Annichino-Bizzacchi
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Co-Principal Investigators:Erich Vinicius de Paula ; Fernanda Loureiro de Andrade Orsi ; Katia Borgia Barbosa Pagnano
Assoc. researchers: Beatriz de Moraes Martinelli ; Bruna de Moraes Mazetto Fonseca ; Carmen Silvia Passos Lima ; Carolina Mie Kawagosi Onodera ; Claudio Alberto Torres Suazo ; Fábio Hüsemann Menezes ; Fernanda Dutra Santiago Bassora ; Gerson Jhonatan Rodrigues ; Isabella Macedo Toni ; José Barreto Campello Carvalheira ; Kiara Cristina Senger Zapponi Cerri ; Letícia Queiroz da Silva ; Ljubica Tasic ; Luis Fernando Bittar Sckayer ; Maurício Etchebehere ; Melissa Quintero Escobar ; Nelson Adami Andreollo ; Nelson Wolosker ; Patricia Moriel ; Rubens Maciel Filho ; Silmara Aparecida de Lima Montalvão ; Simone Appenzeller ; Stephany Cares Huber ; Suely Meireles Rezende ; Tayana Bezerra Teixeira Mello ; Tiago Dias Martins ; Vitória Régia Pereira Pinheiro ; Wagner José Fávaro
Associated grant(s):18/02589-5 - EMU granted in process 2016 / 14172-6 - 02 gene rotors Q5plex-HRM platform - Quiagen brand, AP.EMU
17/15021-4 - Multi user equipament granted in process 2016/14172-6: automated optical microscopy for phase contrast system and dual color fluorescence, model incucyte zoom HD/2 channel, Essen Bioscience (exclusivity), AP.EMU
Associated scholarship(s):19/18195-9 - New methodologies for assessing coagulation activation and endothelial barrier integrity, BP.TT
19/06318-9 - Thrombosis and inflammation: participation of innate immunity and NETosis in the pathogenesis of hypercoagulability in chronic myeloproliferative, BP.TT
18/15618-3 - Evaluation of the activity of circulating colony forming endothelial cells (ECFCs) in patients with spontaneous and induced Venous Thrombosis, BP.DR
+ associated scholarships 18/24577-9 - The role of tissue factor in APS hypercoagulability, BP.TT
18/18624-4 - Metabolomic and metabonomic analyzes by nuclear magnetic resonance techniques applied in studies of venous thrombosis, BP.PD
18/20440-9 - Evaluation of risk factors for venous thromboembolism in cancer patients, BP.TT
18/10602-1 - Preditive factors of recurrent venous thromboembolism using design of experiments, BP.IC
18/14349-9 - Thrombosis and inflammation: participation of innate immunity and NETosis in the pathogenesis of hypercoagulability in chronic myeloproliferative diseases, BP.TT
18/11308-0 - The role of tissue factor in hypercoagulability of the SAF, BP.TT
17/19251-4 - MicroRNAs and oxidized biomolecules as possible biomarkers of primary antiphospholipid syndrome, BP.MS - associated scholarships


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)

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)
NOBREGA BARBOSA, AYLA CRISTINA; LIMA MONTALVAO, SILMARA APARECIDA; NOBREGA BARBOSA, KEVAN GUILHERME; COLELLA, MARINA PEREIRA; ANNICHINO-BIZZACCHI, JOYCE MARIA; OZELO, MARGARETH CASTRO; DE PAULA, ERICH VINICIUS. Prolonged APTT of unknown etiology: A systematic evaluation of causes and laboratory resource use in an outpatient hemostasis academic unit. RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, v. 3, n. 4, p. 749-757, OCT 2019. Web of Science Citations: 0.
TOBALDINI, LAIS QUINTEIRO; ARANTES, FERNANDA TALGE; SARAIVA, SABRINA DA SILVA; MAZETTO, BRUNA DE MORAES; COLELLA, MARINA PEREIRA; DE PAULA, ERICH VINICIUS; ANNICHINO-BIZZACHI, JOYCE; ORSI, FERNANDA ANDRADE. Circulating levels of tissue factor and the risk of thrombosis associated with antiphospholipid syndrome. THROMBOSIS RESEARCH, v. 171, p. 114-120, NOV 2018. Web of Science Citations: 0.

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