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Evaluation of hemostasis abnormalities related to hemorrhagic fever diseases

Grant number: 08/11518-2
Support type:Regular Research Grants
Duration: April 01, 2009 - December 31, 2011
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

Abstract

Dengue epidemics have been representing a significant public health and economic burden in Latin America, Africa, India and South-Asia during the last decades. The outbreaks in Brazil are increasing in size and severity. In 2007, according to the Brazilian Ministry of Health, 559,954 cases of dengue fever (DF), 1,541 dengue hemorrhagic fever (DHF) and 158 deaths were reported in the country.The disease is considered to be an arboviruses caused by four different serotypes of a virus belonging to the family Flaviviridae. Although being a self-limited disease, some cases may become severe and even life threatening, the so-called dengue with unusual manifestations and DHF.Bleeding disorders, the most severe complications in these cases, are presumably caused by endothelial damage, thrombocytopenia, coagulation and fibrinolysis impairment. The infection of endothelial cells by the virus would lead to cytokines release and complement system activation, that together would cause cell damage, marked by raised serum thrombomodulin levels, and increased vascular permeability. The mediators of capillary permeability, such as VEGF and angiopoietins 1 and 2, may contribute to the phenomenon, although their importance is uncertain in dengue infections. Thrombocytopenia is due to myelossupression and antibodies, but an increased platelets clearance by von Willebrand factor (VWF) may play a role in the pathogenesis. VWF is secreted by endothelial cells as ultra-large multimers and then cleaved by ADAMTS 13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats) in the plasma. This physiological mechanism prevents the ultra-large multimers to induce abnormal platelet aggregation and consumption. Recently, it was suggested that increased VWF antigen, the presence of ultra-large multimers and impaired ADAMTS 13 activity in plasma were related to the degree of DHF severity. Probably there is also an activation of coagulation and fibrinolysis systems due to the systemic inflammatory response. Clinical trials have shown increased thrombin-antithrombin complex, increased plasma levels of D-dimer and tissue plasminogen activator (tPA) and decreased plasminogen activator inhibitor - 1 (PAI-1) in children with DHF. In summary, current data support the hypothesis that hemorrhagic manifestations in DF depend on the interplay of multiple haemostatic disorders. However, the pathological mechanisms involved in these disorders are poorly understood, particularly among adult patients. It is urgent to develop new therapeutic strategies based on the physiopathology of bleeding manifestations in dengue; whose current recommended treatment is just fluid replacement. Therefore, this study intends to determine, in patients with DF and DHF, the plasma levels of: 1) mediators of inflammation, endothelial damage and capillary permeability; 2) VWF and ADAMTS 13 and; 3) markers of fibrinolysis activation. Those laboratory parameters will also be correlated with the clinical manifestation of the disease. The primary aim is to evaluate the mechanisms underlying the impairment of haemostasis and the bleeding disorders in adults with dengue infection. (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)
ORSI, FERNANDA ANDRADE; ANGERAMI, RODRIGO NOGUEIRA; MAZETTO, BRUNA MORAES; QUAINO, SUSAN KELLY PICOLI; DE PAULA, ERICH VINICIUS; ANNICHINO-BIZZACHI, JOYCE MARIA. Bleeding complications in dengue are not associated with significant changes in the modulators of the endothelial barrier. JOURNAL OF INFECTION IN DEVELOPING COUNTRIES, v. 8, n. 6, p. 799-803, JUN 2014. Web of Science Citations: 0.
ORSI, FERNANDA A.; ANGERAMI, RODRIGO N.; MAZETTO, BRUNA M.; QUAINO, SUSAN K. P.; SANTIAGO-BASSORA, FERNANDA; CASTRO, VAGNER; DE PAULA, ERICH V.; ANNICHINO-BIZZACCHI, JOYCE M. Reduced thrombin formation and excessive fibrinolysis are associated with bleeding complications in patients with dengue fever: a case-control study comparing dengue fever patients with and without bleeding manifestations. BMC INFECTIOUS DISEASES, v. 13, JUL 28 2013. Web of Science Citations: 17.

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