Caracterização das alterações hematológicas em um modelo experimental de dengue hemorrágica

Abstract

Dengue is a mosquito borne viral disease caused by one of the four dengue virus serotypes (DENV-14) and has become a major international public health concern. Treatment of dengue fever and of the severe forms of dengue infection (DHF or DSS) is supportive and until this moment, there are no approved vaccines or antiviral drugs for DENV infection. The pathogenesis of DENV remains poorly understood and involves a complex interplay of viral and host factors. Our group has recently developed murine models of DENV infection which resemble the severe dengue human disease. The primary signs of severe dengue include hemorrhage, increase in vascular permeability and hypovolemic shock, suggesting the occurrence of defects in hemostasis. Hemostasis is maintained by the balance between the activation of coagulation and fibrinolysis. Changes in this system involve mainly three factors: vascular alterations, thrombocytopenia and multiple defects in the coagulation-fibrinolysis system. The present study has evaluated whether there is disturbs of these systems after primary DENV infection in mice. WT (C57BL/6) mice were infected with 10 LD50 of DENV-3, by ip Route, and after 3, 5 or 7 days of infection the analysis were performed. On day 7 after infection, mice presented important hematological alterations, as assessed by the occurrence of thrombocytopenia, platelet dysfunction, hemoconcentration, prolonged partial thromboplastin time (aPTT) and prothrombin time (PT) in comparison with mice infected in previous periods or non-infected mice. In addition, coagulation was measured by whole blood thromboelastography and showed smaller and weaker clot formation after 7 days of infection (represented by reduction of maximum amplitude and R values). So, coagulopathy was found in our experimental model of dengue and showed good association with disease severity. These data corroborate with other findings in literature, including in human infection cases, and allow broader investigations of the impact of changes in this system in the protection or exacerbation the disease. As well, this study signalizes to novel therapeutic targets for severe dengue disease.