Endothelial Activation, FVW and ADAMTS 13 imbalance and Fibrinolysis Impairment in Adults with Dengue Fever with Bleeding Complications,

Abstract 3325

Dengue fever has enormous health and economic impact in Latin America, Africa, India and Southeast Asia. In Brazil, an increasing number of severe cases of dengue have been notified, especially those with bleeding complications. Classically, the bleeding episodes in dengue have been attributed to an increased vascular permeability, but in many cases there is no evidence of vascular changes that justify the clinical bleeding. Several coagulation disorders may contribute to the occurrence of bleeding complications in dengue and knowledge of these disorders can lead to more specific treatment of the disease, in addition to conventional treatment based on fluid replacement. The aim of this study is to evaluate how the different homeostatic mechanisms behave in adults with complicated dengue fever, focusing on the modulators of capillar permeability, VWF, ADAMTS 13 and fibrinolysis parameters, correlating them with the clinical presentation of disease. Patients and methods: We recruited patients with the diagnosis of complicated dengue fever between March and May 2008 in the General Hospital of Ipanema, in Rio de Janeiro, and in the Clinical Hospital of UNICAMP, in Campinas. Alongside healthy individuals were recruited as controls. The analysis of plasma levels of VWF, tPA, D-dimer, TNF-alpha, thrombomodulin and PAI-1 were performed by ELISA. The ADAMTS 13 activity was quantified by residual binding of VWF to collagen. Results: We included 35 adult patients with dengue complicated by bleedings (DCB) and 50 controls. The diagnosis of dengue hemorrhagic fever (DHF) was done only in three patients who had pleural effusion, the other cases had no clinical signs of increased vascular permeability, the criteria for the diagnosis of DHF. The group of patients with DCB presented,comparing to controls, increased levels of VWF (median = 244.1 vs. 136.9 U/ml, P <0.0001), decreased ADAMTS13 activity (median = 72.4 vs. 125 7%, P <0.0001), increased TNF-alpha (median 2.35 vs. 1.90 pg/ml, P = 0.038), increased thrombomodulin (median 6.15 vs. 4.79 ng/ml, P = 0.0003), increased tPA antigen (median 10.8 vs. 4.2 ng/ml, P <0.0001) and increased D-dimer plasma levels (median 1745 versus 478ng/ml, P <0.0001). There was no statistical difference between patients and controls with regard to the serum levels of VEGF (median = 34.8 vs. 19.1 pg/ml) and plasma levels of PAI-1 (median = 7.4 vs. 6.5 U/ml). We also performed correlation analyzes between the different parameters studied. Thus, we found that the platelet count was indirectly correlated with plasma levels of tPA (r = −0.3432, 95% CI = −0.5921 to −0.03451, P = 0.0261) and D-dimer (r = −0.3996, 95% CI = −0.6381 to −0.09112, P = 0.0106). Conclusion: The increased plasma levels of VWF, tPA and thrombomodulin suggest a possible endothelial activation in patients with DCB, followed by stimulation of fibrinolysis. The activation of fibrinolysis in dengue fever have been described in children patients previously. Interestingly, normal levels of VEGF in these patients with DCB suggest that there is no impairment in vascular permeability in these cases. Then, fibrinolysis and thrombocytopenia seems to be the main causes of bleeding in this study. Patients with moderate to severe thrombocytopenia had the highest plasma levels of tPA and D-dimer, thus suggesting that increased levels of these proteins could be related to disease severity in adult patients.