Activation of Endothelial Cells, Coagulation and Fibrinolysis in Thai Children with Dengue Virus Infection.

Dengue virus is an arthropod borne flavivirus that most commonly causes a non-specific febrile illness: Dengue Fever (DF), and less frequently causes a life-threatening illness: Dengue Hemorrhagic Fever (DHF). The fatality rates of DHF are varying from 1 to 5% in tropical countries. Although severe bleeding remains the major cause of death, the pathogenesis of bleeding is poorly understood. This study was primarily designed to determine the extent of activation of endothelial cells, coagulation cascade and fibrinolysis in correlation with clinical severity and also to detect the best prognostic factor(s) for DHF during the febrile phase. We conducted a prospective cohort study in 42 children with Dengue infections (20 with DF and 22 with DHF); 38 age-matched normal Thai children served as the control group. Endothelial cell activation, coagulation and fibrinolysis parameters were measured in each patient during 3 phases of illness: febrile (Days 1–4), toxic (Days 5–6) and convalescent (Day 7–10). Bleeding scores (Buchanan G, et al, J Pediatr 2002) were also classified.

Results: In DHF patients, during the febrile phase, plasma levels of von Willebrand Factor Antigen (VWF:Ag), tissue factor (TF), Thrombin-Antithrombin Complex (TAT), and D-dimer were significantly high, while platelet counts, fibrinogen, Protein C activity (PC:Ac) and thrombin activatable fibrinolysis inhibitor (TAFIa) were significantly low compared to the control group. During the toxic phase, activated Factor VII (FVIIa:c), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) were significantly increased compared to the control group. In DF patients, during the febrile phase, only plasma levels of VWF:Ag were significantly elevated, while platelet count, PC:Ac and TAFIa were significantly lowered compared to the control group. During the toxic phase, soluble thrombomodulin (sTM), FVIIa:c, and TAT were significantly raised compared to the control group. Compared to DF patients, DHF patients had significantly higher plasma concentrations of vWF:Ag (p=0.02), TF (p=0.01), and PAI-1 (p=0.038) during the febrile phase. Bleeding scores were positively correlated with plasma t-PA and clinical severity, and negatively correlated with plasma Factor VIII:C and TAFIa. Using logistic regression analysis, we found that an increase in plasma VWF:Ag was the only significant predictor (p=0.049) of progression to DHF. The endothelial cell injury and release of procoagulant components, activation of the coagulation cascade with thrombin generation, increased antifibrinolytic factors and consumption of natural anticoagulants each play important roles in the development of hemorrhage in Dengue patients. Plasma VWF:Ag is the best indicator of progression to DHF.