Impaired Thrombin Generation in Patients with Dengue.

Bleeding complications are a main problem in dengue. Besides thrombocytopenia and plasma leakage, coagulation disorders may also be involved in the pathological mechanisms of bleedings. The association between dengue hemorrhagic fever (DHF) and activation of coagulation pathways is controversial. Long activated partial thromboplastin time (aTTP) was demonstrated in some but not all clinical studies in patients with DHF, while prothrombin and thrombin times seems to remain unchanged in these patients. Thrombin generation test (TGT) is a global test of coagulation that determines the maximum thrombin generated (thrombin peak) and the total thrombin generated along time (AUC) triggered by tissue factor, in plasma. TGT has been widely used in clinical studies to determine the integrity of coagulation mechanisms and the response to replacement therapy with hemostatic agents, with reproducible results.

To evaluate the coagulation disorder in patients with dengue by TGT.

Twenty-three patients with confirmed dengue infection were included in the study between January and May 2010, during the disease outbreak in Campinas, SP, Brazil. Twenty-three healthy individuals from the same geographic area and pared with the patients by age and gender, were selected as controls. TGT was performed in the platelet-poor plasma (PPP) of all patients and controls and determined by fluorescence assay. Continuous data were compared using non-parametric Kruskal-Wallis analysis.

Seventeen patients were classified as dengue fever (DF) and 6 as DHF. Mild or moderate bleeding episodes were observed in all DHF and in 4 (23%) DF patients. Median platelets counts were 86,500/uL (3,000–400,000/uL) and 14500/uL (5,000–24,000/uL) in DF and DHF, respectively (P<0.001). Blood counts of hemoglobin, hematocrit and leucocytes were similar between dengue groups. Values of aPTT and INR were within the normal range or only slightly increased, median aPTT was 14.4”(13 – 24”) and INR was 1.1 (0.9 – 1.8) in dengue patients. However, thrombin generation was decreased in patients with dengue. Median thrombin peak levels were 338,7nM (145–512,2 nM) in controls, 278,2 nM (70,7 – 432,3 nM) in DF and 226,1 nM (92,2 – 326,7 nM) in DHF (P=0,017). Median AUC values were 3753 (2230–4906) in controls, 3178 (1513–4284) in DF and 2488 (1232–3284) in DHF (P=0,004).

Our results suggest that the thrombin generation is impaired in patients with DHF. Interestingly, patients with DF may also present with bleeding complications and impaired TGT. The causes for coagulation disorders in dengue are not fully understood, plasma coagulation factors seem to have normal activity while the activity of natural anticoagulants may be altered in patients with DHF. Previous studies have failed to confirm the coagulation disorder in dengue possibly because none of them has used global coagulation tests, such as TGT, before. It is possible that the decreased thrombin generation, in association with plasma leakage and thrombocytopenia, contributes to bleeding disorders in dengue.

No relevant conflicts of interest to declare.