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

Abstract

BackgroundDengue cases have been classified according to disease severity into dengue fever (DF) and dengue hemorrhagic fever (DHF). Although DF is considered a non-severe manifestation of dengue, it has been recently demonstrated that DF represents a heterogeneous group of patients with varied clinical complications and grades of severity. Particularly, bleeding complications, commonly associated to DHF, can be detected in half of the patients with DF. Although a frequent complication, the causes of bleedings in DF have not been fully addressed. Thus, the aim of this study was to perform a comprehensive evaluation of possible pathophysiological mechanisms that could contribute to the bleeding tendency observed in patients with DF.MethodsThis is a case–control study that enrolled adults with DF without bleeding and adults with DF and bleeding complications during the defervescence period. Healthy controls were also included. Peripheral blood counts, inflammatory, fibrinolysis and endothelial cell activation markers, and thrombin generation were evaluated in patients and controls.ResultsWe included 33 adults with DF without complications, 26 adults with DF and bleeding and 67 healthy controls. Bleeding episodes were mild in 15 (57.6%) and moderate in 11 (42.4%) patients, 8 (30.7%) patients had bleedings in multiple sites. Patients with DF and bleedings had lower platelet counts than DF without bleeding (median = 19,500 vs. 203,500/mm3, P < 0,0001). Levels of TNF-α, thrombomodulin and VWF were significantly increased in the two dengue groups than in healthy controls, but similar between patients with and without bleedings. Plasma levels of tPA and D-dimer were significantly increased in patients with bleedings (median tPA levels were 4.5, 5.2, 11.7 ng/ml, P < 0.0001 and median D-dimer levels were 515.5, 1028 and 1927 ng/ml, P < 0.0001). The thrombin generation test showed that patients with bleeding complications had reduced thrombin formation (total thrombin generated were 3753.4 in controls, 3367.5 in non-bleeding and 2274.5nM in bleeding patients, P < 0.002).ConclusionsDF can manifest with spontaneous bleedings, which are associated with specific coagulation and fibrinolysis profiles that are not significantly present in DF without this complication. Particularly, thrombocytopenia, excessive fibrinolysis and reduced thrombin formation may contribute to the bleeding manifestations in DF.

Biomarkers in differentiating clinical dengue cases: A prospective cohort study

“…Our study on thrombomodulin level in dengue infection is in agreement with some studies where thrombomodulin could not differentiate the clinical dengue cases [24,30], but not in many other studies [14,18,19,[30][31][32][33]. However, those studies conducted were in children which itself is a higher risk of severe complication and thus reflected in the elevated thrombomodulin levels [14,18,19,31].…”

The coagulation profile of children admitted with dengue fever and correlation with clinical severity

“…This observation was important as impaired fibrinolysis and coagulation is considered to be a potential pathogenic mechanism of severe dengue. [7][8][9][10][11][12][13] Khalil et al showed coagulopathy as a significant risk factor for mortality as well.…”

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

“…Despite being more frequently associated with DHF, a bleeding tendency can independently occur in the absence of plasma leakage, i.e., in DF patients (3). Many factors have been shown to contribute to bleeding in DENV infection, including thrombocytopenia, reduced thrombin formation, and increased fibrinolysis activity (39,40), yet the pathogenesis of bleeding complications is not fully understood. To further investigate whether circulating MPs influence the outcome of bleeding, all dengue virus-infected patients were separated into two groups according to their history of bleeding, i.e., a bleeding group (total number of patients ϭ 18; number of DHF patients ϭ 13, number of DF patients ϭ 5) and a no-bleeding group (total number of patients ϭ 25; number of DHF patients ϭ 11, number of DF patients ϭ 14), regardless of plasma leakage.…”