Hemostatic derangement in dengue hemorrhagic fever

Chuansumrit, Ampaiwan; Chaiyaratana, Wathanee

doi:10.1016/j.thromres.2013.09.028

Cited by 57 publications

(61 citation statements)

References 18 publications

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“…In humans, sunitinib treatment has been reported to reduce hematocrit and both WBC and platelet cell counts (Korkmaz et al, 2014; Kucharz et al, 2016; Zhu et al, 2011). Moreover, elevated TNF levels, hematocrit, and WBC count and thrombocytopenia are associated with Severe Dengue (Chuansumrit and Chaiyaratana, 2014; WHO, 2009). We thus compared these parameters in mice with sunitinib versus vehicle treatment.…”

Section: Resultsmentioning

confidence: 99%

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

et al. 2018

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Dengue virus (DENV) currently circulates in more than 100 countries and causes an estimated 390 million infections per year. While most cases manifest as a self-resolving fever, ∼1.5% of infections develop into a more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes ∼20,000 deaths annually. The underlying pathological feature of DHF/DSS, also known as Severe Dengue, is an acute increase in vascular permeability leading to hypovolemia and shock. Angiogenic factors and cytokines, such as vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF), have been implicated in the increased vascular permeability, suggesting a potential therapeutic strategy for Severe Dengue. Here, we employed a mouse model of antibody-dependent enhancement of DENV infection, which recapitulates the fatal capillary leakage and shock of human Severe Dengue, to investigate the effects of approved VEGF- and TNF-targeting drugs. DENV infection caused a significant increase in serum VEGF levels within 2 days and resulted in ∼80% mortality within 8 days of infection. Treatment of mice with sunitinib, a VEGF receptor tyrosine kinase inhibitor, once (day 2) or twice (days 1 and 2) post-infection reduced mortality by 50-80% compared with untreated mice. Notably, sunitinib treatment decreased serum TNF levels, white blood cell counts, and hematocrit levels relative to untreated mice, but had only marginal effects on tissue viral burden. Combination therapy with anti-TNF antibody and sunitinib significantly reduced vascular leakage and synergized to provide superior protection from lethal DENV infection compared with either agent alone. These data suggest that a two-pronged anti-angiogenic and anti-inflammatory approach may be useful for the rapid treatment of DHF/DSS.

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Section: Resultsmentioning

confidence: 99%

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

et al. 2018

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“…Adding to the initial events leading to DENV-induced thrombocytopenia, 15 thrombin treatment of platelets approximately doubled the number of sites. Therefore, combining treatments to restrict coagulation enzyme activation 11,37 and receptor engagement 12 by DENV may optimally protect Figure 7. Platelet-mediated replication and translation of DENV RNA.…”

Section: Discussionmentioning

confidence: 99%

Dengue virus binding and replication by platelets

Simon

Sutherland

Pryzdial

2015

Blood

142

161

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Key Points• Platelets replicate and produce infectious DENV.• DENV binds directly to platelets using DC-SIGN and heparan sulfate proteoglycan as primary receptors.Dengue virus (DENV) infection causes ∼200 million cases of severe flulike illness annually, escalating to life-threatening hemorrhagic fever or shock syndrome in ∼500 000. Although thrombocytopenia is typical of both mild and severe diseases, the mechanism triggering platelet reduction is incompletely understood. As a probable initiating event, direct purified DENV-platelet binding was followed in the current study by quantitative reverse transcription-polymerase chain reaction and confirmed antigenically. Approximately 800 viruses specifically bound per platelet at 37°C. Fewer sites were observed at 25°C, the blood bank storage temperature (∼350 sites), or 4°C, known to attenuate virus cell entry (∼200 sites). Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and heparan sulfate proteoglycan were implicated as coreceptors because only the combination of anti-DC-SIGN and lowmolecular-weight heparin prevented binding. Interestingly, at 37°C and 25°C, platelets replicated the positive sense single-stranded RNA genome of DENV by up to ∼4-fold over 7 days. Further time course experiments demonstrated production of viral NS1 protein, which is known to be highly antigenic in patient serum. The infectivity of DENV intrinsically decayed in vitro, which was moderated by plateletmediated generation of viable progeny. This was shown using a transcription inhibitor and confirmed by freeze-denatured platelets being incapable of replicating the DENV genome. For the first time, these data demonstrate that platelets directly bind DENV saturably and produce infectious virus. Thus, expression of antigen encoded by DENV is a novel consideration in the pathogen-induced thrombocytopenia mechanism. These results furthermore draw attention to the possibility that platelets may produce permissive RNA viruses in addition to DENV. (Blood. 2015;126(3):378-385)

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“…Of note, we found that APTT prolongation was a prognostic factor in our critically ill adults with severe dengue. DENV can cause derangement of the coagulation system [42], and APTT had more frequently been reported to be prolonged than PT in patients with DHF [43, 44]. Direct liver involvement by dengue virus is common in symptomatic patients with DF, and this can result in decreased production of coagulation factors [45].…”

Section: Discussionmentioning

confidence: 99%

A Cohort Study of Adult Patients with Severe Dengue in Taiwanese Intensive Care Units: The Elderly and APTT Prolongation Matter for Prognosis

et al. 2017

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BackgroundThere was a large dengue outbreak in Taiwan in 2015, in which the ages of the affected individuals were higher than those in other countries. The aim of this study was to explore the characteristics and prognostic factors for adults with severe dengue in intensive care units (ICUs).MethodsAll adults admitted to ICUs with dengue virus infection (DENV) at a medical center from July 1, 2015 to December 31, 2015 were enrolled. DENV was diagnosed by the presence of serum NS1 antigen, IgM antibodies to dengue virus, or dengue virus RNA by real-time reverse transcriptase polymerase chain reaction. Demographic data, clinical features, and lab data were collected, and a multivariate Cox model was used to identify the predictive factors for in-hospital mortality.ResultsSeventy-five patients admitted to ICUs with laboratory-confirmed DENV were enrolled (mean age 72.3±9.3 years). The most common comorbidities included hypertension (72.0%), diabetes (43.7%), and chronic kidney disease (22.7%). The in-hospital case fatality rate (CFR) was 41.3%. The patients who died were predominantly female, had higher disease severity at ICU admission, shorter ICU/hospital stay, longer initial activated partial thromboplastin time (APTT), and higher initial serum aspartate transaminase levels. Cardiac arrest before ICU admission (hazard ratio [HR]: 6.26 [1.91–20.54]), prolonged APTT (>48 seconds; HR: 3.91 [1.69–9.07]), and the presence of acute kidney injury on admission (HR: 2.48 [1.07–5.74]), were independently associated with in-hospital fatality in the Cox multivariate analysis.ConclusionDuring the 2015 dengue outbreak in Taiwan, the patients with severe dengue in ICUs were characterized by old age, multiple comorbidities, and a high CFR. Organ failure (including cardiac failure, and renal failure) and coagulation disturbance (prolongation of initial APTT) were independent predictive factors for in-hospital fatality.

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Hemostatic derangement in dengue hemorrhagic fever

Cited by 57 publications

References 18 publications

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

Dengue virus binding and replication by platelets

A Cohort Study of Adult Patients with Severe Dengue in Taiwanese Intensive Care Units: The Elderly and APTT Prolongation Matter for Prognosis

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