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Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities.

ABSTRACT: Dengue virus (DENV) is transmitted by the mosquito vector, and causes a wide range of symptoms that lead to dengue fever (DF) or life-threatening dengue hemorrhagic fever (DHF). The host and viral correlates that contribute to DF and DHF are complex and poorly understood, but appear to be linked to inflammation and impaired coagulation. Full-length osteopontin (FL-OPN), a glycoprotein, and its activated thrombin-cleaved product, trOPN, integrate multiple immunological signals through the induction of pro-inflammatory cytokines.To understand the role of OPN in DENV-infection, we assessed circulating levels of FL-OPN, trOPN, and several coagulation markers (D-dimer, thrombin-antithrombin complex [TAT], thrombomodulin [TM], and ferritin in blood obtained from 65 DENV infected patients in the critical and recovery phases of DF and DHF during a dengue virus epidemic in the Philippines in 2010.Levels of FL-OPN, trOPN, D-dimer, TAT, and TM were significantly elevated in the critical phase in both the DF and DHF groups, as compared with healthy controls. During the recovery phase, FL-OPN levels declined while trOPN levels increased dramatically in both the DF and DHF groups. FL-OPN levels were directly correlated with D-dimer and ferritin levels, while the generation of trOPN was associated with TAT levels, platelet counts, and viral RNA load.Our study demonstrated the marked elevation of plasma levels of FL-OPN and thrombin-cleaved OPN product, trOPN, in DENV-infection for the first time. Further studies on the biological functions of these matricellular proteins in DENV-infection would clarify its pathogenesis.

SUBMITTER: Chagan-Yasutan H

PROVIDER: S-EPMC4112014 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities.

Chagan-Yasutan Haorile H Lacuesta Talitha Lea TL Ndhlovu Lishomwa C LC Oguma Shigeru S Leano Prisca Susan A PS Telan Elizabeth Freda O EF Kubo Toru T Morita Kouichi K Uede Toshimitsu T Dimaano Efren M EM Hattori Toshio T

Thrombosis research 20140514 2

<h4>Introduction</h4>Dengue virus (DENV) is transmitted by the mosquito vector, and causes a wide range of symptoms that lead to dengue fever (DF) or life-threatening dengue hemorrhagic fever (DHF). The host and viral correlates that contribute to DF and DHF are complex and poorly understood, but appear to be linked to inflammation and impaired coagulation. Full-length osteopontin (FL-OPN), a glycoprotein, and its activated thrombin-cleaved product, trOPN, integrate multiple immunological signal ...[more]

PMID: 24861695

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Project description:BackgroundFactor XII (FXII) activation initiates the intrinsic (contact) coagulation pathway. It has been recently suggested that FXII could act as an autoimmunity mediator in multiple sclerosis (MS). FXII depositions nearby dentritic cells were detected in the central nervous system of MS patients and increased FXII activity has been reported in plasma of relapsing remitting and secondary progressive MS patients. FXII inhibition has been proposed to treat MS.ObjectiveTo investigate in MS patients multiple FXII-related variables, including the circulating amount of protein, its pro-coagulant function, and their variation over time. To explore kinetic activation features of FXII in thrombin generation (TG).MethodsIn plasma from 74 MS patients and 49 healthy subjects (HS), FXII procoagulant activity (FXII:c) and FXII protein (FXII:Ag) levels were assessed. Their ratio (FXII:ratio) values were derived. Intrinsic TG was evaluated by different triggers.ResultsHigher FXII:Ag levels (p = 0.003) and lower FXII:ratio (p < 0.001) were detected in MS patients compared with HS. FXII variables were highly correlated over four time points, which supports investigation of FXII contribution to disease phenotype and progression. A significant difference over time was detected for FXII:c (p = 0.031). In patients selected for the lowest FXII:ratio, TG triggered by ellagic acid showed a trend in lower endogenous thrombin potential (ETP) in MS patients compared with HS (p = 0.042). Intrinsic triggering of TG by nucleic acid addition produced longer time parameters in patients than in HS and substantially increased ETP in MS patients (p = 0.004) and TG peak height in HS (p = 0.008). Coherently, lower FXII:ratio and longer lag time (p = 0.02) and time to peak (p = 0.007) point out a reduced response of FXII to activation in part of MS patients.ConclusionIn MS patients, factor-specific and modified global assays suggest the presence of increased FXII protein level and reduced function within the intrinsic coagulation pathway. These novel findings support further investigation by multiple approaches of FXII contribution to disease phenotype and progression.

Project description:BackgroundCoagulation mechanisms are reported to be affected in dengue illness and evidenced by prolonged activated partial thromboplastin time (APTT) and prothrombin time (PT). The main aim of this systematic review and meta-analysis is to determine the magnitude of coagulation abnormalities among patients with dengue fever infection.MethodThis systematic review and meta-analysis were conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. The Joana Brigg's Institute (JBI) critical appraisal checklist was used for quality appraisal. STATA version 11 software was used for meta-analysis. The magnitude of coagulation abnormalities among dengue fever patients was determined by using a random-effects model. Subgroup and sensitivity analysis were performed to investigate the possible source of heterogeneity. Egger weighted regression tests were used to check the presence of publication bias among the included articles.ResultForty-two studies with a total of 12,221 dengue fever patients were eligible for meta-analysis in this study. Of which 22, 15, and 26 studies were used to determine the magnitude of prolonged APTT, PT, and thrombocytopenia, respectively. The magnitude of prolonged APTT and PT among patients with dengue fever infection were 42.91% (95% CI: 30.95, 54.87) I2 = 99.1% and 16.48% (95% CI: 10.95, 22.01) I2 = 97.0%, respectively. Besides, the magnitude of thrombocytopenia among dengue fever patients was 70.29% (95% CI: 62.69, 77.89) I2 = 99.3%. The magnitude of prolonged APTT in children and adults was 51.21% (95% CI: 24.54, 77.89) and 44.89% (95% CI: 28.32, 61.45), respectively. Similarly, the overall magnitude of prolonged PT in children and adults were 13.40% (95% CI: 6.09, 20.71) and 18.73% (95% CI: 7.49, 29.96), respectively.ConclusionThe result of this study showed that there is a high magnitude of prolonged APTT and PT in dengue fever patients. Therefore, screening and early correction of coagulation abnormalities may be helpful to reduce further complications in those patients.

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Project description:UnlabelledDengue virus (DENV) is the most common cause of viral hemorrhagic fever, and it may lead to life-threating dengue hemorrhagic fever and shock syndrome (DHF/DSS). Because most cases of DHF/DSS occur in patients with secondary DENV infection, anti-DENV antibodies are generally considered to play a role in the pathogenesis of DHF/DSS. Previously, we have found that antithrombin antibodies (ATAs) with both antithrombotic and profibrinolytic activities are present in the sera of dengue patients. However, the mechanism by which these autoantibodies are induced is unclear. In this study, we demonstrated that antibodies induced by DENV immunization in mice and rabbits could bind to DENV antigens as well as to human thrombin and plasminogen (Plg). The binding of anti-DENV antibodies to thrombin and Plg was inhibited by preadsorption with DENV nonstructural protein 1. In addition, affinity-purified ATAs from DENV-immunized rabbit sera could inhibit thrombin activity and enhance Plg activation both in vitro and in vivo. Taken together, our results suggest that molecular mimicry between DENV and coagulation factors can induce the production of autoantibodies with biological effects similar to those of ATAs found in dengue patients. These coagulation-factor cross-reactive anti-DENV antibodies can interfere with the balance of coagulation and fibrinolysis, which may lead to the tendency of DHF/DSS patients to bleed.ImportanceDengue virus (DENV) infection is the most common mosquito-borne viral disease in tropical and subtropical areas. Over 50 million DENV infection cases develop each year, and more than 2.5 billion people are at risk of dengue-induced hemorrhagic fever and shock syndrome. Currently, there is no vaccine or drug treatment for DENV. In the present study, we demonstrated that DENV immunization could induce thrombin and plasminogen (Plg) cross-reactive antibodies, which were able to inhibit thrombin activity and enhance Plg activation. These results suggest that molecular mimicry between DENV antigens, thrombin, and Plg may elicit antibodies that disturb hemostasis. The selection of appropriate candidate antigens for use in DENV vaccines should prevent these potentially dangerous autoimmune responses.

Dataset Information

Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities.

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Elevated levels of full-length and thrombin-cleaved osteopontin during acute dengue virus infection are associated with coagulation abnormalities.

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