Antiplatelet autoantibodies elicited by dengue virus non‐structural protein 1 cause thrombocytopenia and mortality in mice

Background: The mechanisms responsible for thrombocytopenia associated with dengue fever (DF) and dengue hemorrhage fever (DHF) remain unclear. Objective: In this study, we investigated the pathogenic effects of dengue virus (DENV) non‐structural protein 1 (NS1) on the elicitation of platelet cross‐...

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Published in:Journal of thrombosis and haemostasis 2007-11, Vol.5 (11), p.2291-2299
Main Authors: SUN, D.‐S., KING, C.‐C., HUANG, H.‐S., SHIH, Y.‐L., LEE, C.‐C., TSAI, W.‐J., YU, C.‐C., CHANG, H.‐H.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Viral - adverse effects
Autoantibodies - biosynthesis
Autoantibodies - physiology
autoimmunity
Blood Platelets - immunology
dengue
Dengue - complications
Dengue - mortality
Dengue virus
Dengue Virus - chemistry
Dengue Virus - immunology
hemorrhage fever
Humans
Mice
Mice, Inbred C57BL
platelet
Rabbits
Thrombocytopenia - etiology
Thrombocytopenia - virology
Viral Nonstructural Proteins - immunology
warfarin
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Summary:Background: The mechanisms responsible for thrombocytopenia associated with dengue fever (DF) and dengue hemorrhage fever (DHF) remain unclear. Objective: In this study, we investigated the pathogenic effects of dengue virus (DENV) non‐structural protein 1 (NS1) on the elicitation of platelet cross‐reactive antibodies. Results: The results showed that anti‐DENV NS1 immunoglobulins (Igs) derived from both patients with DF/DHF and recombinant NS1‐immunized rabbits could opsonize normal human platelets and enhance platelet–macrophage engagements in vitro. In addition, treatments with anti‐NS1 Igs abnormally activated human platelets and induced thrombocytopenia in mice. These prothrombotic characteristics of anti‐NS1 Ig might increase the disease burden of coagulant‐aberrant DHF patients. To test this hypothesis, we injected anti‐NS1 Igs into C57BL/6J mice that were preconditioned into a hypercoagulable state by warfarin treatments. When given before but not after platelet‐lysate pre‐adsorption, the anti‐NS1 Igs injection treatments significantly increased mortality, fibrin deposition in lung, and plasma D‐dimer levels, but significantly decreased anticoagulant proteins C, protein S and antithrombin III. Conclusions: These results suggest that the platelet‐bound antibody fractions of anti‐NS1 Ig are prothrombotic, which might exacerbate the severity of disease in hosts with an imbalanced coagulant system.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2007.02754.x