Targeting serotonin receptors reduces thrombocytopenia by limiting platelet activation. (A) DENV infection in WT mice decreased platelet counts 3 days postinfection, which was reversed by ketanserin treatment (8 mg/kg; n = 7). (B) Ketanserin treatment in DENV-infected mice significantly reduced platelet activation compared with vehicle-treated controls, determined by flow cytometry, after staining blood isolated 24 hours postinfection for activated platelets (CD41+CD62P+) (n = 4). Flow cytometry gating strategy is presented in supplemental Figure 2A. (C) Platelets were labeled in mice through injection of an antibody against GP1b before infection. Spleens of DENV2-infected mice were isolated 3 days postinfection, and cells were stained for CD11b and F4/80 and analyzed by flow cytometry. There was a significant decrease in the numbers of Platelet+ Macrophages (CD11b+F4/80+GP1b+) in ketanserin-treated mice compared with vehicle-treated controls (n = 3-4). Flow cytometry gating strategy is presented in supplemental Figure 2B. (D) Staining of peripheral blood smears day 3 postinfection showed the presence of aggregates (surrounded by dashed lines) in vehicle-treated mice but no aggregates (individual platelets indicated by arrow) in ketanserin-treated mice. Scale bar, 25 μm. (E-F) IFNR-KO mice were infected with DENV2 and treated with 8 mg/kg ketanserin or vehicle daily. (E) Ketanserin treatment rescued platelet counts during DENV infection. (F) Ketanserin treatment of DENV-infected mice resulted in a significant reduction in platelet activation compared with vehicle treated-controls at day 3 postinfection (n = 4-5 per group). (G) WT mice were infected with DENV2 and treated with ketanserin (8 mg/kg), sarpogrelate (3 mg/kg), or vehicle. Treatment with either 5HT2A antagonist rescued thrombocytopenia during DENV infection, compared with vehicle-treated controls. Data represent the mean and error bars represent the standard error of the mean. P values were determined by Student’s unpaired t test or by 1-way ANOVA (G). *P < .05; **P < .01; ***P < .001; ****P < .0001.