A novel canine model of immune thrombocytopenia: has immune thrombocytopenia (ITP) gone to the dogs?

Canine immune thrombocytopenia (ITP) is analogous to human ITP, with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody-mediated ITP was developed. Infusion of healthy dogs with 2F9, a murine IgG2a monoclonal antibody to the canine platelet glycoprotein GPIIb (a common target of autoantibodies in ITP) resulted in profound, dose-dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2F9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin-8 (IL8) in dogs. This finding was confirmed in humans with ITP, suggesting that platelet IL8 may be a previously unrecognized modulator of platelet-neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP

Effect of thrombopoietin-receptor agonists on circulating cytokine and chemokine levels in patients with primary immune thrombocytopenia (ITP)

Background: Thrombopoietin-receptor-agonists (TPO-RAs) increase platelet production in Immune Thrombocytopenia (ITP) by stimulating Mpl. The effect of TPO-RAs on inflammatory cytokine production in ITP patients has not been well investigated. Methods: Plasma samples from 48 ITP patients treated with TPO-RAs (median age 50 years (inter-quartile range; IQR 20–69), median platelet counts 24 × 109/L (IQR 15–47 × 109/L), 28 females) and 16 healthy controls (nine females, median age 37 years, IQR 22–51 years) were collected before and during treatment, and analyzed for a panel of cytokines and chemokines by enzyme-linked immunosorbent assay and immuno-bead-based multiplex assay. Results: Elevated levels of C-X-C motif chemokine 10 (CXCL10; p < 0.001) and osteoprotegerin (OPG; p < 0.05) were observed in pretreatment samples compared to controls; these levels decreased during 6 months of treatment. Pretreatment levels of transforming growth factor (TGF)-β were lower than in healthy controls and increased after 6 months of treatment (p < 0.05). Levels of sCD40L increased after 6 months of treatment (p < 0.05), but decreased thereafter to pretreatment values. The increase in TGF-β and sCD40L may reflect increased platelet turnover. Levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-10 did not change during treatment. Conclusion: These findings suggest that treatment with TPO-RA creates a more balanced steady-state of immune activation