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Dissecting pathways to thrombocytopenia in a mouse model of visceral leishmaniasis

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JournalBlood Advances
DateAccepted/In press - 8 Feb 2021
DateE-pub ahead of print (current) - 12 Mar 2021
Issue number6
Volume5
Number of pages11
Pages (from-to)1627-1637
Early online date12/03/21
Original languageEnglish

Abstract

Visceral leishmaniasis is an important yet neglected parasitic disease caused by infection with Leishmania donovani or L infantum. Disease manifestations include fever, weight loss, hepatosplenomegaly, immune dysregulation, and extensive hematological complications. Thrombocytopenia is a dominant hematological feature seen in both humans and experimental models, but the mechanisms behind this infection-driven thrombocytopenia remain poorly understood. Using a murine model of experimental visceral leishmaniasis (EVL), we demonstrated a progressive decrease in platelets from day 14 after infection, culminating in severe thrombocytopenia by day 28. Plasma thrombopoietin (TPO) levels were reduced in infected mice, at least in part because of the alterations in the liver microenvironment associated with granulomatous inflammation. Bone marrow (BM) megakaryocyte cytoplasmic maturation was significantly reduced. In addition to a production deficit, we identified significant increases in platelet clearance. L donovani-infected splenectomized mice were protected from thrombocytopenia compared with sham operated infected mice and had a greater response to exogenous TPO. Furthermore, infection led to higher levels of platelet opsonization and desialylation, both associated with platelet clearance in spleen and liver, respectively. Critically, these changes could be reversed rapidly by drug treatment to reduce parasite load or by administration of TPO agonists. In summary, our findings demonstrate that the mechanisms underpinning thrombocytopenia in EVL are multifactorial and reversible, with no obvious residual damage to the BM microenvironment.

Bibliographical note

© 2021 by The American Society of Hematology.

    Research areas

  • Animals, Disease Models, Animal, Leishmaniasis, Visceral/complications, Megakaryocytes, Mice, Thrombocytopenia, Thrombopoietin

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