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Direct and indirect effects of Puumala hantavirus on platelet function
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
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2024 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 233, p. 41-54Article in journal (Refereed) Published
Abstract [en]

Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target.

Place, publisher, year, edition, pages
2024. Vol. 233, p. 41-54
Keywords [en]
Hemorrhagic fever with renal syndrome, Immunothrombosis, Infection, Platelet dysfunction, Puumala hantavirus, Thrombocytopenia
National Category
Hematology
Identifiers
URN: urn:nbn:se:umu:diva-217532DOI: 10.1016/j.thromres.2023.11.017Scopus ID: 2-s2.0-85177814613OAI: oai:DiVA.org:umu-217532DiVA, id: diva2:1819511
Funder
Region Västerbotten, RV-967545Region Västerbotten, RV-734361Umeå UniversitySwedish Heart Lung Foundation, 20170334Swedish Research Council, 2020-06235The Kempe Foundations, SMK-1560Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2023-12-14Bibliographically approved

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Waltraud, SchrottmaierThunberg, ThereseWigren, JuliaFors Connolly, Anne-MarieAhlm, ClasForsell, Mattias N. E.

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