Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury

Adam L. Bailey, Liang I. Kang, Luiz Gonzaga Francisco De Assis Barros D'Elia Zanella, Cassia G.T. Silveira, Yeh Li Ho, Lander Foquet, Greg Bial, Broc T. McCune, Amaro Nunes Duarte-Neto, Archana Thomas, Hans Peter Raue, Kathleen Byrnes, Esper G. Kallas, Mark K. Slifka, Michael S. Diamond

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Yellow fever (YF) is a mosquito-transmitted viral disease that causes tens of thousands of deaths each year despite the longstanding deployment of an effective vaccine. In its most severe form, YF manifests as a hemorrhagic fever that causes severe damage to visceral organs. Although coagulopathy is a defining feature of severe YF in humans, the mechanism by which it develops remains uncertain. Hepatocytes are a major target of yellow fever virus (YFV) infection, and the coagulopathy in severe YF has long been attributed to massive hepatocyte infection and destruction that results in a defect in clotting factor synthesis. However, when we analyzed blood from Brazilian patients with severe YF, we found high concentrations of plasma D-dimer, a fibrin split product, suggestive of a concurrent consumptive process. To define the relationship between coagulopathy and hepatocellular tropism, we compared infection and disease in Fah-/-, Rag2-/-, and Il2r.-/-mice engrafted with human hepatocytes (hFRG mice) and rhesus macaques using a highly pathogenic African YFV strain. YFV infection of macaques and hFRG mice caused substantial hepatocyte infection, liver damage, and coagulopathy as defined by virological, clinical, and pathological criteria. However, only macaques developed a consumptive coagulopathy whereas YFV-infected hFRG mice did not. Thus, infection of cell types other than hepatocytes likely contributes to the consumptive coagulopathy associated with severe YF in primates and humans. These findings expand our understanding of viral hemorrhagic disease and associated coagulopathy and suggest directions for clinical management of severe YF cases.

    Original languageEnglish (US)
    Pages (from-to)32648-32656
    Number of pages9
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume117
    Issue number51
    DOIs
    StatePublished - Dec 22 2020

    Keywords

    • Coagulopathy
    • D-dimer
    • Hepatitis
    • Pathogenesis
    • Yellow fever virus

    ASJC Scopus subject areas

    • General

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