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Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis.
J Innate Immun 2019; 11(2):168-180JI

Abstract

Platelet-dense (δ) granules are important for platelet function. Platelets contribute to host defense and vascular integrity during pneumonia and sepsis, and δ granule products, including adenosine diphosphate (ADP), can influence inflammatory responses. We therefore aimed to study the role of platelet δ granules in the host response during sepsis. Hermansky-Pudlak syndrome (Hps)3coa mice (with reduced δ granule content), mice treated with the platelet ADP receptor inhibitor clopidogrel, and appropriate control mice were infected with the human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia and sepsis. In order to override potential redundancy in platelet functions, we also studied Hps3coa and control mice with moderate antibody-induced thrombocytopenia (10%) prior to infection. We found that sepsis-induced thrombocytopenia tended to be less severe in Hps3coa mice, and was significantly ameliorated in Hps3coa mice with low pre-infection platelet counts. Bacterial growth was similar in Hps3coa and control mice in the presence of normal platelet counts prior to infection, but lower in the lungs of Hps3coa mice with low pre-infection platelet counts. Hps3coa mice had unaltered lung pathology and distant organ injury during pneumosepsis, irrespective of pre-infection platelet counts; lung bleeding did not differ between Hps3coa and control mice. Clopidogrel did not influence any host response parameter. These data suggest that platelet δ granules can play a detrimental role in pneumosepsis by aggravating thrombocytopenia and impairing local antibacterial defense, but that these unfavorable effects only become apparent in the presence of low platelet counts.

Authors+Show Affiliations

Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, t.a.claushuis@amc.uva.nl.Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30557883

Citation

Claushuis, Theodora A M., et al. "Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia During Gram-Negative Pneumonia-Derived Sepsis." Journal of Innate Immunity, vol. 11, no. 2, 2019, pp. 168-180.
Claushuis TAM, de Vos AF, Roelofs JJTH, et al. Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis. J Innate Immun. 2019;11(2):168-180.
Claushuis, T. A. M., de Vos, A. F., Roelofs, J. J. T. H., de Boer, O. J., van 't Veer, C., & van der Poll, T. (2019). Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis. Journal of Innate Immunity, 11(2), pp. 168-180. doi:10.1159/000494147.
Claushuis TAM, et al. Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia During Gram-Negative Pneumonia-Derived Sepsis. J Innate Immun. 2019;11(2):168-180. PubMed PMID: 30557883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Platelet-Dense Granules Worsen Pre-Infection Thrombocytopenia during Gram-Negative Pneumonia-Derived Sepsis. AU - Claushuis,Theodora A M, AU - de Vos,Alex F, AU - Roelofs,Joris J T H, AU - de Boer,Onno J, AU - van 't Veer,Cornelis, AU - van der Poll,Tom, Y1 - 2018/12/17/ PY - 2018/08/11/received PY - 2018/09/23/accepted PY - 2018/12/18/pubmed PY - 2018/12/18/medline PY - 2018/12/18/entrez KW - Animal models KW - Bacterial infection KW - Host defense KW - Platelets KW - Sepsis SP - 168 EP - 180 JF - Journal of innate immunity JO - J Innate Immun VL - 11 IS - 2 N2 - Platelet-dense (δ) granules are important for platelet function. Platelets contribute to host defense and vascular integrity during pneumonia and sepsis, and δ granule products, including adenosine diphosphate (ADP), can influence inflammatory responses. We therefore aimed to study the role of platelet δ granules in the host response during sepsis. Hermansky-Pudlak syndrome (Hps)3coa mice (with reduced δ granule content), mice treated with the platelet ADP receptor inhibitor clopidogrel, and appropriate control mice were infected with the human sepsis pathogen Klebsiella pneumoniae via the airways to induce pneumonia and sepsis. In order to override potential redundancy in platelet functions, we also studied Hps3coa and control mice with moderate antibody-induced thrombocytopenia (10%) prior to infection. We found that sepsis-induced thrombocytopenia tended to be less severe in Hps3coa mice, and was significantly ameliorated in Hps3coa mice with low pre-infection platelet counts. Bacterial growth was similar in Hps3coa and control mice in the presence of normal platelet counts prior to infection, but lower in the lungs of Hps3coa mice with low pre-infection platelet counts. Hps3coa mice had unaltered lung pathology and distant organ injury during pneumosepsis, irrespective of pre-infection platelet counts; lung bleeding did not differ between Hps3coa and control mice. Clopidogrel did not influence any host response parameter. These data suggest that platelet δ granules can play a detrimental role in pneumosepsis by aggravating thrombocytopenia and impairing local antibacterial defense, but that these unfavorable effects only become apparent in the presence of low platelet counts. SN - 1662-8128 UR - https://www.unboundmedicine.com/medline/citation/30557883/Platelet_Dense_Granules_Worsen_Pre_Infection_Thrombocytopenia_during_Gram_Negative_Pneumonia_Derived_Sepsis_ L2 - https://www.karger.com?DOI=10.1159/000494147 DB - PRIME DP - Unbound Medicine ER -