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      Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

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          Abstract

          Publisher's Note: There is a [Related article:] Blood Commentary on this article in this issue.

          Key Points

          • PGN infusion mimics the systemic inflammation and coagulopathy observed in late-stage B anthracis challenge.

          • PGN directly activates the extrinsic coagulation and promotes contact pathway amplification in nonhuman primates.

          Abstract

          Anthrax infections exhibit progressive coagulopathies that may contribute to the sepsis pathophysiology observed in fulminant disease. The hemostatic imbalance is recapitulated in primate models of late-stage disease but is uncommon in toxemic models, suggesting contribution of other bacterial pathogen-associated molecular patterns (PAMPs). Peptidoglycan (PGN) is a bacterial PAMP that engages cellular components at the cross talk between innate immunity and hemostasis. We hypothesized that PGN is critical for anthrax-induced coagulopathies and investigated the activation of blood coagulation in response to a sterile PGN infusion in primates. The PGN challenge, like the vegetative bacteria, induced a sepsis-like pathophysiology characterized by systemic inflammation, disseminated intravascular coagulation (DIC), organ dysfunction, and impaired survival. Importantly, the hemostatic impairment occurred early and in parallel with the inflammatory response, suggesting direct engagement of coagulation pathways. PGN infusion in baboons promoted early activation of contact factors evidenced by elevated protease-serpin complexes. Despite binding to contact factors, PGN did not directly activate either factor XII (FXII) or prekallikrein. PGN supported contact coagulation by enhancing enzymatic function of active FXII (FXIIa) and depressing its inhibition by antithrombin. In parallel, PGN induced de novo monocyte tissue factor expression in vitro and in vivo, promoting extrinsic clotting reactions at later stages. Activation of platelets further amplified the procoagulant state during PGN challenge, leading to DIC and subsequent ischemic damage of peripheral tissues. These data indicate that PGN may be a major cause for the pathophysiologic progression of Bacillus anthracis sepsis and is the primary PAMP behind the pathogen-induced coagulopathy in late-stage anthrax.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          23 August 2018
          19 June 2018
          23 August 2018
          : 132
          : 8
          : 849-860
          Affiliations
          [1 ]Department of Arthritis and Clinical Immunology and
          [2 ]Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK;
          [3 ]Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK;
          [4 ]Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
          [5 ]Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands;
          [6 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN; and
          [7 ]Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR
          Author notes
          [*]

          N.I.P and R.S. contributed equally to this work.

          [†]

          F.L. and K.M.C. jointly supervised the study.

          Author information
          http://orcid.org/0000-0002-4809-9885
          http://orcid.org/0000-0001-9590-6160
          http://orcid.org/0000-0002-4177-9095
          http://orcid.org/0000-0001-8101-8269
          http://orcid.org/0000-0001-8142-8014
          http://orcid.org/0000-0001-6212-2247
          http://orcid.org/0000-0003-1249-9278
          http://orcid.org/0000-0003-4797-9095
          Article
          PMC6107880 PMC6107880 6107880 2017/813618
          10.1182/blood-2017-10-813618
          6107880
          29921614
          9b7d9f64-d75b-4ce4-abaa-b485761df73f
          © 2018 by The American Society of Hematology
          History
          : 27 October 2017
          : 14 June 2018
          Page count
          Pages: 12
          Categories
          37
          Thrombosis and Hemostasis
          Custom metadata
          free

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