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

Narcis I. Popescu, Robert Silasi, Ravi S. Keshari, Alanson Girton, Tarea Burgett, Sacha S. Zeerleder, David Gailani, Andras Gruber, Florea Lupu, K. Mark Coggeshall

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)849-860
Number of pages12
JournalBlood
Volume132
Issue number8
DOIs
StatePublished - Aug 23 2018

Fingerprint

Peptidoglycan
Papio
Disseminated Intravascular Coagulation
Coagulation
Chemical activation
Anthrax
Factor XII
Sepsis
Hemostatics
Primates
Prekallikrein
Serpins
Bacillus anthracis
Antithrombins
Platelet Activation
Thromboplastin
Blood Coagulation
Pathogens
Bacilli
Platelets

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Popescu, N. I., Silasi, R., Keshari, R. S., Girton, A., Burgett, T., Zeerleder, S. S., ... Mark Coggeshall, K. (2018). Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. Blood, 132(8), 849-860. https://doi.org/10.1182/blood-2017-10-813618

Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. / Popescu, Narcis I.; Silasi, Robert; Keshari, Ravi S.; Girton, Alanson; Burgett, Tarea; Zeerleder, Sacha S.; Gailani, David; Gruber, Andras; Lupu, Florea; Mark Coggeshall, K.

In: Blood, Vol. 132, No. 8, 23.08.2018, p. 849-860.

Research output: Contribution to journalArticle

Popescu, NI, Silasi, R, Keshari, RS, Girton, A, Burgett, T, Zeerleder, SS, Gailani, D, Gruber, A, Lupu, F & Mark Coggeshall, K 2018, 'Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways', Blood, vol. 132, no. 8, pp. 849-860. https://doi.org/10.1182/blood-2017-10-813618
Popescu, Narcis I. ; Silasi, Robert ; Keshari, Ravi S. ; Girton, Alanson ; Burgett, Tarea ; Zeerleder, Sacha S. ; Gailani, David ; Gruber, Andras ; Lupu, Florea ; Mark Coggeshall, K. / Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways. In: Blood. 2018 ; Vol. 132, No. 8. pp. 849-860.
@article{481d0c3f19cd49f0a02483b122808bec,
title = "Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways",
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.",
author = "Popescu, {Narcis I.} and Robert Silasi and Keshari, {Ravi S.} and Alanson Girton and Tarea Burgett and Zeerleder, {Sacha S.} and David Gailani and Andras Gruber and Florea Lupu and {Mark Coggeshall}, K.",
year = "2018",
month = "8",
day = "23",
doi = "10.1182/blood-2017-10-813618",
language = "English (US)",
volume = "132",
pages = "849--860",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - Peptidoglycan induces disseminated intravascular coagulation in baboons through activation of both coagulation pathways

AU - Popescu, Narcis I.

AU - Silasi, Robert

AU - Keshari, Ravi S.

AU - Girton, Alanson

AU - Burgett, Tarea

AU - Zeerleder, Sacha S.

AU - Gailani, David

AU - Gruber, Andras

AU - Lupu, Florea

AU - Mark Coggeshall, K.

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052152253&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052152253&partnerID=8YFLogxK

U2 - 10.1182/blood-2017-10-813618

DO - 10.1182/blood-2017-10-813618

M3 - Article

VL - 132

SP - 849

EP - 860

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -