TY - JOUR
T1 - Coagulopathy signature precedes and predicts severity of end-organ heat stroke pathology in a mouse model
AU - Proctor, Elizabeth A.
AU - Dineen, Shauna M.
AU - Van Nostrand, Stephen C.
AU - Kuhn, Madison K.
AU - Barrett, Christopher D.
AU - Brubaker, Douglas K.
AU - Yaffe, Michael B.
AU - Lauffenburger, Douglas A.
AU - Leon, Lisa R.
N1 - Funding Information:
This work was supported by the Institute for Collaborative Biotechnologies through contracts W911NF‐09‐D‐0001 and W911NF‐19‐2‐0026 from the US Army Research Office, and by a grant from the USAMRAA program W81XWH‐13‐MOMJPC5‐IPPEHA. EAP was partially supported by the MIT CEHS Training Grant in Environmental Toxicology T32‐ES007020. CDB and MBY were supported by NIH‐DOD Grant UM1‐HL120877. The authors thank Brian A. Joughin and Justin R. Pritchard for their valuable input. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. In conducting the research described in this report, the investigators adhered to the as prepared by the Committee for the Update of the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research, National Research Council. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations. Guide for the Care and Use of Laboratory Animals
Funding Information:
This work was supported by the Institute for Collaborative Biotechnologies through contracts W911NF-09-D-0001 and W911NF-19-2-0026 from the US Army Research Office, and by a grant from the USAMRAA program W81XWH-13-MOMJPC5-IPPEHA. EAP was partially supported by the MIT CEHS Training Grant in Environmental Toxicology T32-ES007020. CDB and MBY were supported by NIH-DOD Grant UM1-HL120877. The authors thank Brian A. Joughin and Justin R. Pritchard for their valuable input. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. In conducting the research described in this report, the investigators adhered to the Guide for the Care and Use of Laboratory Animals as prepared by the Committee for the Update of the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research, National Research Council. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.
Publisher Copyright:
© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Background: Immune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear. Objectives: We sought to understand the effect of immune challenge on heat stroke pathology. Patients/Methods: Using a mouse model of classic heat stroke, we examined the impact of prior viral or bacterial infection on hematological aspects of recovery. Mice were exposed to heat either 48 or 72 hours following polyinosinic:polycytidylic acid (poly I:C) or lipopolysaccharide injection, time points when symptoms of illness (fever, lethargy, anorexia) were minimized or completely absent. Results: Employing multivariate supervised machine learning to identify patterns of molecular and cellular markers associated with heat stroke, we found that prior viral infection simulated with poly I:C injection resulted in heat stroke presenting with high levels of factors indicating coagulopathy. Despite a decreased number of platelets in the blood, platelets are large and non-uniform in size, suggesting younger, more active platelets. Levels of D-dimer and soluble thrombomodulin were increased in more severe heat stroke, and in cases of the highest level of organ damage markers D-dimer levels dropped, indicating potential fibrinolysis-resistant thrombosis. Genes corresponding to immune response, coagulation, hypoxia, and vessel repair were up-regulated in kidneys of heat-challenged animals; these correlated with both viral treatment and distal organ damage while appearing before discernible tissue damage to the kidney itself. Conclusions: Heat stroke-induced coagulopathy may be a driving mechanistic force in heat stroke pathology, especially when exacerbated by prior infection. Coagulation markers may serve as accessible biomarkers for heat stroke severity and therapeutic strategies.
AB - Background: Immune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear. Objectives: We sought to understand the effect of immune challenge on heat stroke pathology. Patients/Methods: Using a mouse model of classic heat stroke, we examined the impact of prior viral or bacterial infection on hematological aspects of recovery. Mice were exposed to heat either 48 or 72 hours following polyinosinic:polycytidylic acid (poly I:C) or lipopolysaccharide injection, time points when symptoms of illness (fever, lethargy, anorexia) were minimized or completely absent. Results: Employing multivariate supervised machine learning to identify patterns of molecular and cellular markers associated with heat stroke, we found that prior viral infection simulated with poly I:C injection resulted in heat stroke presenting with high levels of factors indicating coagulopathy. Despite a decreased number of platelets in the blood, platelets are large and non-uniform in size, suggesting younger, more active platelets. Levels of D-dimer and soluble thrombomodulin were increased in more severe heat stroke, and in cases of the highest level of organ damage markers D-dimer levels dropped, indicating potential fibrinolysis-resistant thrombosis. Genes corresponding to immune response, coagulation, hypoxia, and vessel repair were up-regulated in kidneys of heat-challenged animals; these correlated with both viral treatment and distal organ damage while appearing before discernible tissue damage to the kidney itself. Conclusions: Heat stroke-induced coagulopathy may be a driving mechanistic force in heat stroke pathology, especially when exacerbated by prior infection. Coagulation markers may serve as accessible biomarkers for heat stroke severity and therapeutic strategies.
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U2 - 10.1111/jth.14875
DO - 10.1111/jth.14875
M3 - Article
C2 - 32367690
AN - SCOPUS:85085015559
SN - 1538-7933
VL - 18
SP - 1900
EP - 1910
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 8
ER -