Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model
Name
jth.14875.pdf
Description
Published version
Size
3.56 MB
Format
Unknown
Checksum (MD5)
9706cf654db8c304b3a6bed5654a6dca
Author(s)
Proctor, Elizabeth A
Dineen, Shauna M.
Van Nostrand, Stephen C.
Kuhn, Madison K.
Barrett, Christopher D
Brubaker, Douglas
Yaffe, Michael B
Lauffenburger, Douglas A
Leon, Lisa R.
Date Issued
April 2020
Journal
Journal of Thrombosis and Haemostasis
Publisher
Wiley
Version
Final published version
Abstract
© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
Persistent DSpace Link
DOI of Published Version
10.1111/JTH.14875
