Coagulopathy signature precedes and predicts severity of endorgan heat stroke pathology in a mouse model

Abstract

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 poly I:C or LPS 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.

ICB Affiliated Authors

Authors
Elizabeth A. Proctor, Shauna M. Dineen, Stephen C. Van Nostrand, Madison K. Kuhn, Christopher D. Barrett, Douglas K. Brubaker, Michael B. Yaffe, Douglas A. Lauffenburger, Lisa R. Leon
Date
Type
Peer-Reviewed Article
Journal
Journal of Thrombosis and Haemostasis
Pages
1-11