Coagulopathy signature precedes and predicts severity of end-organ heat stroke pathology in a mouse model

Abstract

Text word count: 3,988; Abstract word count: 250; Number of figures: 5; Number of tables: 0; Number of references: 32 Scientific category: Thrombosis and HemostasisKey points:• A signature of pro-coagulation markers predicts circadian core body temperature and levels of organ damage in heat stroke • Changes in coagulopathy-related gene expression are evidenced before histopathological organ damage AbstractHeat stroke is a life-threatening condition characterized by loss of thermoregulation and severe elevation of core body temperature, which can cause organ failure and damage to the central nervous system. While no definitive test exists to measure heat stroke severity, immune challenge is known to increase heat stroke risk, although the mechanism of this increased risk is unclear. In this study, we used a mouse model of classic heat stroke to test the effect of immune challenge on pathology. 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 presenting with the highest level of organ damage markers D-dimer levels dropped, indicating potential fibrinolysisresistant thrombosis. Genes corresponding to immune response, coagulation, hypoxia, and vessel repair were up-regulated in kidneys of heat-challenged animals, and these increases correlated with both viral treatment and distal organ damage while appearing before discernible tissue damage to the kidney itself. We conclude that heat stroke-induced coagulopathy may be a driving mechanistic force in heat stroke pathology, especially when exacerbated by prior infection, and that coagulation markers may serve as an accessible biomarker for heat stroke severity and therapeutic strategies.

Meta-analysis of coagulation parameters associated with disease severity and poor prognosis of COVID-19

“…Therefore, COVID-19 coagulopathy does not lead to a bleeding state, but to a thrombotic state (Pryzdial et al, 2020). Although the role of anticoagulant therapy in inhibiting progression of disease and reducing death is not yet clear, most hospitals have begun to use preventive medium doses or even therapeutic doses of anticoagulant therapy for specific patients to prevent potential thrombosis complications (Patel and Sengupta, 2020;Proctor et al, 2020;Yin et al, 2020b). The study by Liu et al (2020c) demonstrated that when treated with heparin molecules, not only did heparin act as an anticoagulant, but it also bound to the SARS-COV-2 spike protein, preventing the virus from binding to the receptor cells.…”

Hot environment aggravated hemorrhagic shock-induced organ dysfunction and protective effects of cold fluid resuscitation

“…Severe heatstroke would lead to multiple organ dysfunction and death. For example, Proctor and other studies found that when mice were exposed to 39.5 ℃ would cause coagulation dysfunction [14]; Zhou et al found that when rats were exposed to a simulated desert environment (41℃), the liver (AST, ALT), kidney (BUN, Crea), heart (CK-MB, CK kinase) and lung function (BEecf, HCO3 − ) were signi cantly damaged. At the same time, the morphology and structure of liver, kidney, heart, and lungs were changed signi cantly after heatstroke, and as the duration of heatstroke prolong, the damage to organ function was aggravated [15].…”

Heatstroke-induced coagulopathy: Biomarkers, mechanistic insights, and patient management

“…Therefore, more specific and reliable biomarkers are needed. Proctor et al 44 demonstrated increased D-dimer and soluble thrombomodulin levels in a severe non-exertional heatstroke mouse model. Bouchama et al 59 compared the levels of thrombin-antithrombin complex, fibrin monomers, plasminantiplasmin complex, and D-dimer between heatstroke and heat-illness at hospital presentation.…”

“…43 Similarly, even if the global coagulation markers do not change significantly, HSIC may be diagnosed by increased levels of sensitive coagulation biomarkers such as D-dimer, thrombin-antithrombin complex, and soluble thrombomodulin. 44…”