Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model
© 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 s...
| Main Authors: | , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Wiley
2021
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| Online Access: | https://hdl.handle.net/1721.1/133446.2 |
| _version_ | 1811091559744012288 |
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| author | 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. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering 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. |
| author_sort | Proctor, Elizabeth A |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T15:03:59Z |
| format | Article |
| id | mit-1721.1/133446.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:03:59Z |
| publishDate | 2021 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/133446.22022-08-31T20:59:32Z Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model 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. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT © 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. US Army Medical Research Acquisition Agency (Grant/Award W81XWH-13-MOMJPC5-IPPEHA) USARO, Grant/Award (W911NF- 09-D-0001) NIH-DOD, Grant/Award (UM1-HL120877) National Institute of Environmental Health Sciences (Grant/ Award T32-ES007020) 2021-12-01T18:49:46Z 2021-10-27T19:52:53Z 2021-12-01T18:49:46Z 2020-04 2021-08-04T15:24:49Z Article http://purl.org/eprint/type/JournalArticle 1538-7933 1538-7836 https://hdl.handle.net/1721.1/133446.2 en 10.1111/JTH.14875 Journal of Thrombosis and Haemostasis Creative Commons Attribution NonCommercial License 4.0 https://creativecommons.org/licenses/by-nc/4.0/ application/octet-stream Wiley Wiley |
| spellingShingle | 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. Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title | Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title_full | Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title_fullStr | Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title_full_unstemmed | Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title_short | Coagulopathy signature precedes and predicts severity of end‐organ heat stroke pathology in a mouse model |
| title_sort | coagulopathy signature precedes and predicts severity of end organ heat stroke pathology in a mouse model |
| url | https://hdl.handle.net/1721.1/133446.2 |
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