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Hemorrhagic shock and tissue injury provoke distinct components of trauma-induced coagulopathy in a swine model

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Abstract

Introduction

Tissue injury (TI) and hemorrhagic shock (HS) are the major contributors to trauma-induced coagulopathy (TIC). However, the individual contributions of these insults are difficult to discern clinically because they typically coexist. TI has been reported to release procoagulants, while HS has been associated with bleeding. We developed a large animal model to isolate TI and HS and characterize their individual mechanistic pathways. We hypothesized that while TI and HS are both drivers of TIC, they provoke different pathways; specifically, TI reduces time to clotting, whereas, HS decreases clot strength stimulates hyperfibrinolysis.

Methods

After induction of general anesthesia, 50 kg male, Yorkshire swine underwent isolated TI (bilateral muscle cutdown of quadriceps, bilateral femur fractures) or isolated HS (controlled bleeding to a base excess target of − 5 mmol/l) and observed for 240 min. Thrombelastography (TEG), calcium levels, thrombin activatable fibrinolysis inhibitor (TAFI), protein C, plasminogen activator inhibitor 1 (PAI-1), and plasminogen activator inhibitor 1/tissue-type plasminogen activator complex (PAI-1-tPA) were analyzed at pre-selected timepoints. Linear mixed models for repeated measures were used to compare results throughout the model.

Results

TI resulted in elevated histone release which peaked at 120 min (p = 0.02), and this was associated with reduced time to clot formation (R time) by 240 min (p = 0.006). HS decreased clot strength at time 30 min (p = 0.003), with a significant decline in calcium (p = 0.001). At study completion, HS animals had elevated PAI-1 (p = 0.01) and PAI-1-tPA (p = 0.04), showing a trend toward hyperfibrinolysis, while TI animals had suppressed fibrinolysis. Protein C, TAFI and skeletal myosin were not different among the groups.

Conclusion

Isolated injury in animal models can help elucidate the mechanistic pathways leading to TIC. Our results suggest that isolated TI leads to early histone release and a hypercoagulable state, with suppressed fibrinolysis. In contrast, HS promotes poor clot strength and hyperfibrinolysis resulting in hypocoagulability.

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Funding

This research is funded in part by the Trans-Agency Consortium for Trauma-Induced Coagulopathy (TACTIC) contract number UM1-HL120877. Research support is also provided by the National Institute of General Medical Sciences of the National Institutes of Health (T32 GM008315). The current major funding source is an RM1 grant (1RM1GM131968-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Surgery, University of Colorado, Aurora, CO, USA

    Alexis L. Cralley, Ernest E. Moore, Julia R. Coleman, Navin Vigneshwar, Matt Bartley, Daniel Kissau, Andrew Eitel, Patrick Hom, Sanchayita Mitra, Arsen Ghasabyan, Miguel Fragoso, Mitchell J. Cohen & Anirban Banerjee

  2. Department of Surgery, Ernest E. Moore Shock Trauma Center at Denver Health, Denver, CO, USA

    Ernest E. Moore

  3. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA

    Zihan Guo, Hiroshi Deguchi & John H. Griffin

  4. Department of Medicine, University of California, San Diego, CA, USA

    John H. Griffin

  5. Vitalant Research Institute, Denver, CO, USA

    Christopher C. Silliman

  6. Department of Pediatrics, University of Colorado, Aurora, CO, USA

    Christopher C. Silliman

  7. Department of Proteomics and Metabolomics, University of Colorado, Aurora, CO, USA

    Kirk Hansen

  8. Department of Health Systems, Management and Policy, School of Public Health, University of Colorado Denver, Aurora, CO, USA

    Angela Sauaia

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  1. Alexis L. Cralley
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Correspondence to Alexis L. Cralley.

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Conflict of interest

E.E.M. has patents pending related to coagulation and fibrinolysis diagnostics and therapeutic fibrinolytics and is a cofounder with stock options in ThromboTherepeutics. E.E.M. has received grant support from Haemonetics, Inc., Stago, Hemosonics, Instrumentation Laboratories, Inc, and Diapharma outside the submitted work.

Ethical approval

This animal study was conducted in compliance with the Animal Welfare Act, implementing Animal Welfare Regulations, and the principles of the Guide for the Care and Use of Laboratory Animals, National Research Council. Results are reported in accordance with the ARRIVE guidelines [1]. The University of Colorado Institutional Animal Care and Use Committee approved this animal study under protocol #0323, and the research was conducted in a fully accredited Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) facility.

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Cralley, A.L., Moore, E.E., Coleman, J.R. et al. Hemorrhagic shock and tissue injury provoke distinct components of trauma-induced coagulopathy in a swine model. Eur J Trauma Emerg Surg 49, 1079–1089 (2023). https://doi.org/10.1007/s00068-022-02148-x

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