Abstract

Background: Traumatic brain injury (TBI) results in neurovascular damage that initiates intrinsic mechanisms of hypercoagulation, which can contribute to the development of life-threatening complications, such as coagulopathy and delayed thrombosis. Clinical studies have hypothesized that tissue factor (TF) induces hypercoagulability after TBI; however, none have directly shown this relationship. Objectives: In the current study, we took a stepwise approach to understand what factors are driving thrombin generation following experimental TBI. Methods: We employed the contusion-producing controlled cortical impact (CCI) model and the diffuse closed head injury (CHI) model to investigate these mechanisms as a function of injury severity and modality. Whole blood was collected at 6 hours and 24 hours after injury, and platelet-poor plasma was used to measure thrombin generation and extracellular vesicle (EV) TF. Results: We found that plasma thrombin generation, dependent on TF present in the plasma, was greater in CCI-injured animals compared to sham at both 6 hours (120.4 ± 36.9 vs 0.0 ± 0.0 nM*min endogenous thrombin potential) and 24 hours (131.0 ± 34.0 vs 32.1 ± 20.6 nM*min) after injury. This was accompanied by a significant increase in EV TF at 24 hours (328.6 ± 62.1 vs 167.7 ± 20.8 fM) after CCI. Further, EV TF is also increased at 6 hours (126.6 ± 17.1 vs 63.3 ± 14.4 fM) but not 24 hours following CHI. Conclusion: TF-mediated thrombin generation is time-dependent after injury and TF increases resolve earlier following CHI as compared to CCI. Taken together, these data support a TF-mediated pathway of thrombin generation after TBI and pinpoint TF as a major player in TBI-induced coagulopathy.

Original languageEnglish
Article numbere12734
JournalResearch and Practice in Thrombosis and Haemostasis
Volume6
Issue number4
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
This project was supported by NIH R01 NS112693-01A1 (PGS), BLR&D Career Development Award Number IK2 BX004618 from the Department of Veterans Affairs (WBH), NIH R21 NS114771 (KES), and NIH National Heart, Lung, and Blood Institute grant HL129193 (JPW). JPW also has an investigator-initiated grant through Pfizer, which is unrelated to this project. The authors thank Malinda Spry, Jenn Gooch, and Binoy Joseph, PhD, for their assistance in the experimental TBI models.

Funding Information:
This project was supported by NIH R01 NS112693‐01A1 (PGS), BLR&D Career Development Award Number IK2 BX004618 from the Department of Veterans Affairs (WBH), NIH R21 NS114771 (KES), and NIH National Heart, Lung, and Blood Institute grant HL129193 (JPW). JPW also has an investigator‐initiated grant through Pfizer, which is unrelated to this project.

Publisher Copyright:
© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).

Keywords

  • controlled cortical impact
  • extracellular vesicle
  • phospholipid
  • thrombosis
  • tissue factor
  • traumatic brain injury

ASJC Scopus subject areas

  • Hematology

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