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The reduced form of coagulation factor XI is associated with illness severity and coagulopathy in critically-ill septic patients

  • Ronit Mor-Cohen
  • Michal Zucker
  • Colin Grissom
  • Samuel M. Brown
  • Uri Seligsohn
  • Robert A. Campbell
  • Antoinette M. Blair
  • Matthew T. Rondina
Article

Abstract

Coagulation Factor XI (FXI) contributes to the pathobiology of sepsis-associated thrombosis and is a target for new therapeutics. Through cleavage of disulfide bonds, FXI becomes reduced (rFXI), accelerating intrinsic coagulation cascade activation. The role of rFXI in human sepsis has never been studied. We determined levels of total FXI and rFXI in critically-ill septic patients with and without overt disseminated intravascular coagulation (DIC, a dysregulated pro-thrombotic condition). Total FXI and rFXI plasma levels were measured on ICU admission in prospectively enrolled septic patients (n = 32) from three academic medical centers and matched, healthy controls (n = 15). In septic patients, hematologic and physiologic parameters and pathological thrombosis (presence or absence of overt DIC) were determined. rFXI was higher in septic patients than controls (p < 0.05). In septic patients, rFXI was significantly associated with platelet count (r = 0.3511, p < 0.05) and APACHE II score (r = − 0.359, p < 0.05), indices of illness severity. rFXI was lower in patients with overt DIC (p = 0.088), suggesting a consumptive coagulopathy. In contrast, while total FXI levels were reduced in sepsis, they failed to correlate with illness severity, thrombosis, or hematologic parameters. We establish, for the first time, that rFXI is increased in patients with sepsis and correlates with illness severity (APACHE II score and platelet count) and pathological coagulopathy (overt DIC). Total FXI levels, in contrast, are decreased in sepsis but fail to associate with any indices. These findings suggest that rFXI has unique activity in human sepsis.

Keywords

Sepsis Coagulation Factor XI Outcomes 

Notes

Acknowledgements

We appreciate the excellent assistance of Ms. Diana Lim with generation of figures and all subjects for participating in the study.

Author contributions

RMC and MZ designed the study, analyzed and interpreted the data, and wrote the manuscript. US and MTR contributed to study design, data analysis and interpretation, and writing/editing of the manuscript. CG, SMB, AMB, and RAC contributed critically to the study design and patient recruitment, data interpretation, and editing of the manuscript.

Funding

This work was supported by the National Heart, Lung, and Blood Institute (HL112311, HL130541, and HL126547 to MTR), the National Institute on Aging (AG048022 to MTR), the U.S. Department of Veterans Affairs (VA Merit Award I01CX001696 to MTR) and from a pilot award funded by the University of Utah (MTR). This material is the result of work supported with resources and the use of facilities at the George E. Wahlen VA Medical Center, Salt Lake City, Utah. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The research reported in this publication was supported (in part or in full) by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001067. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ronit Mor-Cohen
    • 1
  • Michal Zucker
    • 1
  • Colin Grissom
    • 2
    • 3
    • 4
  • Samuel M. Brown
    • 2
    • 3
    • 4
  • Uri Seligsohn
    • 1
  • Robert A. Campbell
    • 4
    • 5
  • Antoinette M. Blair
    • 5
  • Matthew T. Rondina
    • 4
    • 5
    • 6
    • 7
  1. 1.The Amalia Biron Research Institute of Thrombosis and Hemostasis, Tel Hashomer and Sackler Faculty of Medicine, Chaim Sheba Medical CenterTel Aviv UniversityTel AvivIsrael
  2. 2.Shock Trauma ICUIntermountain Medical CenterMurrayUSA
  3. 3.Pulmonary and Critical Care MedicineIntermountain Medical CenterMurrayUSA
  4. 4.Department of Internal MedicineUniversity of UtahSalt Lake CityUSA
  5. 5.Molecular Medicine ProgramUniversity of UtahSalt Lake CityUSA
  6. 6.George E. Wahlen VAMC Geriatric Research, Education and Clinical CenterSalt Lake CityUSA
  7. 7.Department of PathologyUniversity of UtahSalt Lake CityUSA

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