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Variable Response to Antifibrinolytics Correlates with Blood-loss and Transfusion in Posterior Spinal Fusion

A Correction to this article was published on 13 April 2022

This article has been updated

Abstract

Purpose

Posterior spinal fusion (PSF) activates the fibrinolytic protease plasmin, which is implicated in blood loss and transfusion. While antifibrinolytic drugs have improved blood loss and reduced transfusion, variable blood loss has been observed in similar PSF procedures treated with the same dose of antifibrinolytics. However, both the cause of this and the appropriate measures to determine antifibrinolytic efficacy during high-blood-loss spine surgery are unknown, making clinical trials to optimize antifibrinolytic dosing in PSF difficult. We hypothesized that patients undergoing PSF respond differently to antifibrinolytic dosing, resulting in variable blood loss, and that specific diagnostic markers of plasmin activity will accurately measure the efficacy of antifibrinolytics in PSF.

Methods

A prospective study of 17 patients undergoing elective PSF with the same dosing regimen of TXA was conducted. Surgery-induced plasmin activity was exhaustively analyzed in perioperative blood samples and correlated to measures of inflammation, bleeding, and transfusion.

Results

While markers of in vivo plasmin activation (PAP and D-dimer) suggested significant breakthrough plasmin activation and fibrinolysis (P < 0.01), in vitro plasmin assays, including TEG, did not detect plasmin activation. In vivo measures of breakthrough plasmin activation correlated with blood loss (R2 = 0.400, 0.264; P < 0.01), transfusions (R2 = 0.388; P < 0.01), and complement activation (R2 = 0.346, P < 0.05).

Conclusions

Despite all patients receiving a high dose of TXA, its efficacy among patients was variable, indicated by notable intra-operative plasmin activity. Markers of in vivo plasmin activation best correlated with clinical outcomes. These findings suggest that the efficacy of antifibrinolytic therapy to inhibit plasmin in PSF surgery should be determined by markers of in vivo plasmin activation in future studies.

Level of evidence

Level II-diagnostic.

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Availability of data and materials

The authors certify that the data support the results presented within this study and agree to provide materials upon request.

Code availability

Not applicable.

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Acknowledgements

The authors would like to thank members of the Division of Pediatric Orthopaedics, the Division of Pediatric anesthesiology, and the numerous pediatric nurses for their care of patients at our institution; this work would not have been possible without their dedication. We would also like to thank members of the Schoenecker laboratory and the Department of Orthopaedics, specifically Vaibhav Tadepalli, J. Court Reese and Julie Shelton for their contributions to this work, and Drs. David Gailani, Joey Barnett, Brian Wadzinski, and Alan Brash for their feedback and direction. Finally, we would also like to thank our family and friends for their continual support.

Funding

Funding for this study was supported by the Caitlin Lovejoy Fund, the Vanderbilt University Medical Center Department of Orthopaedics (JGS), the Katherine Dodd Faculty Scholar Fund (AJB), the Vanderbilt Center for Musculoskeletal Research Faculty Award (MTD), the Vanderbilt University School of Medicine Research Immersion Program (LJM), UL1 TR002245 (MTD) and NHLBI-F31HL149340-02 (BHYG).

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Authors and Affiliations

Authors

Contributions

BG: study conception, data acquisition/analysis, original manuscript draft, critical revisions, final manuscript approval, accountability for work. MD: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. LM: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. TB: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. TW: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. JM: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. GM: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. BE: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. SM-L: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. AB: study conception, data acquisition/analysis, critical revisions, final manuscript approval, accountability for work. JS: study conception, data acquisition/analysis original manuscript draft, critical revisions, final manuscript approval, accountability for work.

Corresponding author

Correspondence to Jonathan G. Schoenecker.

Ethics declarations

Conflict of interest

JGS has funding unrelated to this work from the NIH (NIGMS), the Department of Defense, and OrthoPediatrics. All other authors have nothing further to disclose.

Ethics approval

All study procedures were previously approved by the Institutional Review Board (IRB #181982, Clinicaltrials.gov #NCT03741023) and conducted in accordance with the ethical standards described in the updated Declaration of Helsinki.

Consent to participate

Informed consent was obtained from legal guardians and/or patients (depending on age) to participate in this study.

Consent for publication

All patients included in this study provided informed consent to publish study findings.

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The original online version of this article was revised: the resource number UL1 TR002245 (MTD) was added to the list of funding sources.

Supplementary Information

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43390_2022_489_MOESM1_ESM.tif

Supplementary file1 Figure S1: TEG coagulation values demonstrated a mild, nonsignificant decrease in clotting potential intra-operatively by A-B) increased reaction (R) and clotting time (K) and C-D) decreased max amplitude and overall clot strength (G parameter). N=8, points represent the mean with 95% confidence intervals. (TIF 682 KB)

43390_2022_489_MOESM2_ESM.tif

Supplementary file2 Figure S2: A) uPA levels did not change significantly throughout surgery, and B), uPA receptor (uPAR), decreased slightly intra-operatively and returned to baseline in the post-operative monitoring period. Markers of coagulopathy, C) protein C antigen and platelet activation, D) P-selectin, and E) CD40L and endothelial activation F) thrombomodulin, do not change significantly during or after PSF. N=17, points represent the mean with 95% confidence intervals. (TIF 1040 KB)

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Gibson, B.H.Y., Duvernay, M.T., McKeithan, L.J. et al. Variable Response to Antifibrinolytics Correlates with Blood-loss and Transfusion in Posterior Spinal Fusion. Spine Deform 10, 841–851 (2022). https://doi.org/10.1007/s43390-022-00489-6

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Keywords

  • Posterior spinal fusion
  • Antifibrinolytic
  • TXA
  • Elective surgery
  • Plasmin activity