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

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.

Trial registration: ClinicalTrials.gov NCT03741023.

Keywords: Antifibrinolytic; Elective surgery; Plasmin activity; Posterior spinal fusion; TXA.

Fig. 1

A PSF in the absence of antifibrinolytic treatment provokes significant blood loss and coagulopathy, requiring transfusions. B The administration of antifibrinolytics during PSF greatly reduces blood loss, inflammation, coagulopathy, and transfusion requirements. C In PSF treated with antifibrinolytics, it’s unclear how different patients respond to the same dosing scheme, how plasmin activation in the presence of an antifibrinolytic might affect blood loss and inflammation, and how best to measure the efficacy of antifibrinolytics to prevent negative outcomes

Fig. 2

Blood collection procedures for the study

Fig. 3

Posterior spinal fusion surgery significantly activates coagulation, causing a detectable increase in A TAT throughout the case, B a postoperative drop in platelet count. C Both idiopathic and neuromuscular patients exhibited significant blood loss throughout the procedures

Fig. 4

A Pro-inflammatory cytokine IL-6 peaked by POD1 while B complement activation peaked intra-operatively with reactivation occurring on POD1 and POD2. C No significant changes in leukocyte activation marker, L-selectin, occurred during hospitalization. N = 17, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with pre-operative values. Points represent the mean with 95% confidence intervals

Fig. 5

A Fibrinolysis measured by TEG clot lysis (LY30, N = 8) and B SK-based plasmin activity decreased in the intra-operative period during TXA administration. C Plasmin activation (PAP) and D fibrinolysis (D-dimer) increased significantly during the procedure. E Plasma plasminogen antigen levels decrease intra-operatively and remain decreased through POD2 N = 17, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 compared with pre-operative values. Points represent the mean with 95% confidence intervals. F Plasminogen antigen levels strongly correlated with SK-based plasmin activity quantification (R² = 0.637, P < 0.0001)

Fig. 6

A While LY30 and plasminogen decrease or remain level during PSF procedure, PAP and D-dimer increase significantly. PAP and D-dimer also follow different time courses during and after surgery. PAP increases prior to fibrinolysis (D-dimer) but is undetectable in the post-operative period until POD2, while D-dimer increases intra-operatively and remains elevated in the post-operative period. (Values expressed as a percent of baseline values for each patient). B Different assays used to measure plasmin activity and fibrinolysis depict different aspects of plasmin biology