Effect of therapeutic plasma exchange on tissue factor and tissue factor pathway inhibitor in septic shock

Abstract

Background: Coagulopathy is part of the pathological host response to infection in sepsis. Higher plasma concentrations of both tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are associated with occurrence of disseminated intravascular coagulation (DIC), multi-organ dysfunction and increased mortality in patients with sepsis. Currently no treatment approaches specifically targeting this axis are available. We hypothesize that therapeutic plasma exchange (TPE) might limit this coagulopathy by restoring the balance of plasma proteins.

Methods: This was a pooled post-hoc biobank analysis including 51 patients with early (shock onset < 24 h) and severe (norepinephrine dose > 0.4 μg/kg/min) septic shock, who were either receiving standard of care treatment (SOC, n = 14) or SOC + one single TPE (n = 37). Plasma concentrations of TF and TFPI were measured both at- and 6 h after study inclusion. The effect of TPE on concentrations of TF and TFPI was investigated and compared to SOC patients. Further, baseline TF and TFPI concentrations were used to modulate and predict clinical response to adjunctive TPE, indicated by longitudinal reduction of lactate concentrations over the first 24 h following study inclusion.

Results: TPE led to a significant reduction in circulating concentrations of both TF and TFPI while no difference was observed in the SOC group. Relative change of TF within 6 h was + 14 (-0.8 to + 30.4) % (p = 0.089) in the SOC and -18.3 (-32.6 to -2.2) % (p < 0.001) in the TPE group (between group p < 0.001). Similarly, relative change of TFPI was + 14.4 (-2.3 to + 30.9) % (p = 0.076) in the SOC and -20 (-32.8 to -7.9) % (p < 0.001) in the TPE group (between group p = 0.022). The ratio of TF to TFPI remained unchanged in both SOC and TPE groups. SOC patients exhibited an increase in lactate over the initial 24 h when TF and TFPI concentrations were higher at baseline. In contrast, patients undergoing TPE experienced a sustained longitudinal reduction of lactate concentrations across all levels of baseline TF and TFPI elevations. In a multivariate mixed-effects model, higher baseline TF (p = 0.003) and TFPI (p = 0.053) levels led to greater longitudinal lactate concentration reduction effects in the TPE group.

Conclusions: Adjunctive TPE in septic shock is associated with a significant removal of both TF and TFPI, which may contribute to the early hemodynamic improvement observed in septic shock patients receiving TPE. Higher baseline TF (and TFPI) plasma concentrations were identified as a putative predictor of treatment response that could be useful for predictive enrichment strategies in future clinical trials.

Keywords: Apheresis; Coagulation; Extracorporeal treatment; Plasmapheresis; Precision medicine; Sepsis; Tissue factor; Tissue factor pathway inhibitor.

Fig. 1

Flow chart of study participants. Shown are screening, inclusion and analysis of patients. Inclusion criteria were early (< 24 h) and severe (norepinephrine (NE) dose ≥ 0.4 μg/kg/min despite adequate fluid resuscitation) septic shock. The study compared standard of care (SOC) with SOC + a single therapeutic plasma exchange (TPE). This was a post-hoc biobank analysis pooled from both a pilot non-randomized prospective observational study (EXCHANGE-Pilot) and an open-label RCT (EXCHANGE-I)

Fig. 2

Effect of TPE on tissue factor concentrations. Violin plots showing tissue factor (TF) plasma concentrations at study inclusion and 6 h after study inclusion in patients with septic shock who received either standard of care (SOC) alone or SOC in combination with therapeutic plasma exchange (TPE) (A). Both relative (B) and absolute (C) change of TF concentrations over time are shown for SOC and TPE groups

Fig. 3

Effect of TPE on tissue factor pathway inhibitor concentrations. Violin plots showing tissue factor pathway inhibitor (TFPI) plasma concentrations at study inclusion and 6 h after study inclusion in patients with septic shock who received either standard of care (SOC) alone or SOC in combination with therapeutic plasma exchange (TPE) (A). Both relative (B) and absolute (C) change of TFPI concentrations over time are shown for SOC and TPE groups

Fig. 4

Prediction of longitudinal lactate concentration response to therapeutic plasma exchange stratified by baseline tissue factor elevation. Shown are estimated longitudinal lactate concentrations for both the standard of care (SOC) and therapeutic plasma exchange (TPE) group stratified by different baseline tissue factor (TF) concentrations at study inclusion. Estimated values were calculated using a triple interaction model with TPE/SOC and time, as well as all simple interactions terms between fixed effects. The model indicates that SOC patients with increasing TF concentrations experienced diminishing lactate concentration reductions over 24 h in contrast to patients under TPE which experienced sustained lactate reductions across all levels of TF (p = 0.003). At baseline TF concentrations of 50 pg/ml both groups exhibited a reduction in lactate concentrations (left panel). Above TF concentrations of 150 pg/ml, patients in the SOC group showed no lactate reduction, whereas NE reduction was maintained in the TPE group (middle panel). Above 300 pg/ml, patients in the SOC group showed increasing lactate concentrations over time, while lactate reduction was further maintained in the TPE group (right panel). The thresholds for baseline TF concentrations employed were chosen post hoc in order to best illustrate the continuous effect of TF concentrations within the model

Fig. 5

Prediction of longitudinal lactate concentration response to therapeutic plasma exchange stratified by baseline tissue factor pathway inhibitor elevation. Shown are estimated longitudinal lactate concentrations for both the standard of care (SOC) and therapeutic plasma exchange (TPE) group stratified by different baseline tissue factor pathway inhibitor (TFPI) concentrations at study inclusion. Estimated values were calculated using a triple interaction model with TPE/SOC and time, as well as all simple interactions terms between fixed effects. The model indicates that SOC patients with increasing TF concentrations experienced diminishing lactate concentration reductions over 24 h in contrast to patients under TPE which experienced sustained lactate reductions across all levels of TFPI (p = 0.053). At baseline TFPI concentrations of 360.000 pg/ml both groups exhibited a reduction in lactate concentrations (left panel). Above TFPI concentrations of 800.000 pg/ml, patients in the SOC group showed no lactate reduction, whereas NE reduction was maintained in the TPE group (middle panel). Above 1.500.000 pg/ml, patients in the SOC group showed increasing lactate concentrations over time, while lactate reduction was further maintained in the TPE group (right panel). The thresholds for baseline TFPI concentrations employed were chosen post hoc in order to best illustrate the continuous effect of TFPI concentrations within the model