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. 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. 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. 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.

中文翻译：

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治疗性血浆置换对脓毒性休克患者组织因子和组织因子通路抑制剂的影响


凝血病是脓毒症中宿主对感染的病理反应的一部分。组织因子 （TF） 和组织因子途径抑制剂 （TFPI） 的血浆浓度较高与脓毒症患者弥散性血管内凝血 （DIC） 的发生、多器官功能障碍和死亡率增加有关。目前没有专门针对该轴的治疗方法。我们假设治疗性血浆置换 （TPE） 可能通过恢复血浆蛋白的平衡来限制这种凝血病。这是一项汇总的事后生物样本库分析，包括 51 例早期 （休克发作 < 24 h） 和严重 （去甲肾上腺素剂量 > 0.4 μg/kg/min） 感染性休克患者，他们正在接受标准护理治疗 （SOC，n = 14） 或 SOC + 单一 TPE （n = 37）。在研究纳入后 6 小时和 6 小时测量 TF 和 TFPI 的血浆浓度。研究了 TPE 对 TF 和 TFPI 浓度的影响，并与 SOC 患者进行了比较。此外，基线 TF 和 TFPI 浓度用于调节和预测对辅助 TPE 的临床反应，表现为研究纳入后前 24 小时内乳酸浓度的纵向降低。TPE 导致 TF 和 TFPI 的循环浓度显著降低，而在 SOC 组中未观察到差异。6 小时内 TF 的相对变化在 SOC 中为 + 14 （-0.8 至 + 30.4） % （p = 0.089），TPE 组为 -18.3 （-32.6 至 -2.2） % （p < 0.001） （在组 p < 0.001 之间）。同样，SOC 中 TFPI 的相对变化为 + 14.4 （-2.3 至 + 30.9） % （p = 0.076），TPE 组为 -20 （-32.8 至 -7.9） % （p < 0.001） （在组 p = 0.022 之间）。SOC 组和 TPE 组的 TF 与 TFPI 比值保持不变。 当基线时 TF 和 TFPI 浓度较高时，SOC 患者在最初的 24 小时内表现出乳酸增加。相比之下，接受 TPE 的患者在基线 TF 和 TFPI 升高的所有水平上都经历了乳酸浓度的持续纵向降低。在多变量混合效应模型中，较高的基线 TF （p = 0.003） 和 TFPI （p = 0.053） 水平导致 TPE 组的纵向乳酸浓度降低效应更大。脓毒性休克中的辅助 TPE 与 TF 和 TFPI 的显著去除有关，这可能有助于在接受 TPE 的脓毒性休克患者中观察到的早期血流动力学改善。较高的基线 TF （和 TFPI） 血浆浓度被确定为治疗反应的假定预测因子，可用于未来临床试验中的预测富集策略。