Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, United States.
Elife. 2022 Jan 11;11:e74268. doi: 10.7554/eLife.74268.
Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults (Mast et al., 2021). Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that "pulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs". They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported.
Mast 等人分析了 COVID-19 患者支气管肺泡灌洗液 (BALF) 样本的 RNA 测序 (RNA-seq) 衍生的转录组数据，与一项研究 BALF RNA-seq 样本进行比较，该研究调查了肥胖和哮喘成年人中的微生物组和炎症相互作用（Mast 等人，2021 年）。基于对这些数据的分析，Mast 等人得出结论，外源性凝血级联和纤维蛋白溶解的关键调节剂的 mRNA 表达在 COVID-19 患者中显著降低。值得注意的是，他们报告说外源性凝血级联主调节剂组织因子（F3）的表达保持不变，而其同源抑制剂组织因子途径抑制剂（TFPI）的表达上调了 8 倍。由此他们得出结论，“肺部纤维蛋白沉积不是源自增强的局部 [组织因子] 产生，而且与直觉相反，COVID-19 可能会抑制肺部的 [组织因子] 依赖性机制”。他们还报告了激活蛋白 C (aPC) 介导的抗凝活性降低，纤维蛋白原表达和其他关键凝块形成调节剂的大量增加。这些结果中有许多与大多数领域的发现相矛盾，特别是关于外源性凝血级联介导的凝血障碍的发现。在这里，我们对 Mast 等人分析的数据集进行了完整的重新分析。重新分析表明，彼此之间相互利用的两个数据集不可比，而且 COVID-19 样本集不适合 Mast 等人进行的转录组分析。我们还发现了他们回顾性分析设计中的其他重大缺陷，例如质量控制和过滤标准差。鉴于数据集和分析存在问题，他们的结论得不到支持。
