Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA.
Department of Pathology, Weill Cornell Medical College, New York, New York, USA.
J Thromb Haemost. 2021 Sep;19(9):2268-2274. doi: 10.1111/jth.15451. Epub 2021 Jul 18.
A substantial proportion of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe/critical coronavirus disease 2019 (COVID-19) characterized by acute respiratory distress syndrome (ARDS) with thrombosis.
We tested the hypothesis that SARS-CoV-2--induced upregulation of tissue factor (TF) expression may be responsible for thrombus formation in COVID-19.
We compared autopsy lung tissues from 11 patients with COVID-19--associated ARDS with samples from 6 patients with ARDS from other causes (non-COVID-19 ARDS) and 11 normal control lungs.
Dual RNA in situ hybridization for SARS-CoV-2 and TF identified sporadic clustered SARS-CoV-2 with prominent co-localization of SARS-CoV-2 and TF RNA. TF expression was 2-fold higher in COVID-19 than in non-COVID-19 ARDS lungs (P = .017) and correlated with the intensity of SARS-CoV-2 staining (R = .36, P = .04). By immunofluorescence, TF protein expression was 2.1-fold higher in COVID-19 versus non-COVID-19 ARDS lungs (P = .0048) and 11-fold (P < .001) higher than control lungs. Fibrin thrombi and thrombi positive for platelet factor 4 (PF4) were found in close proximity to regions expressing TF in COVID-19 ARDS lung, and correlated with TF expression (fibrin, R = .52, P < .001; PF4, R = .59, P < .001).
These data suggest that upregulation of TF expression is associated with thrombus formation in COVID-19 lungs and could be a key therapeutic target. Correlation of TF expression with SARS-CoV-2 in lungs of COVID-19 patients also raises the possibility of direct TF induction by the virus.
相当一部分感染严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的患者发展为严重/危重新冠病毒病 2019（COVID-19），其特征为急性呼吸窘迫综合征（ARDS）伴血栓形成。
我们检验了 SARS-CoV-2 诱导组织因子（TF）表达上调可能导致 COVID-19 中血栓形成的假设。
我们比较了 11 例 COVID-19 相关 ARDS 患者的尸检肺组织样本与 6 例其他原因（非 COVID-19 ARDS）ARDS 患者和 11 例正常对照肺组织样本。
SARS-CoV-2 和 TF 的双重 RNA 原位杂交鉴定出散在聚集的 SARS-CoV-2，SARS-CoV-2 和 TF RNA 明显共定位。COVID-19 患者的 TF 表达水平比非 COVID-19 ARDS 患者高 2 倍（P =.017），且与 SARS-CoV-2 染色强度相关（R =.36，P =.04）。通过免疫荧光法，COVID-19 患者的 TF 蛋白表达比非 COVID-19 ARDS 患者高 2.1 倍（P =.0048），比对照组高 11 倍（P <.001）。在 COVID-19 ARDS 肺中，发现 TF 表达附近存在与纤维蛋白血栓和血小板因子 4（PF4）阳性的血栓，且与 TF 表达相关（纤维蛋白，R =.52，P <.001；PF4，R =.59，P <.001）。
这些数据表明，TF 表达上调与 COVID-19 肺部血栓形成有关，可能是一个关键的治疗靶点。COVID-19 患者肺部 TF 表达与 SARS-CoV-2 的相关性也提示病毒可能直接诱导 TF 表达。
