University of North Carolina (UNC) Blood Research Center, UNC at Chapel Hill, Chapel Hill, NC.
Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil.
Blood Adv. 2022 Jun 14;6(11):3367-3377. doi: 10.1182/bloodadvances.2021006620.
Coagulation activation is a prominent feature of severe acute respiratory syndrome coronavirus 2 (COVID-19) infection. Activation of the contact system and intrinsic pathway has increasingly been implicated in the prothrombotic state observed in both sterile and infectious inflammatory conditions. We therefore sought to assess activation of the contact system and intrinsic pathway in individuals with COVID-19 infection. Baseline plasma levels of protease:serpin complexes indicative of activation of the contact and intrinsic pathways were measured in samples from inpatients with COVID-19 and healthy individuals. Cleaved kininogen, a surrogate for bradykinin release, was measured by enzyme-linked immunosorbent assay, and extrinsic pathway activation was assessed by microvesicle tissue factor-mediated factor Xa (FXa; MVTF) generation. Samples were collected within 24 hours of COVID-19 diagnosis. Thirty patients with COVID-19 and 30 age- and sex-matched controls were enrolled. Contact system and intrinsic pathway activation in COVID-19 was demonstrated by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:α1-antitrypsin, and FIXa:antithrombin (AT). MVTF levels were also increased in patients with COVID-19. Because FIXa:AT levels were associated with both contact/intrinsic pathway complexes and MVTF, activation of FIX likely occurs through both contact/intrinsic and extrinsic pathways. Among the protease:serpin complexes measured, FIXa:AT complexes were uniquely associated with clinical indices of disease severity, specifically total length of hospitalization, length of intensive care unit stay, and extent of lung computed tomography changes. We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19. Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.
凝血激活是严重急性呼吸综合征冠状病毒 2（COVID-19）感染的一个显著特征。接触系统和内源性途径的激活越来越多地与无菌和感染性炎症状态下观察到的血栓前状态有关。因此，我们试图评估 COVID-19 感染个体中接触系统和内源性途径的激活。在 COVID-19 住院患者和健康个体的样本中测量了指示接触和内源性途径激活的蛋白酶：丝氨酸蛋白酶抑制剂复合物的基线血浆水平。通过酶联免疫吸附试验测量了缓激肽释放的替代物裂解激肽原，通过微泡组织因子介导的因子 Xa（MVTF）生成评估了外源性途径的激活。样本是在 COVID-19 诊断后 24 小时内采集的。共纳入 30 名 COVID-19 患者和 30 名年龄和性别匹配的对照者。COVID-19 患者的接触系统和内源性途径激活表现为 FXIIa：C1 酯酶抑制剂（C1）、激肽释放酶：C1、FXIa：C1、FXIa：α1-抗胰蛋白酶和 FIXa：抗凝血酶（AT）的血浆水平升高。MVTF 水平在 COVID-19 患者中也升高。由于 FIXa：AT 水平与接触/内源性途径复合物和 MVTF 相关，FIX 的激活可能通过接触/内源性和外源性途径发生。在所测量的蛋白酶：丝氨酸蛋白酶抑制剂复合物中，FIXa：AT 复合物与疾病严重程度的临床指标（特别是总住院时间、重症监护病房住院时间和肺部计算机断层扫描变化程度）独特相关。我们得出结论，接触/内源性途径可能有助于 COVID-19 血栓前状态的发病机制。需要更大的前瞻性研究来确认 FIXa：AT 复合物是否是不良临床结局的有用临床生物标志物。
