Among patients diagnosed with coronavirus disease 2019 (COVID-19), the contact/intrinsic pathway may have a causal link with pathogenesis of the prothrombotic state, according to research published in Blood Advances. Furthermore, it may be that microvesicle tissue factor (MVTF)-mediated factor Xa (FXa):antithrombin (AT) complexes may be linked with poor outcomes in this setting.

Previous research has suggested that coagulation pathways play a crucial role in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. Specifically, alterations of coagulation biomarkers have been linked with severe disease, venous thromboembolism, and pulmonary microvascular thrombi.

It was, however, previously unclear how specific complexes, such as FXa:AT, affect SARS-CoV-2 pathogenesis. For this study, researchers aimed to elucidate mechanisms of coagulation activation among a cohort of patients with COVID-19. The researchers also aimed to determine any link between these biomarkers and clinical outcomes in the setting of COVID-19.

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Data from a cohort of 30 patients were compared with those of 30 volunteer participants without COVID-19. In the COVID-19 and volunteer cohorts, the mean ages were 52.7 and 50.3 years, respectively, and the male:female sex ratios were both 16:14. In the COVID-19 group, the mean length of hospital stay was 12.9 days, and 6.7% of patients died.

All patient samples were taken within 24 hours of COVID-19 diagnosis. Analysis showed that, in patients with COVID-19, contact system and intrinsic pathway activation was noted by increased plasma levels of FXIIa:C1 esterase inhibitor (C1), kallikrein:C1, FXIa:C1, FXIa:a1-antitrypsin, and FIXa:AT. MVTF levels were also elevated in the patient samples.

Notably, FIXa:AT complexes were directly linked with disease severity, including length of hospitalization, length of intensive care unit stay, and degree of changes in lung computed tomography.

“We conclude that the contact/intrinsic pathway may contribute to the pathogenesis of the prothrombotic state in COVID-19,” the authors wrote in their report. “Larger prospective studies are required to confirm whether FIXa:AT complexes are a clinically useful biomarker of adverse clinical outcomes.”


Henderson MW, Lima F, Moraes CRP, et al. Contact and intrinsic coagulation pathways are activated and associated with adverse clinical outcomes in COVID-19. Blood Adv. 2022;6(11):3367-3377. doi:10.1182/bloodadvances.2021006620