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Antithrombin, a 432-aminoacid serpin produced by the liver, is now recognized as one of the most powerful endogenous anticoagulants, which functions by competitively inhibiting the activity of thrombin and activated factor X (FXa).1,2 Both inherited and acquired antithrombin deficiencies are associated with a magnified thrombotic risk, especially venous thromboembolism.3 Importantly, reduced antithrombin levels are also observed in patientswith intravascular consumption coagulopathies, including those caused by bacteria, viruses, and other microorganisms.2 Since both venous and arterial thrombotic complications are commonly observed in patients with coronavirus disease 2019 (COVID-19) and appear to have a significant impact on patient prognosis,4 we performed a literature search to identify all clinical studies that measured antithrombin in COVID-19 patients and correlated the values of this endogenous inhibitor with disease severity. A digital search was conducted of PubMed, Scopus, and Web of Science, with the keywords “coronavirus disease 2019” OR “COVID-19”AND “antithrombin” in all fields, up to present time (i.e., July 25, 2020), without language restriction. Two independent reviewers analyzed the title, abstract, and full text of all documents. Studies reporting plasma antithrombin values in patients with or without severe COVID-19 illness and with a sample size of> 10 patients were finally selected. The reference lists of all articles were also analyzed, with the scope of detecting additional potentially eligible studies. A pooled analysis was finally performed, calculating the weighted mean difference (WMD) along with its 95% confidence interval (95% CI), of antithrombin values in COVID-19 patients with or without severe illness. When mean value and standard deviation were not directly reported, they were calculated from the sample size, median, and interquartile range, according to the method proposed by Hozo et al.5 A random-effect model was applied for adjusting for potential heterogeneity arising across the different studies. Heterogeneity was evaluated with χ test and I statistic. The statistical analysis was performed using MetaXL software Version 5.3 (EpiGear International Pty Ltd.). The study was performed in accordance with the declaration of Helsinki and within the terms of local legislation. Our initial electronic search generated a total number of 60 documents, of which 54were excluded because theywere review articles (n1⁄4 24), did not report antithrombin data (n1⁄4 12), were editorial material (n1⁄4 9) or case reports (n1⁄4 5), did not stratify antithrombin values according to disease severity (n1⁄4 3), or had an insufficient sample size (n1⁄4 1). No inter-reviewer disagreement emerged. The final analysis thereby included six studies,6–11 five cross-sectional and one prospective, totaling 471 COVID-19 patients, of whom 197 (41.8%) had severe disease (►Table 1). Three studies were performed in China, two in Italy, and one in France. Severe COVID-19 illness was defined as the need for intensive care unit (ICU) admission in four studies, and terminal stage of disease or severe hemostatic derangement in the remaining two investigations. The results of both individual investigations and the pooled analysis are shown in ►Fig. 1. In five studies, antithrombin values were found to be lower in COVID-19 patients with severe illness (in all except for one, the difference was statistically significant), with differences ranging These authors have equal senior authorship on this work.

Plasma Antithrombin Values Are Significantly Decreased in Coronavirus Disease 2019 (COVID-19) Patients with Severe Illness