Differential Host Response Contributing to Incidence of Arterial and Venous Thromboembolism at Index Hospitalization for Sars-Cov-2 Infection across Wuhan, Delta, Omicron and Omicron BA.x Variants

Abstract

Introduction SARS-CoV-2 induced coagulopathy has been associated with increased risk of arterial and venous thromboembolism. Literature demonstrates that incidence of thromboembolism has varied widely throughout the COVID-19 pandemic, with many reports preceding emergence of Delta and Omicron variants. This study aimed to characterize the incidence of arterial and venous thromboembolic events among patients hospitalized with acute SARS-CoV-2 infection during Wuhan, Delta, Omicron, or Omicron BA.x waves. To our knowledge, this study debuts variant specific analyses to shed some light on reported substantive differences pooled across SARS-CoV-2 variants regarding host response, clinical course, and outcomes. Intensity of pathophysiologic anomalies may have been associated with macro- and micro-circulatory clotting. Therefore, we hypothesized variant idiosyncratic host responses would be evoked and aimed to link our patient's demographics and comorbidity patterns with risk of thromboembolism. Methods This is a retrospective study including patients with laboratory confirmed SARS-CoV-2 infection who underwent index hospitalization during Wuhan (March 14, 2020- June 18, 2021), Delta (June 19, 2021- December 18, 2021), Omicron (December 19-March 30, 2022) or Omicron BA.x (March 31, 2022 - April 14, 2023) variant waves at an 820-bed academic public health trust hospital in Florida. Demographics, laboratory at presentation, ICD-10-CM-based comorbidity, SARS-CoV-2 directed treatment and administrative data were extracted under IRB exemption from electronic medical records. Generalized regression with adaptive LASSO identified variables associated with embolism in at least one variant wave controlling for extant dysrhythmia, chronic anticoagulation therapy, and COVID-19 directed treatment. Prespecified 2-way ANOVA examined interactions between intra- vs. inter-variant waves but was ruled out due to strong imbalances in variation. Thus, only within-variant contrasts were performed. Continuous data summarized with mean [±SD] were compared using an ANOVA test adjusting p-value for parametric vs. non-parametric distribution. Discrete data summarized as proportions were compared with chi-squared test. A p<.05 was considered significant. Results We studied 6490 patients consecutively discharged across Wuhan (n=2249), Delta (n=1196), Omicron (n=953) and Omicron BA.x (n=2092) variants with respective embolic event(s) of 3%, 2%, 2%, and 4%. Table 1 summarizes demographics, anthropometric, comorbidities and laboratory biomarkers obtained within 24h of hospitalization across variants. Table 2 presents clinical course and outcomes. Discussion Incidence of embolic events was isomorphically distributed among waves tending to affect older males harboring hypertension, neurologic disease, and/or heart failure. D-dimer levels at presentation significantly distinguished risk of thromboembolism with Wuhan, Delta, or Omicron, but not Omicron BA.x variant infection. Indeed, Omicron BA.x infection was associated with numerically lower ICU visits, mechanical ventilation requirement, hospital LOS and mortality. Elevated D-dimer consistently has been associated with excess risk of progression to severe illness and mortality (Milenkovic M et al., 2022), mostly via pooled results across SARS-CoV variant waves. Some have suggested that D-dimer guided anticoagulation management improves outcomes in patients with COVID-19 (Ronderos Botero DM et al., 2023). Deeper phenotyping of patients infected with Omicron BA.x variants may reveal unique prothrombotic features driving what appears to be a less severe hypercoagulable state.