Whole Blood Viscosity and Thromboembolic Events in Hospitalized Patients with COVID-19: Post hoc Analysis of the ATTACC/ACTIV-4a Trial

Research Letter The coronavirus disease 2019 (COVID-19) posed unprecedented challenges to health care systems worldwide, necessitating comprehensive research efforts to gain a better understanding of its diverse clinical presentations and associated complications. Among the numerous consequences of infection with the severe acute respiratory syndrome coronavirus 2, venous thromboembolism stands out as a critical concern, significantly contributing to both the morbidity and mortality of individuals hospitalized with COVID-19.[ 1 ] [ 2 ] Whole blood viscosity (WBV) serves as a validated measure of the resistance to shear stress encountered during blood flow within the circulatory system. Several studies have directly assessed WBV in COVID-19 patients and consistently reported elevated values when compared with uninfected individuals.[ 3 ] [ 4 ] Alterations in blood viscosity can influence microcirculation, exacerbate inflammation, and potentiate thrombosis, thereby playing a pivotal role in the pathogenesis of COVID-19-associated thromboembolic complications.[ 5 ] In retrospective cohort studies of hospitalized COVID-19 patients, increased high-shear and low-shear blood viscosity were significantly associated with higher in-hospital mortality and poor prognosis.[ 6 ] [ 7 ] Specifically, a 1 centipoise rise in high-shear viscosity was linked to a 36% increased risk of death ( p < 0.001),[ 7 ] and there was a decreased likelihood of being respiratory organ support-free at 21 days, with an odds ratio (OR) of 0.68 ( p < 0.001).[ 6 ] The Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC; NCT04372589) and A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a; NCT04505774) platforms investigated therapeutic strategies to mitigate the thrombotic risk associated with COVID-19.[ 8 ] [ 9 ] These platforms reported improved survival and clinical outcomes with therapeutic-dose anticoagulation among noncritically ill patients with COVID-19, but not among those with critical illness. In this context, we conducted a post hoc analysis to explore the relationship between WBV and thromboembolic events in hospitalized patients with COVID-19. The study design and primary results of the trial has been previously published.[ 8 ] [ 9 ] The study received approval from the ethics committee and written or oral informed consent was obtained from all participants or their surrogates. Hospitalized patients with COVID-19 were enrolled in the trial. Exclusion criteria included patients with an imminent risk of death, a high risk of bleeding, those receiving dual antiplatelet therapy, individuals with a separate clinical indication for therapeutic-dose anticoagulation, or a history of heparin-induced cytopenia. Detailed exclusion criteria were published in a previous study.[ 8 ] [ 9 ] Estimated blood viscosity was calculated using the Walburn–Schneck model, which has been previously validated in a study involving COVID-19 patients.[ 10 ] [ 11 ] [ 12 ] The primary outcome of interest was composite outcome of 90-day mortality, venous thromboembolism events, and arterial thromboembolism events. Based on the calculated high-shear and low-shear blood viscosity values, participants were categorized into high- and low-blood viscosity groups using the median value. We used chi-square tests for categorical variables and t -tests for continuous variables to assess statistical significance between the high- and low-blood viscosity groups. Multivariable logistic regression was then conducted to determine ORs and their corresponding 95% confidence intervals (CIs) for the primary outcomes. Considered covariates were age, sex and oxygen requirement at presentation. All analyses were performed using SAS 9.4. We considered p -values less than 0.05 as statistically significant, and all p -values were evaluated using two-tailed tests. Baseline characteristics of the study population are presented in [ Table 1 ]. Participants with higher blood viscosity were more likely to be male, of White or Hispanic ethnicity, younger in age, and had fewer comorbidities compared with those with lower blood viscosity. [ Table 2 ] shows the associated of blood viscosity and primary outcome. A total of 149 primary composite outcome events were identified with a total event rate of 15.7%. However, COVID-19 patients with higher high-shear blood viscosity did not exhibit significantly different odds of developing the primary composite outcome (OR: 0.72, 95% CI: 0.51–1.02, p = 0.07). Table 1 Baseline characteristics of the study population Variables High-shear BV lower half High-shear BV upper half p -Value BV range, cP 1.90–2.93 2.94–4.37 Severity status (%) 0.074 Severe 65 (13.7%) 47 (9.9%) Moderate 410 (86.3%) 426 (90.1%) Sex (%) <0.001 Male 194 (40.8%) 364 (77%) Female 281 (59.2%) 109 (23%) Age (median [IQR]) 63.0 [56–71] 59.0 [49–68] <0.001 Race (%) <0.001 White 209 (44%) 267 (56.4%) Black 135 (28.4%) 67 (14.2%) Asian 22 (4.6%) 20 (4.2%) Other 109 (22.9%) 119 (25.2%) Ethnicity (%) 0.003 Hispanic 125 (26.3%) 167 (35.3%) Not Hispanic 20 (4.2%) 22 (4.7%) Comorbidity (%) Hypertension 319 (67.2%) 222 (46.9%) <0.001 Diabetes mellitus 205 (43.2%) 126 (26.6%) <0.001 Chronic kidney disease 69 (14.5%) 20 (4.2%) <0.001 Coronary artery disease 38 (8%) 31 (6.6%) 0.391 Oxygen support (%) 0.029 No support 89 (18.7%) 70 (14.8%) Low-flow support 314 (66.1%) 350 (74%) High-flow support 72 (15.2%) 53 (11.2%) Anticoagulation (%) 0.133 Therapeutic 245 (51.6%) 267 (56.4%) Prophylactic 230 (48.4%) 206 (43.6%) Labs (%) WBC, 10 9 /L 6.4 [5–9] 6.7 [5–9] 0.29 CRP, mg/L 101.0 [50–173] 81.0 [47–126] 0.004 D-dimer, µg/L (FEU) 940.0 [580–1,680] 803.0 [510–1,231] 0.001 Fibrinogen, mg/dL 602.0 [476–726] 666.0 [555–740] 0.005 Abbreviations: BV, blood viscosity; cP, centipoise; CRP, C-reactive protein; FEU, fibrinogen equivalent unit; IQR, interquartile range; WBC, white blood cell count. Table 2 Association of high-shear blood viscosity and primary composite outcome High-shear BV lower half High-shear BV upper half p -Value BV range, cP 1.90–2.93 2.94–4.37 Unadjusted OR (95% CI) 1.00 (reference) 0.72 (0.51–1.02) 0.07 Adjusted OR (95% CI) 1.00 (reference) 0.69 (0.46–1.05) 0.08 Abbreviations: BV, blood viscosity; CI, confidence interval; cP, centipoise; OR, odds ratio; VTE, venous thromboembolism. Notes: Composite outcome is participants that died within 90 days or had a VTE or arterial thromboembolism events. Event rate = (149/948) × 100 = 15.72%. Unadjusted odds ratio between high-shear blood viscosity 2-level categorical variable and outcome variable. Odds ratio adjusted for age, sex, oxygen To date, no prospective study has evaluated the association between blood viscosity and composite outcome of 90-day mortality, venous thromboembolism events and arterial thromboembolism events. This limited observational study did not reveal a significant difference in 90-day mortality and thromboembolic events associated with increased blood viscosity, likely due to the low event rate and the small study population. These limitations highlight the need for larger, prospective trials to comprehensively explore the relationship between blood viscosity and thromboembolic risk in acute illness settings including non-COVID-19 pneumonia, given similarities in the inflammatory and prothrombotic pathways activated in a range of infectious and inflammatory conditions. Authors' Contribution R.S.R. is the corresponding author for the study. P.R.L. and R.S.R. had full access to all of the data in the study and takes responsibility for study design, integrity of the data, the accuracy of analysis. D.C. and J.D.F. contributed substantially to the study design, data acquisition, data analysis, and data interpretation. D.C. authors additionally contributed drafting of the manuscript. P.R.L., M.D.N., R.Z., and R.S.R. contributed critical revision of the manuscript. All authors read and approved the final manuscript. Publication History Received: 19 February 2024 Accepted: 15 March 2024 Article published online: 16 April 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

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