<scp>COVID</scp>‐19 thromboembolism incidence, risk factors, and anticoagulation practices from a Chicago metropolitan <scp>US</scp> population
Authors: Stephanie Berg, Seo‐Hyun Kim, Amy Wozniak, Oluwatobi Odetola, Saad Arain, Ahmed Aleem, James Coggan, Ami Dave, Elizabeth Elliott, Ryan Guerrettaz, Hina Dalal, Raymond Lee, Abhigna Kodali, Patrick Moore, Sonam Patel, Priya Rajakumar, Shuai Qin, Glenda Delgado Ramos, Candice Schwartz, Fatema Esmail, Rebecca Feltman Frank, Ellen Murchie, Laura Pax, Nicole Yun, Yanyu Zhang, Kevin Barton, Patrick Hagen, Nasheed Hossain, Melissa L. Larson, Hanh Mai, Sucha Nand, Kathleen Phelan, Parameswawran Venugopal, Patrick Stiff, Santosh Saraf
Journal: American Journal of Hematology (2022)

Coronavirus 2019 (COVID-19), caused by the novel severe acute respiratory (SARS) coronavirus 2 (CoV-2), has infected millions worldwide. Abnormal coagulation parameters are often present in COVID-19-hospitalized patients, which may increase their risk of arterial or venous thrombosis. Current studies report 10%–46% of COVID-19-hospitalized patients develop venous thromboembolism (VTE) and 2%–5% develop arterial thrombosis with higher ranges (11%–69%) for patients admitted to the intensive care unit (ICU).1, 2 Most studies investigating thrombosis in COVID-19 infections have been conducted in ethnically homogenous populations. Certain ethnicities, such as non-Hispanic Blacks (NHB) and Hispanics (H), have a higher risk of hospitalization and disease severity from COVID-19 compared to non-Hispanic Whites (NHW).3 These observed differences in outcomes by ethnicity may be due to dissimilarities in the prevalence of comorbidities, access to care, or inherent biological variances.3 The Chicago-Naperville-Elgin Metropolitan Statistical area (CNE-MSA) is a diverse population made up of over 9.4 million residents and is third largest in the United States by population. The purpose of our study is to describe the rate and risk factors for thrombosis in our ethnically diverse patient population hospitalized for COVID-19 infection representing the CNE-MSA. We conducted a multicenter retrospective study of three health systems in the CNE-MSA from March 1, 2020 to May 31, 2020: Loyola University Health System (LUHS; includes Loyola University Medical Center, Gottlieb Memorial Hospital, MacNeal Hospital), Rush University Health System (RUSH; includes Rush University Medical Center, Rush Oak Park Hospital, and Rush Copley Hospital), and the University of Illinois at Chicago (UIC). This study included consecutive patients with documented seropositivity of SARS-CoV-2 by rapid antigen detection or reverse transcription polymerase chain reaction and required hospital admission for at least 24 h. Thromboembolism prophylaxis was standard of care at each hospital unless a patient was already receiving full doses of anticoagulation for a pre-existing condition (prior VTE, atrial flutter/fibrillation, stroke history) or had a contraindication to prophylaxis (platelets <50 000, current hemorrhage, or documented allergy) at the time of admission. Readmitted patients were not included in the analysis. All data were collected at least 30 days posthospital admission date, and all deaths are recorded based on in-hospital mortality. Institutional review board committee approvals were obtained prior to data collection, and data use agreements were obtained between all institutions prior to data analysis. The primary outcome of interest is any thrombotic event (TE) defined as a documented venous or arterial thrombosis identified by computed tomography pulmonary embolism scan, venous or arterial duplex ultrasonography, or magnetic resonance imaging. Secondary outcomes investigated the associated risk factors of ICU admission or death. Bleeding events during hospital admission are presented only for LUHS. Nonparametric Wilcoxon tests were used to compare complete case univariate differences in continuous risk factors. Fisher's test or Chi-squared tests were used to compare differences in categorical risk factors. Multivariable logistic regression models with random effects for institution were used to estimate the association between risk factors and the odds of TE or the composite outcome of ICU admission or death. Maximum likelihood was estimated using Gaussian quadrature. If a variable had over 10% missing, an indicator variable was created in order to use complete case analysis in multivariable models. Variance inflation factors were evaluated to ensure appropriate model fit. All analyses were performed using SAS 9.4 (Cary, NC); p-values < .05 were deemed statistically significant. A total of 2898 hospitalized patients are included in the final analysis. Overall, 1024 (35.4%) were deemed critically ill; 973 patients required ICU admission, and 51 patients died prior to ICU admission. Table 1 describes the total study population characteristics by TE status. Patient characteristics by institution are described in Table S2. The median age was 59 years (IQR, 24.6), 1602 (55%) were men, and 52% were obese (BMI >30). The ethnicity breakdown is as follows: 1291 (45%) NHW, 911 (31%) Hispanic, 452 (16%) NHB, and 243 (8%) other. Baseline patient co-morbidities were common and included 1507 (52%) having hypertension, 1218 (42%) with diabetes, 634 (25%) with any tobacco use history, and 469 (16%) with chronic kidney disease. For LUHS and RUSH, 111/2599 (4.3%) of patients had a diagnosis of VTE before COVID-19 infection; UIC did not have this data available. During hospital admission, 2121 (74%) of patients were placed on prophylactic anticoagulation per each institution's guidelines, 436 (11%) were already prescribed full-dose anticoagulation, and 316 (11%) were given no anticoagulation therapy due to contraindications as described above. If patients were on intermediate intensity anticoagulation, as defined per site, these were grouped into the treatment categories. Baseline lab values are as follows: 403 (22%) of patients had D-dimer levels >5-times the upper limit of normal (ULN) for the specific institution (LUHS >2500 ng, UIC >2.5 mg, RUSH >3 mg); 117 (4%) had elevated platelet values (>450 × 103/μL), 394 (13.7%) had low platelet values (<140 × 103/μL), and 557 (19%) had white blood cell (WBC) counts >10 500 × 103/μL. There were 213 (7.3%) COVID-19 patients who had a documented TE during hospitalization: LUHS = 65 (6%), RUSH = 130 (8%), and UIC = 18 (6%) (Table S2). Of the 213 TE, 150 (70%) patients had VTE only, 38 (18%) patients had arterial thrombosis, 14 (7%) patients had both venous and arterial thrombosis, and 11 (5%) patients had superficial venous thrombosis. Bleeding complications from anticoagulation were documented in 42 patients from the LUHS cohort with intracranial hemorrhage (N = 10) as the most common event (Figure S1). COVID-19-infected patients that developed a TE had a higher D-dimer, WBC, and platelet count, were more frequently on therapeutic anticoagulation, and more commonly Hispanic compared to NHB or NHW (Figure 1A). In multivariable analysis, risk factors for a TE included a D-dimer >5-times the ULN (OR 2.93, [95% confidence interval (CI) 2.03–4.25, p < .0001]), WBC greater than 10.5 K/UL (OR 2.05, [95% CI 1.46–2.88, p < .0001]), and being of Hispanic ethnicity (H vs. NHB OR 1.95 [95% CI 1.17–3.25, p = .011]), H vs. NHW (OR 1.53 [95% CI 1.07–2.19, p = .019]). Administration of prophylactic anticoagulation reduced the risk of TE (OR 0.32, 95% CI 0.21–0.50, p < .0001). Table S1 describes patient characteristic by ICU or death. The composite outcome of ICU admission or in-hospital mortality was observed in 1024 (35%) hospitalized COVID-19 patients. The overall mortality in the ICU patient population was 35.5% (N = 346). A TE was observed in 166 (16.2%) critically ill patients. Elevations of D-dimer, WBC, older age, male sex, chronic kidney disease, diabetes, and use of therapeutic anticoagulation were predictive of the composite outcome of ICU admission or death during hospitalization in multivariable analysis (Figure 1B). Our large multicenter study describes patterns and risk factors for TE and for ICU or death in hospitalized COVID-19 patients representing the multiethnic CNE-MSA. In our large, ethnically diverse population, we confirmed that an elevated D-dimer was an independent predictor for TE.4 We also found that an elevated WBC count on admission was predictive of TE, which may represent underlying inflammatory responses during acute COVID-19 illness. In addition, Hispanics had an approximately 2-fold higher risk of TE compared to NHB. Bilaloglu et al. described a New York City COVID-19 hospitalized population with a 16% incidence of any TE.5 They reported an OR of 1.91 for Hispanic patients versus NHW, similar to the OR of 1.53 for Hispanic versus NHW that we observed. In a large meta-analysis of 68 studies, Hispanic individuals were at a 4.7-fold greater risk of developing COVID-19 infection and a higher area deprivation index was associated with mortality risk in this population.3 This raises a question regarding disparity among the Hispanic population for COVID-19 severity and TE risk and if further anticoagulation prevention strategies should be explored in this high-risk group. An elevated D-dimer was an independent predictor of admission to the ICU or death highlighting the clinical importance of coagulopathy in the morbidity and mortality of COVID-19-hospitalized patients. Strengths of our study include our large patient population in the CNE-MSA with representative distributions of the local population and identifying risk factors for TE that both confirm other studies and identify new potential risk factors. Limitations of this study include its retrospective nature and missing data from patients early in the pandemic for certain coagulation parameters (D-dimer, prothrombin time/international normalized ratio, partial thromboplastin time). Future directions studying COVID-19 and thrombosis should include determining the optimal dosing of anticoagulation for high-risk populations, specifically the critically ill, those with underlying comorbidities, and exploring possible ethnic differences. This need is highlighted in a recent randomized clinical trial demonstrating therapeutic versus prophylactic-dose anticoagulation reduced TE or death in non-ICU but not ICU patients.6 Vaccination against SARS-CoV-2 will hopefully lower the incidence of COVID-19 thrombosis in hospitalized patients, although COVID-19 vaccine linked TEs have been reported. The presence of new SARS-Co-V2 variants as leading strains (Delta, Omicron) may change TE incidence, and clinical updates will be necessary for future guidelines and recommendations for prophylaxis in hospitalized patients. Current society guidelines recommended by ASH and CHEST recommend all COVID-19-hospitalized patients (including the critically ill) receive thromboprophylaxis in absence of contraindications, and findings from our multicenter cohort support these guidelines. The authors declare no conflicts of interest. Stephanie Berg, Seo-Hyun Kim, Amy Wozniak, and Santosh Saraf designed and performed the research, analyzed and interpreted the data, and wrote the manuscript. All other authors performed the research and edited the manuscript. All authors approved the manuscript prior to submission. Figure S1. Bleeding events reported from LUHS (Loyola University Health System) of coronavirus disease 2019 (COVID-19) hospitalized patients receiving therapeutic or full-dose anticoagulation. RP, retroperitoneal. Table S1. Patient characteristics by MICU and/or death. Missing: BMI = 116, tobacco = 391, WBC = 29, PLT = 22, D-dimer = 1099, anticoagulation 25; *=p < .05; **=p < .01. BMI, body mass index; H, Hispanic; MICU, medical intensive care unit; NHB, non-Hispanic Black; NHW, non-Hispanic White; PLT, platelet; WBC, white blood cell. Table S2. Patient characteristic separated by institution. Missing: BMI = 116, tobacco = 391, WBC = 29, PLT = 29, D-dimer = 1105, anticoagulation = 25, MICU/death = 8, BMI, body mass index; LUHS, Loyola University Health System; MICU, medical intensive care unit; PLT, platelet; TE, thrombotic event; UIC, University of Illinois-Chicago; WBC, white blood cell. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.