d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019

Abstract

Objectives: Hypercoagulability may be a key mechanism for acute organ injury and death in patients with severe coronavirus disease 2019, but the relationship between elevated plasma levels of d-dimer, a biomarker of coagulation activation, and mortality has not been rigorously studied. We examined the independent association between d-dimer and death in critically ill patients with coronavirus disease 2019.

Design: Multicenter cohort study.

Setting: ICUs at 68 hospitals across the United States.

Patients: Critically ill adults with coronavirus disease 2019 admitted to ICUs between March 4, 2020, and May 25, 2020, with a measured d-dimer concentration on ICU day 1 or 2.

Interventions: None.

Measurements and main results: The primary exposure was the highest normalized d-dimer level (assessed in four categories: < 2×, 2-3.9×, 4-7.9×, and ≥ 8× the upper limit of normal) on ICU day 1 or 2. The primary endpoint was 28-day mortality. Multivariable logistic regression was used to adjust for confounders. Among 3,418 patients (63.1% male; median age 62 yr [interquartile range, 52-71 yr]), 3,352 (93.6%) had a d-dimer concentration above the upper limit of normal. A total of 1,180 patients (34.5%) died within 28 days. Patients in the highest compared with lowest d-dimer category had a 3.11-fold higher odds of death (95% CI, 2.56-3.77) in univariate analyses, decreasing to a 1.81-fold increased odds of death (95% CI, 1.43-2.28) after multivariable adjustment for demographics, comorbidities, and illness severity. Further adjustment for therapeutic anticoagulation did not meaningfully attenuate this relationship (odds ratio, 1.73; 95% CI, 1.36-2.19).

Conclusions: In a large multicenter cohort study of critically ill patients with coronavirus disease 2019, higher d-dimer levels were independently associated with a greater risk of death.

Trial registration: ClinicalTrials.gov NCT04401293.

Conflict of interest statement

Dr. Gupta’s institution received funding from the Foundation for the National Institutes of Health (NIH) 5 F32 DC 17342-2; she received funding from GlaxoSmithKline; she is a scientific coordinator for the Anemia Studies in CKD: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat (ASCEND) trial (GlaskoSmithKline). Dr. Srivastava received funding from CVS Caremark, AstraZeneca, Horizon Therapeutics, PLC, and Tate & Latham. Dr. Shaefi’s institution received funding from the National Institute on Aging/NIH R03AG060179 and the National Institute of General Medical Sciences/NIH K08GM134220; he received support for article research from the NIH. Dr. Bagchi's institution received funding from the American Heart Association 20IPA35360009. He received funding from Lungpacer Medical, Inc. Dr. Al-Samkari received funding from Agios, Dova, Rigel, Argenx, and Amgen. Dr. Zakai’s institution received funding from the NIH and Centers for Disease Control and Prevention. Dr. Leaf received research support from BioPorto. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Figures

Figure 1.

D-dimer distribution and correlates with mortality. A, The relative frequencies of D-dimer levels, defined as the highest value measured within two days following ICU admission, by 28-day mortality status. B-E, Correlation of D-dimer categories with death by age, sex, race, and body mass index (BMI) categories, respectively. ULN = upper limit of normal.

Figure 2.

Logistic regression models for 28 d mortality by D-dimer category. Model 1 is unadjusted. Model 2 is adjusted for age, sex, race, body mass index, diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, current smoking status, and active malignancy. Model 3 is further adjusted for receipt of invasive mechanical ventilation, shock, and the renal, coagulation, and liver components of the Sequential Organ Failure Assessment score, each assessed within the first 2 d following ICU admission. Model 4 is further adjusted for home anticoagulation as well as receipt of therapeutic anticoagulation, aspirin, and steroids in the first 2 d following ICU admission. Covariates are further defined in the Supplemental Methods (Supplemental Digital Content 1, http://links.lww.com/CCM/G206). ULN = upper limit of normal.