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OBJECTIVE: The optimal anticoagulant treatment regimen in hospitalized coronavirus disease 2019 (COVID-19) patients is uncertain. This study aimed to compare the rates of disease progression and mortality in patients treated with low-molecular-weight heparin (LMWH) according to baseline d-dimer levels and in those who received a fixed-dose regimen irrespective of the d-dimer level. MATERIAL AND METHODS: This was a retrospective analysis of all patients admitted to a university hospital for COVID-19 pneumonia during a 1-year period. The protocol for d-dimer-driven therapy (on-protocol) was as follows: prophylactic dose when the baseline level is <1000 ng/mL, intermediate dose when the level is between 1000 and 3000 ng/mL, and therapeutic dose when the level is >3000 ng/mL. We compared the progression and mortality rates between the on-protocol and off-protocol treatment groups. The offprotocol group consisted of patients that received a fixed-dose LMWH regimen, which was not in accordance with the defined protocol. RESULTS: Of 384 patients (mean age 61.5 ± 15.9 years, 216 male), 294 patients with complete data composed the study group, and 174 patients were treated on-protocol and 120 patients were treated off-protocol. The on-protocol group had lower C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and d-dimer levels and higher SpO2/FiO2 levels at admission. Disease progression developed in 45/174 on-protocol patients (25.9%) vs. 53/120 off-protocol patients (44.2%) during the follow-up (P = .001), and mortality was 29 (16.7%) vs. 32 (26.7%), respectively (P = .041). Logistic regression analysis was performed and included age, presence of comorbidities, LMWH regimen, baseline SpO2/FiO2, CRP, and LDH levels as independent variables. The presence of cardiac comorbidity, age, CRP, and LDH levels, but not the LMWH treatment regimen, were associated with both disease progression and mortality. CONCLUSION: A d-dimer-driven LMWH treatment protocol is not associated with better clinical outcomes in hospitalized COVID-19 patients. [ABSTRACT FROM AUTHOR]