Anticoagulation Therapy in Patients With Coronavirus Disease 2019

Results From a Multicenter International Prospective Registry (Health Outcome Predictive Evaluation for Corona Virus Disease 2019 (HOPE-COVID19))

Francesco Santoro, MD, PhD; Ivan J. Núñez-Gil, MD, PhD; María C. Viana-Llamas, MD; Charbel Maroun Eid, MD; Rodolfo Romero, MD; Inmaculada Fernández Rozas, MD; Alvaro Aparisi, MD; Victor Manuel Becerra-Muñoz, MD; Marcos García Aguado, MD; Jia Huang, MD; Ludovica Maltese, MD; Enrico Cerrato, MD; Emilio Alfonso-Rodriguez, MD; Alex Fernando Castro Mejía, MD; Francisco Marin, MD; Sergio Raposeiras Roubin, MD; Martino Pepe, MD; Victor H. Moreno Munguia, MD; Gisela Feltes, MD; Jesus Varas Navas, MD; Bernardo Cortese, MD; Luis Buzón, MD; Cristoph Liebetrau, MD; Raquel Ramos-Martinez, MD; Antonio Fernandez-Ortiz, MD; Vicente Estrada, MD; Natale Daniele Brunetti, MD, PhD


Crit Care Med. 2021;49(6):e624-e633. 

In This Article


We report safety and efficacy of anticoagulation therapy from a large multicenter international registry on COVID-19. We found that anticoagulation therapy among general population with COVID-19 was not associated with better survival rates but with higher bleeding risk. Patients admitted with respiratory failure requiring invasive ventilation may benefit in terms of lower mortality through use of anticoagulation therapy.

COVID-19 is novel infectious disease that affects mainly respiratory system but also several organs. Indeed, severe acute respiratory syndrome coronavirus 2 enters human cells mainly by binding the ACE2, which is expressed in lung alveolar cells, vascular endothelial cells, cardiac myocytes, and other cells.[9]

COVID-19 is featured by hemostatic abnormalities including mild thrombocytopenia and increased D-dimer levels. Recent literature showed that coagulopathy associated with COVID-19 is a combination of low-grade DIC and localized pulmonary thrombotic microangiopathy, which could have an impact among most severely affected patients.[7]

Severe forms of COVID-19 are associated with increased concentrations of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin (IL), including IL-1 and IL-6.[10] IL-6 can induce tissue factor expression on mononuclear cells, which subsequently initiates coagulation activation and thrombin generation.

Furthermore, a remarkable activation of the fibrinolytic system can be found in Coronavirus infections. Indeed, Plasma concentrations of tissue-type plasminogen activator were six times higher in patients infected with human severe acute respiratory syndrome coronavirus 1 than in patients with no infection.[11]

Severe inflammatory response, critical illness, and underlying traditional comorbidities may predispose to thrombotic events, as previously found in severe acute respiratory syndrome.[12] Hospitalized patients with acute medical illness, including infections such as pneumonia, are at increased risk of venous thromboembolism (VTE).[13] Therefore, especially in severe forms of COVID-19, there is a hypercoagulable state that could increase the risk of thromboembolic complications.

Most of the studies on the prevalence of thrombosis in COVID-19 have been performed in autopsies or in severe forms.

Autopsy studies showed various stages of diffuse alveolar damage in both lungs and thrombosis of small- and mid-sized pulmonary arteries in all patients associated with infarction in 72% of cases.[14] Interestingly, all these patients were treated with prophylactic anticoagulation.[11] Wichmann et al[2] found in an autopsy study DVT in seven out of 12 patients (58%) and PE was the direct cause of death in four patients.

Initial clinical series are supporting this finding, showing the common occurrence of VTE in patients with severe COVID-19.[3] The prevalence of PE among COVID-19 patients in ICU is about 20%[4] and 46% of patients may develop lower extremity DVT.[5]

Klok et al[15] found an occurrence of PE among critically ill ICU patients of 35% and these patients had five times higher risk of death. Bompard et al,[16] in a series of 135 patients, identified 24% (n = 32) of PE. Among these cases, 31% were proximal PE, 56% involved segmental pulmonary arteries, and 13% multiple subsegmental pulmonary arteries. Patients with PE required more frequently ICU stay and longer hospitalization.

Data on standard of care for anticoagulation therapy in COVID-19 are lacking and therapy is mainly based on operator choice. Some clinicians use prophylactic dosing and others intermediate- or full-dose (therapeutic) parenteral anticoagulation to prevent microvascular thrombosis.

Tang et al[17] evaluated a cohort of 449 patients with severe COVID-19; 22% of patients received heparin (mainly with low-molecular-weight heparin), and no differences were found in term of mortality according to anticoagulation therapy (30.3% vs 29.7%). Only patients with D-dimer levels six-fold higher than the upper limit of normal receiving heparin had lower mortality rate (32.8% vs 52.4%). Klok et al[15] found in critically ill ICU COVID-19 patients that chronic anticoagulation therapy at admission was associated with a lower risk of death.[13]

In a large series from United States (2,773 patients), among patients who required mechanical ventilation (n = 395), anticoagulation was associated with lower in-hospital mortality (29.1% vs 62.7%).[18]

These data are in line with the present study where anticoagulation is associated with better outcome among patients with severe forms of COVID-19 admitted with respiratory failure. These patients, especially those requiring invasive ventilation, may benefit most from anticoagulation. This high-risk population might benefit from full doses of anticoagulation in order to prevent thromboembolic complication that are associated with worse outcome. However, in the present study, only 30% of patients with respiratory failure received full doses of anticoagulation therapy. On the other side, in general population, full doses of anticoagulation before and during admission were associated with higher mortality, probably because of underlying severe comorbidities in such patients.

Several multicenter, randomized, controlled trials (NCT04372589, NCT04367831, NCT04345848, and NCT04366960) are currently evaluating the use of anticoagulation and will provide additional insights.