The use of full anticoagulation should be considered in patients with COVID-19 who are not in the intensive care unit (ICU) but are at high risk for progression of thrombosis and at low risk for bleeding. In contrast, patients with COVID-19 in the ICU should be routinely treated with prophylactic anticoagulants if not otherwise indicated. Results of a recent review on this subject have been published in the European Journal of Internal Medicine.1

The most severe clinical presentation of COVID-19 is acute respiratory distress syndrome (ARDS). Moreover, the presence of an underlying hypercoagulable state that is associated with venous thromboembolic events has been reported in approximately 30% of patients with COVID-19 worldwide.

The SARS-CoV-2 infection is likely responsible for a specific mechanism of thrombo-inflammation that has been termed the “immunothrombosis model.”2 In this scenario, the viral-mediated direct cellular damage and the immune response precipitate the release of proinflammatory cytokines. These cytokines are ultimately responsible for the establishment of an immune-mediated hypercoagulable state.3

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This atypical ARDS working hypothesis has been named “microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS).”4 This syndrome is likely caused by alveolar endothelial damage, which is followed by progressive endothelial pulmonary involvement. Next, the inflammation and thrombotic milieu affect the microcirculation of other organs, which eventually leads to multiple organ failure,as well as to a disseminated intravascular coagulation-like state in some instances.

Heparin-based anticoagulation therapy has been recommended by a number of international guidelines for all patients hospitalized with COVID-19. The recommendation is based on the results of large observational studies that support the efficacy of anticoagulation therapy. Randomized clinical trials that compare the use of heparin vs placebo, however, are lacking.

The beneficial effects of heparin include its antithrombotic, anti-inflammatory, and probable antiviral effects. Further, unlike the other oral anticoagulants, heparin has fewer pharmacologic interactions with experimental agents used to treat patients with COVID-19. In spite of these recommendations, however, the appropriate dosage of anticoagulant therapy (ie, prophylactic vs full dose), as well as the exact time to initiate anticoagulants, remains largely uncertain.

If all prior theories on the subject are considered, the hypercoagulable state associated with COVID-19 may be managed first by inhibition of the pro-inflammatory state, followed by the establishment of anticoagulation at the appropriate dosage, based on the disease course, in order to avoid the development or worsening of any thrombotic complications.

The investigators concluded that additional randomized clinical trials in homogeneous patient populations are warranted, in order to confirm these observational results and to inform guidelines. Anti-inflammatory agents have been shown to play a pivotal role in the management of MicroCLOTS.


1. Sofia R, Carbone M, Landoni G, Zangrillo A, Dagna L. Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19.
Eur J Intern Med. 2022;100:21-24. doi:10.1016/j.ejim.2022.04.009

2. Abou-Ismail MY, Diamond A, Kapoor S, Arafah Y, Nayak L. The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management. Thromb Res. 2020;194:101-115. doi:10.1016/j.thromres.2020.06.029 

3. Bonaventura A, Vecchié A, Dagna L, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol. 2021;21(5):319-329. doi:10.1038/s41577-021-00536-9

4. Ciceri F, Beretta L, Scandroglio AM, et al. Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis. Crit Care Resusc. 2020;22(2):95-97.

5. Renzi S, Landoni G, Zangrillo A, Ciceri F. MicroCLOTS pathophysiology in COVID 19.Korean J Intern Med. Published online September 9, 2020. doi:10.3904/kjim.2020.336

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