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Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, ItalyUnit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, ItalyUnit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, ItalyFaculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy
Since February 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been responsible for one of the major pandemic we have experienced in the last 100 years [
]. The most severe clinical presentation of COVID-19 is through acute respiratory distress syndrome (ARDS) classifying it as a respiratory illness. The presence of an underlying hypercoagulable state, associated to venous thrombotic events with a prevalence of 30%, was extensively reported worldwide in COVID-19 patients [
]. The viral-mediated direct cellular damage and the immune response result in the release of proinflammatory cytokines. Cytokines determine the subsequent activation and dysfunction of the endothelium, which contributes to the establishment of an immuno-mediated hypercoagulable state [
], this atypical ARDS working hypothesis was named microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS). This syndrome is thought to be caused by alveolar endothelial damage, followed by progressive endothelial pulmonary involvement. Subsequently, the inflammation and the thrombotic milieu also affect the microcirculation of other organs, eventually leading to multiple organ failure (MOF) [
] and, in certain circumstances, also to a disseminated intravascular coagulation-like state. Among COVID-19 patients with normal angiographic studies, thromboinflammatory markers (D-dimer, C-reactive protein, ferritin, and interleukin 6) are often elevated [
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3.
] suggesting the presence of microvascular damage. Nailfold videocapillaroscopy performed on COVID-19 patients showed microvascular abnormalities, resembling acute and post-acute microvascular damage [
]. Furthermore, the COVID-19 radiological pattern is characterized by a unique distribution of pulmonary venous thromboses (PVTs) which overlaps with lung inflamed areas, confirming that in situ thromboses are not embolisms [
American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate intensity anticoagulation in critically ill patients.
Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19.
Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.
] which support the efficacy of anticoagulation therapy, while randomized clinical trials (RCTs) comparing the use of heparin versus placebo are lacking. Advantages of heparin include its antithrombotic, anti-inflammatory, and likely antiviral effects [
]. Moreover, heparin has fewer pharmacologic interactions with experimental drugs used in COVID-19 patients, alike the other oral anticoagulants. Despite all of these recommendations, the proper dosage of anticoagulant therapy (prophylactic vs full dose) and the exact time to start anticoagulants remain uncertain [
Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.
Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.
Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.
Morici N, Podda G, Birocchi S, et al. Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: The X-COVID-19 Randomized Trial. Eur J Clin Invest. n/a(n/a):e13735. doi:10.1111/eci.13735.
Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.
] COVID-19 patients. According to these results, full dose anticoagulation (therapeutic dose) among non-critically ill patients may increase the probability of survival free of organ support, [
Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.
Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.
Morici N, Podda G, Birocchi S, et al. Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: The X-COVID-19 Randomized Trial. Eur J Clin Invest. n/a(n/a):e13735. doi:10.1111/eci.13735.
Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.
]. Although these RCTs did not include homogeneous populations and the mortality reduction was not confirmed in all studies, it is possible to hypothesize that the efficacy of the anticoagulation strategy may depend on the initiation time of the therapy with respect to the disease course.
If COVID-19 MicroCLOTS are similar to the immunothrombosis model, they are probably resistant to classical anticoagulants drugs. In this case, heparin may stop the progression of the coagulation cascade avoiding the increase in thrombi size, but is not able to dissolve clots. As a consequence, it may be reasonable to suggest that the rationale for the use of heparin would not be primary prevention, but secondary prevention and avoidance of thrombi progression and development of multisystemic thrombotic complications.
Within the context of mild-to-moderate respiratory illness, hospitalized SARS-CoV-2 infected patients may benefit from full-dose anticoagulation as secondary prevention. On the other hand, critically ill COVID-19 patients have probably already developed extensive lung thrombi. In this case, full-dose anticoagulation may not be able to reverse the established disease process. For these reasons, routine full-dose anticoagulation among ICU critically ill patients while not avoiding thrombotic complications can increase bleeding risk. Thus, anticoagulation therapy for critically ill COVID-19 patients should probably follow the same recommendation that are in place for critically ill non-COVID-19 patients.
Even if it reasonable to think that COVID-19 outpatients can benefit from (low dose) anticoagulants, a recent RCT showed no difference in clinical outcomes in patients treated with aspirin, apixaban, or placebo [
Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.
]. This might be attributed to the relatively low sample size of the study and/or to the use of drugs different from heparin. An observational large study also suggested that patients on chronic anticoagulants do not have reduced mortality if they develop COVID-19 [
Montorfano M, Leoni O, Andreassi A, et al. Chronic anticoagulant treatment and risk of mortality in SARS-Cov2 patients: a large population-based study. Minerva Med. Published online February 2022. doi:10.23736/S0026-4806.22.07797-7.
As previously highlighted, Sars-CoV-2 exhibits a bidirectional crosstalk between inflammation and thrombosis, or immunothrombosis, and this unique mechanism of inducing coagulopathy paves the way to therapies including antithrombin supplementation, recombinant thrombomodulin, and multiple anti-inflammatory agents. Therefore, monoclonal antibodies targeting pro-inflammatory mediators have been proposed for the treatment of COVID-19 induced microvasculature injury and endothelial damage leading to thrombotic microangiopathy (TMA) [
Belletti A, Campochiaro C, Marmiere M, et al. Efficacy and safety of IL-6 inhibitors in patients with COVID-19 pneumonia: a systematic review and meta-analysis of multicentre, randomized trials. Ann Intensive Care. 2021;11(1):152. doi:10.1186/s13613-021-00941-2.
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
] in COVID-19 patients, especially when administered early after hospitalization in moderate-to-severe patients outside the ICU. Future studies should investigate the concomitant use of therapeutic dose anticoagulation with anti-inflammatory drugs to prevent the development of critical illness and immunothrombosis.
Neutrophils extracellular traps (NETs) play a direct role in the immune-thrombotic process in COVID-19. Some experimental drugs, targeting NET formation, may limit endothelial damage and improve the prognosis [
]. Complement activation, secondary to endothelial injury, suggests the rational use of monoclonal antibodies against C5 and C3, such as Eculizumab and Ravulizumab (ClinicalTrials.gov Identifier: NCT04570397, NCT04288713, NCT04390464), for the treatment of COVID-19 associated thrombotic microangiopathy [
Summarizing all previous considerations, the hypercoagulable state associated with COVID-19 may be managed firstly by inhibiting the pro-inflammatory state and secondly by establishing anticoagulation at proper dosage, according to the disease course, to avoid the development or worsening of thrombotic complications.
In conclusion, our reasoning, which is supported by initial evidence, suggests that full anticoagulation maybe considered in non-ICU patients with COVID-19 at high risk of thrombosis progression and at low risk of bleeding. Other patients (eg ICU patients) might be routinely treated with prophylactic anticoagulants if not otherwise indicated. Further RCTs in homogeneous populations are needed to confirm these observations and to inform guidelines .
Fig. 1Anticoagulation therapy in COVID-19 according to the disease severity.
RS: study conception and design, data interpretation, manuscript drafting. MC: data interpretation, manuscript drafting. GL: study conception and design, critical review of the manuscript. LD: study conception and design, manuscript drafting. AZ: study conception and design, critical review of the manuscript. All Authors read and approved the final version of the manuscript.
Declaration of Competing Interest
The authors report no conflicts of interest.
Acknowledgement
Thanks to all the peer reviewers and editors for their opinions and suggestions.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3.
American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate intensity anticoagulation in critically ill patients.
Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19.
Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.
Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial.
Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial.
Morici N, Podda G, Birocchi S, et al. Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: The X-COVID-19 Randomized Trial. Eur J Clin Invest. n/a(n/a):e13735. doi:10.1111/eci.13735.
Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.
Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.
Montorfano M, Leoni O, Andreassi A, et al. Chronic anticoagulant treatment and risk of mortality in SARS-Cov2 patients: a large population-based study. Minerva Med. Published online February 2022. doi:10.23736/S0026-4806.22.07797-7.
Belletti A, Campochiaro C, Marmiere M, et al. Efficacy and safety of IL-6 inhibitors in patients with COVID-19 pneumonia: a systematic review and meta-analysis of multicentre, randomized trials. Ann Intensive Care. 2021;11(1):152. doi:10.1186/s13613-021-00941-2.
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
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