Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Abstract

•COVID-19 related thrombosis are immune-mediated and detectable as lung MicroCLOTS.•COVID-19 radiological pattern confirms that in situ thrombosis are not embolisms.•Full anticoagulation may prevent MicroCLOTS in non-ICU COVID-19 patients.•Routine full anticoagulation might increase bleeding risk in advanced stages.•Anti-inflammatory drugs play a pivotal role in the management of MicroCLOTS. TextSince 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 [[1]World Health Organization Coronavirus Disease 2019 (COVID-19). https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?sfvrsn=1ba62e57_10.Google Scholar]. 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 [2De Cobelli F Palumbo D Ciceri F et al.Pulmonary Vascular Thrombosis in COVID-19 Pneumonia.J Cardiothorac Vasc Anesth. January 1, 2021; (Published online)https://doi.org/10.1053/j.jvca.2021.01.011Abstract Full Text Full Text PDF Scopus (23) Google Scholar, 3Roncon L Zuin M Barco S et al.Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis.Eur J Intern Med. 2020; 82: 29-37https://doi.org/10.1016/j.ejim.2020.09.006Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 4Reichert G Bunel V Dreyfuss D Saker L Khalil A Mal H. Prevalence of proximal deep vein thrombosis in hospitalized COVID-19 patients.Eur J Intern Med. 2021; 89: 118-120https://doi.org/10.1016/j.ejim.2021.03.034Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Moreover, several autopsy studies reported microvascular thromboses in lungs and most organs of deceased patients [[5]Carsana L Sonzogni A Nasr A et al.Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.Lancet Infect Dis. 2020; 20: 1135-1140https://doi.org/10.1016/S1473-3099(20)30434-5Abstract Full Text Full Text PDF PubMed Scopus (673) Google Scholar,[6]Wichmann D Sperhake JP Lütgehetmann M et al.Autopsy Findings and Venous Thromboembolism in Patients With COVID-19.Ann Intern Med. 2020; 173: 268-277https://doi.org/10.7326/M20-2003Crossref PubMed Scopus (1375) Google Scholar].SARS-CoV-2 infection is thought to be responsible for a specific mechanism of thrombo-inflammation, called the “immunothrombosis model” [[7]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: 101-115https://doi.org/10.1016/j.thromres.2020.06.029Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]. 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 [[8]Bonaventura A Vecchié A Dagna L et al.Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.Nat Rev Immunol. 2021; 21: 319-329https://doi.org/10.1038/s41577-021-00536-9Crossref PubMed Scopus (259) Google Scholar]. The pro-thrombotic state is a condition that may precede morbidity and mortality.According to Ciceri et al. [[9]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 J Australas Acad Crit Care Med. 2020; 22: 95-97Google Scholar], 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) [[10]Renzi S Landoni G Zangrillo A Ciceri F. MicroCLOTS pathophysiology in COVID 19.Korean J Intern Med. September 9, 2020; (Published onlineAccessed September 22, 2021)https://www.kjim.org/journal/view.php?doi=10.3904/kjim.2020.336Crossref PubMed Google Scholar] 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 [11Mahat RK Panda S Rathore V Swain S Yadav L Sah SP. The dynamics of inflammatory markers in coronavirus disease-2019 (COVID-19) patients: A systematic review and meta-analysis.Clin Epidemiol Glob Health. 2021; 11100727https://doi.org/10.1016/j.cegh.2021.100727Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 12Zhou 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.Google Scholar, 13Tang N Li D Wang X Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost JTH. 2020; 18: 844-847https://doi.org/10.1111/jth.14768Crossref PubMed Scopus (3254) Google Scholar] suggesting the presence of microvascular damage. Nailfold videocapillaroscopy performed on COVID-19 patients showed microvascular abnormalities, resembling acute and post-acute microvascular damage [[14]Natalello G De Luca G Gigante L et al.Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement.Microvasc Res. 2021; 133104071https://doi.org/10.1016/j.mvr.2020.104071Crossref PubMed Scopus (22) Google Scholar]. 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 [[2]De Cobelli F Palumbo D Ciceri F et al.Pulmonary Vascular Thrombosis in COVID-19 Pneumonia.J Cardiothorac Vasc Anesth. January 1, 2021; (Published online)https://doi.org/10.1053/j.jvca.2021.01.011Abstract Full Text Full Text PDF Scopus (23) Google Scholar].Several international guidelines recommend heparin-based anticoagulation therapy in all COVID-19 hospitalized patients [15Cuker A Tseng EK Nieuwlaat R et al.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.Blood Adv. 2021; (bloodadvances.2021005493)https://doi.org/10.1182/bloodadvances.2021005493Crossref Scopus (21) Google Scholar, 16Spyropoulos AC Levy JH Ageno W et al.Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19.J Thromb Haemost. 2020; 18: 1859-1865https://doi.org/10.1111/jth.14929Crossref PubMed Scopus (418) Google Scholar, 17Barnes GD Burnett A Allen A et al.Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum.J Thromb Thrombolysis. 2020; 50: 72-81https://doi.org/10.1007/s11239-020-02138-zCrossref PubMed Scopus (280) Google Scholar, 18Moores LK Tritschler T Brosnahan S et al.Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease 2019.Chest. 2020; 158: 1143-1163https://doi.org/10.1016/j.chest.2020.05.559Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 19Bikdeli B Madhavan MV Jimenez D et al.COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up.J Am Coll Cardiol. 2020; 75: 2950-2973https://doi.org/10.1016/j.jacc.2020.04.031Crossref PubMed Scopus (1745) Google Scholar, 20Information on COVID-19 Treatment, Prevention and Research.COVID-19 Treatment Guidelines. October 5, 2021; (Accessed)https://www.covid19treatmentguidelines.nih.gov/Google Scholar]. This recommendation is based on large observational studies [[21]Paranjpe I Fuster V Lala A et al.Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19.J Am Coll Cardiol. 2020; 76: 122-124https://doi.org/10.1016/j.jacc.2020.05.001Crossref PubMed Scopus (601) Google Scholar,[22]Rentsch CT Beckman JA Tomlinson L et al.Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study.BMJ. 2021; 372: n311https://doi.org/10.1136/bmj.n311Crossref PubMed Scopus (101) Google Scholar] 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 [[23]Buijsers B Yanginlar C Maciej-Hulme ML de Mast Q der Vlag J van Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients.EBioMedicine. 2020; : 59https://doi.org/10.1016/j.ebiom.2020.102969Abstract Full Text Full Text PDF Scopus (79) Google Scholar]. 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 [[24]Giannis D Douketis JD Spyropoulos AC. Anticoagulant therapy for COVID-19: What we have learned and what are the unanswered questions?.Eur J Intern Med. 2022; 96: 13-16https://doi.org/10.1016/j.ejim.2021.11.003Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar].Large RCTs evaluated different anticoagulation strategies in critically ill (ATTAC-ACTIV-4a-REMAP-CAP, HEP-COVID) [[25]REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC InvestigatorsTherapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.N Engl J Med. 2021; 385: 777-789https://doi.org/10.1056/NEJMoa2103417Crossref PubMed Scopus (328) Google Scholar,[26]Spyropoulos AC Goldin M Giannis D et al.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.JAMA Intern Med. 2021; 181: 1612-1620https://doi.org/10.1001/jamainternmed.2021.6203Crossref PubMed Scopus (130) Google Scholar] and noncritically ill (ATTAC-ACTIV-4a-REMAP-CAP, RAPID, X-COVID, BEMICOP, HEP-COVID) [26Spyropoulos AC Goldin M Giannis D et al.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.JAMA Intern Med. 2021; 181: 1612-1620https://doi.org/10.1001/jamainternmed.2021.6203Crossref PubMed Scopus (130) Google Scholar, 27ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP InvestigatorsTherapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.N Engl J Med. 2021; 385: 790-802https://doi.org/10.1056/NEJMoa2105911Crossref PubMed Scopus (315) Google Scholar, 28Sholzberg M Tang GH Rahhal H et al.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.BMJ. 2021; 375: n2400https://doi.org/10.1136/bmj.n2400Crossref PubMed Scopus (91) Google Scholar, 29Morici 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.Google Scholar, 30Marcos-Jubilar M Carmona-Torre F Vidal R et al.Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.Thromb Haemost. 2021; 12 (Published online October)https://doi.org/10.1055/a-1667-7534Crossref Scopus (20) Google Scholar] 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, [[27]ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP InvestigatorsTherapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.N Engl J Med. 2021; 385: 790-802https://doi.org/10.1056/NEJMoa2105911Crossref PubMed Scopus (315) Google Scholar] the probability of 28-day survival, [[28]Sholzberg M Tang GH Rahhal H et al.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.BMJ. 2021; 375: n2400https://doi.org/10.1136/bmj.n2400Crossref PubMed Scopus (91) Google Scholar,[30]Marcos-Jubilar M Carmona-Torre F Vidal R et al.Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.Thromb Haemost. 2021; 12 (Published online October)https://doi.org/10.1055/a-1667-7534Crossref Scopus (20) Google Scholar] and it may reduce the probability to developed venous thromboembolism (VTE) [[29]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.Google Scholar] with respect to prophylactic dose anticoagulation. However, these findings were not confirmed in patients treated in intensive care units (ICU) [[25]REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC InvestigatorsTherapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.N Engl J Med. 2021; 385: 777-789https://doi.org/10.1056/NEJMoa2103417Crossref PubMed Scopus (328) Google Scholar,[26]Spyropoulos AC Goldin M Giannis D et al.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.JAMA Intern Med. 2021; 181: 1612-1620https://doi.org/10.1001/jamainternmed.2021.6203Crossref PubMed Scopus (130) Google Scholar]. 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 [[31]Connors JM Brooks MM Sciurba FC et al.Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.JAMA. 2021; 326: 1703-1712https://doi.org/10.1001/jama.2021.17272Crossref PubMed Scopus (72) Google Scholar]. 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 [[32]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.Google Scholar].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) [[7]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: 101-115https://doi.org/10.1016/j.thromres.2020.06.029Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar,[8]Bonaventura A Vecchié A Dagna L et al.Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.Nat Rev Immunol. 2021; 21: 319-329https://doi.org/10.1038/s41577-021-00536-9Crossref PubMed Scopus (259) Google Scholar]. Tocilizumab, an interleukin-6 inhibitor (IL-6), may reduce endothelial inflammation, microvascular thrombosis, and mortality [33Levi M. Tocilizumab in severe COVID-19: A promise fulfilled.Eur J Intern Med. 2022; 95: 38-39https://doi.org/10.1016/j.ejim.2021.11.015Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 34Campochiaro C Tomelleri A Matucci-Cerinic M Dagna L. One year later: The case of tocilizumab in COVID-19.Eur J Intern Med. 2022; 95: 5-6https://doi.org/10.1016/j.ejim.2021.10.024Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 35Belletti 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.Google Scholar].Anakinra, an antagonist of interleukin 1 receptor, may dampen systemic inflammation, and reduce mortality [[36]Cavalli G De Luca G Campochiaro C et al.Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.Lancet Rheumatol. 2020; 2: e325-e331https://doi.org/10.1016/S2665-9913(20)30127-2Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar] 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 [[37]Barnes BJ Adrover JM Baxter-Stoltzfus A et al.Targeting potential drivers of COVID-19: Neutrophil extracellular trapsNeutrophil extracellular traps in COVID-19.J Exp Med. 2020; 217e20200652https://doi.org/10.1084/jem.20200652Crossref PubMed Scopus (808) Google Scholar]. 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 [[38]Annane D Heming N Grimaldi-Bensouda L et al.Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.eClinicalMedicine. 2020; 28https://doi.org/10.1016/j.eclinm.2020.100590Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,[39]Mastellos DC Pires da Silva BGP Fonseca BAL et al.Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy.Clin Immunol Orlando Fla. 2020; 220108598https://doi.org/10.1016/j.clim.2020.108598Crossref Scopus (135) Google Scholar].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 .CRediT authorship contribution statementRS: 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. TextSince 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 [[1]World Health Organization Coronavirus Disease 2019 (COVID-19). https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?sfvrsn=1ba62e57_10.Google Scholar]. 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 [2De Cobelli F Palumbo D Ciceri F et al.Pulmonary Vascular Thrombosis in COVID-19 Pneumonia.J Cardiothorac Vasc Anesth. January 1, 2021; (Published online)https://doi.org/10.1053/j.jvca.2021.01.011Abstract Full Text Full Text PDF Scopus (23) Google Scholar, 3Roncon L Zuin M Barco S et al.Incidence of acute pulmonary embolism in COVID-19 patients: Systematic review and meta-analysis.Eur J Intern Med. 2020; 82: 29-37https://doi.org/10.1016/j.ejim.2020.09.006Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 4Reichert G Bunel V Dreyfuss D Saker L Khalil A Mal H. Prevalence of proximal deep vein thrombosis in hospitalized COVID-19 patients.Eur J Intern Med. 2021; 89: 118-120https://doi.org/10.1016/j.ejim.2021.03.034Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Moreover, several autopsy studies reported microvascular thromboses in lungs and most organs of deceased patients [[5]Carsana L Sonzogni A Nasr A et al.Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study.Lancet Infect Dis. 2020; 20: 1135-1140https://doi.org/10.1016/S1473-3099(20)30434-5Abstract Full Text Full Text PDF PubMed Scopus (673) Google Scholar,[6]Wichmann D Sperhake JP Lütgehetmann M et al.Autopsy Findings and Venous Thromboembolism in Patients With COVID-19.Ann Intern Med. 2020; 173: 268-277https://doi.org/10.7326/M20-2003Crossref PubMed Scopus (1375) Google Scholar].SARS-CoV-2 infection is thought to be responsible for a specific mechanism of thrombo-inflammation, called the “immunothrombosis model” [[7]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: 101-115https://doi.org/10.1016/j.thromres.2020.06.029Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]. 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 [[8]Bonaventura A Vecchié A Dagna L et al.Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.Nat Rev Immunol. 2021; 21: 319-329https://doi.org/10.1038/s41577-021-00536-9Crossref PubMed Scopus (259) Google Scholar]. The pro-thrombotic state is a condition that may precede morbidity and mortality.According to Ciceri et al. [[9]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 J Australas Acad Crit Care Med. 2020; 22: 95-97Google Scholar], 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) [[10]Renzi S Landoni G Zangrillo A Ciceri F. MicroCLOTS pathophysiology in COVID 19.Korean J Intern Med. September 9, 2020; (Published onlineAccessed September 22, 2021)https://www.kjim.org/journal/view.php?doi=10.3904/kjim.2020.336Crossref PubMed Google Scholar] 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 [11Mahat RK Panda S Rathore V Swain S Yadav L Sah SP. The dynamics of inflammatory markers in coronavirus disease-2019 (COVID-19) patients: A systematic review and meta-analysis.Clin Epidemiol Glob Health. 2021; 11100727https://doi.org/10.1016/j.cegh.2021.100727Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 12Zhou 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.Google Scholar, 13Tang N Li D Wang X Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost JTH. 2020; 18: 844-847https://doi.org/10.1111/jth.14768Crossref PubMed Scopus (3254) Google Scholar] suggesting the presence of microvascular damage. Nailfold videocapillaroscopy performed on COVID-19 patients showed microvascular abnormalities, resembling acute and post-acute microvascular damage [[14]Natalello G De Luca G Gigante L et al.Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement.Microvasc Res. 2021; 133104071https://doi.org/10.1016/j.mvr.2020.104071Crossref PubMed Scopus (22) Google Scholar]. 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 [[2]De Cobelli F Palumbo D Ciceri F et al.Pulmonary Vascular Thrombosis in COVID-19 Pneumonia.J Cardiothorac Vasc Anesth. January 1, 2021; (Published online)https://doi.org/10.1053/j.jvca.2021.01.011Abstract Full Text Full Text PDF Scopus (23) Google Scholar].Several international guidelines recommend heparin-based anticoagulation therapy in all COVID-19 hospitalized patients [15Cuker A Tseng EK Nieuwlaat R et al.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.Blood Adv. 2021; (bloodadvances.2021005493)https://doi.org/10.1182/bloodadvances.2021005493Crossref Scopus (21) Google Scholar, 16Spyropoulos AC Levy JH Ageno W et al.Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19.J Thromb Haemost. 2020; 18: 1859-1865https://doi.org/10.1111/jth.14929Crossref PubMed Scopus (418) Google