key: cord-0971946-9e5mzsh2 authors: Sofia, Rosaria; Carbone, Mattias; Landoni, Giovanni; Zangrillo, Alberto; Dagna, Lorenzo title: Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19 date: 2022-04-13 journal: Eur J Intern Med DOI: 10.1016/j.ejim.2022.04.009 sha: 85cac3a58c33ebc8ff9fd9f6752773e37ebecfd9 doc_id: 971946 cord_uid: 9e5mzsh2 nan SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; MicroCLOTS: microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome; ARDS: acute respiratory distress syndrome; MOF: multiple organ failure; PVTs: pulmonary venous thromboses; RCT: randomized clinical trials; TMA: thrombotic microangiopathy; IL-6: interleukin-6 inhibitor. 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 1 . 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 2-4 . Moreover, several autopsy studies reported microvascular thromboses in lungs and most organs of deceased patients 5,6 . SARS-CoV-2 infection is thought to be responsible for a specific mechanism of thromboinflammation, called the "immunothrombosis model" 7 . 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 . The pro-thrombotic state is a condition that may precede morbidity and mortality. According to Ciceri et al. 9 , 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 and, in certain circumstances, also to a disseminated intravascular coagulation-like state. Among COVID-19 patients with normal angiographic studies, thromboinflammatory markers (D-dimer, Creactive protein, ferritin, and interleukin 6) are often elevated [11] [12] [13] suggesting the presence of microvascular damage. Nailfold videocapillaroscopy performed on COVID-19 patients showed microvascular abnormalities, resembling acute and post-acute microvascular damage 14 . 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 . Several international guidelines recommend heparin-based anticoagulation therapy in all COVID-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 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 . 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 . 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, 8 . Tocilizumab, an interleukin-6 inhibitor (IL-6), may reduce endothelial inflammation, microvascular thrombosis, and mortality 33, 34, 35 . Anakinra, an antagonist of interleukin 1 receptor, may dampen systemic inflammation, and reduce mortality 36 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 . 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, 39 . 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. The authors report no conflicts of interest. 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. 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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.