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      Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19

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      1 , , 2 , 3 , 4 , 1 , 1 , 1 , 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 3 , 4 , 5 , 6 , 7 , 9 , 36 , 37 , 2 , 36 , 37 , 38 , 35
      Blood Cancer Journal
      Nature Publishing Group UK
      Risk factors, Myeloproliferative disease, Infectious diseases

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          Abstract

          In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count ( p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (−23.3%, p < 0.0001) than in PV (−16.4%, p = 0.1730) and was associated with higher mortality rate ( p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.

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          Endothelial cell infection and endotheliitis in COVID-19

          Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1, 2 SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells. 3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro. 4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient's condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8. Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B ). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested. Figure Pathology of endothelial cell dysfunction in COVID-19 (A, B) Electron microscopy of kidney tissue shows viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops. Aggregates of viral particles (arrow) appear with dense circular surface and lucid centre. The asterisk in panel B marks peritubular space consistent with capillary containing viral particles. The inset in panel B shows the glomerular basement membrane with endothelial cell and a viral particle (arrow; about 150 nm in diameter). (C) Small bowel resection specimen of patient 3, stained with haematoxylin and eosin. Arrows point to dominant mononuclear cell infiltrates within the intima along the lumen of many vessels. The inset of panel C shows an immunohistochemical staining of caspase 3 in small bowel specimens from serial section of tissue described in panel D. Staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections, indicating that apoptosis is induced in a substantial proportion of these cells. (D) Post-mortem lung specimen stained with haematoxylin and eosin showed thickened lung septa, including a large arterial vessel with mononuclear and neutrophilic infiltration (arrow in upper inset). The lower inset shows an immunohistochemical staining of caspase 3 on the same lung specimen; these staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections. COVID-19=coronavirus disease 2019. Patient 2 was a woman, aged 58 years, with diabetes, arterial hypertension, and obesity. She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. On day 16, mesenteric ischaemia prompted removal of necrotic small intestine. Circulatory failure occurred in the setting of right heart failure consequent to an ST-segment elevation myocardial infarction, and cardiac arrest resulted in death. Post-mortem histology revealed lymphocytic endotheliitis in lung, heart, kidney, and liver as well as liver cell necrosis. We found histological evidence of myocardial infarction but no sign of lymphocytic myocarditis. Histology of the small intestine showed endotheliitis (endothelialitis) of the submucosal vessels. Patient 3 was a man, aged 69 years, with hypertension who developed respiratory failure as a result of COVID-19 and required mechanical ventilation. Echocardiography showed reduced left ventricular ejection fraction. Circulatory collapse ensued with mesenteric ischaemia, and small intestine resection was performed, but the patient survived. Histology of the small intestine resection revealed prominent endotheliitis of the submucosal vessels and apoptotic bodies (figure C). We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs. 3 Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D). The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. 5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state. 6 Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.
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            Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy

            Background Few data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19. Methods We studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020–10.04.2020). The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI). Secondary outcome was overt disseminated intravascular coagulation (DIC). Results We included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]). Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward. Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%–11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward). Half of the thromboembolic events were diagnosed within 24 h of hospital admission. Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%). Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA). The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively. Overt DIC was present in 8 (2.2%) patients. Conclusions The high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.
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              COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection

              Publisher's Note: There is a Blood Commentary on this article in this issue.
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                Author and article information

                Contributors
                tbarbui@fondazionefrom.it
                Journal
                Blood Cancer J
                Blood Cancer J
                Blood Cancer Journal
                Nature Publishing Group UK (London )
                2044-5385
                4 February 2021
                4 February 2021
                February 2021
                : 11
                : 2
                : 21
                Affiliations
                [1 ]GRID grid.460094.f, ISNI 0000 0004 1757 8431, FROM Research Foundation, , Papa Giovanni XXIII Hospital, ; Bergamo, Italy
                [2 ]GRID grid.414603.4, Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, , Fondazione Policlinico “A. Gemelli” IRCCS, ; Rome, Italy
                [3 ]GRID grid.410458.c, ISNI 0000 0000 9635 9413, Hospital Clinic de Barcelona, ; Barcelona, Spain
                [4 ]GRID grid.414818.0, ISNI 0000 0004 1757 8749, Hematology Division, , Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, ; Milan, Italy
                [5 ]GRID grid.412725.7, Spedali Civili, ; Brescia, Italy
                [6 ]GRID grid.415025.7, ISNI 0000 0004 1756 8604, Hematology Division and Bone Marrow Transplant, San Gerardo Hospital, , ASST Monza, ; Monza, Italy
                [7 ]GRID grid.411142.3, ISNI 0000 0004 1767 8811, Hospital del Mar – IMIM, ; Barcelona, Spain
                [8 ]GRID grid.81821.32, ISNI 0000 0000 8970 9163, Hospital Universitario la Paz, ; Madrid, Spain
                [9 ]GRID grid.413328.f, ISNI 0000 0001 2300 6614, Hospital Saint-Louis, ; Paris, France
                [10 ]GRID grid.412311.4, Azienda Ospedaliero-Universitaria di Bologna, ; Via Albertoni 15, Bologna, Italia
                [11 ]GRID grid.432329.d, ISNI 0000 0004 1789 4477, AOU Città della Salute e della Scienza di Torino, ; Torino, Italy
                [12 ]GRID grid.420232.5, ISNI 0000 0004 7643 3507, Hospital Ramon y Cajal, , IRYCIS, ; Madrid, Spain
                [13 ]GRID grid.411083.f, ISNI 0000 0001 0675 8654, Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), , Vall d’Hebron Hospital Universitari, ; Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035 Barcelona, Spain
                [14 ]GRID grid.414761.1, Hospital Universitario Infanta Leonor, ; Madrid, Spain
                [15 ]GRID grid.411094.9, ISNI 0000 0004 0506 8127, Hospital General Universitario de Albacete, ; Albacete, Spain
                [16 ]GRID grid.8982.b, ISNI 0000 0004 1762 5736, Department of molecular medicine, , University of Pavia, ; Pavia, Italy
                [17 ]GRID grid.410526.4, ISNI 0000 0001 0277 7938, Hospital Gregorio Maranon, ; Madrid, Spain
                [18 ]GRID grid.411068.a, ISNI 0000 0001 0671 5785, Hospital Clinico San Carlos, ; Madrid, Spain
                [19 ]GRID grid.411475.2, ISNI 0000 0004 1756 948X, Ospedale Policlinico “G.B. Rossi”, Borgo Roma, ; Verona, Italy
                [20 ]GRID grid.440814.d, ISNI 0000 0004 1771 3242, Hospital Universitario de Mostoles, ; Madrid, Spain
                [21 ]GRID grid.418701.b, ISNI 0000 0001 2097 8389, ICO L’Hospitalet-Hospital Moises Broggi, Sant Joan Despì, ; Barcelona, Spain
                [22 ]GRID grid.144756.5, ISNI 0000 0001 1945 5329, Hospital Universitario 12 de Octubre, ; Madrid, Spain
                [23 ]GRID grid.4495.c, ISNI 0000 0001 1090 049X, Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, , Wroclaw Medical University, ; Wrocław, Poland
                [24 ]GRID grid.18887.3e, ISNI 0000000417581884, IRCCS Ospedale San Raffaele, ; Milano, Italy
                [25 ]AOU Maggiore della Carità, Novara, Italy
                [26 ]Hospital Moncloa, Madrid, Spain
                [27 ]GRID grid.411295.a, ISNI 0000 0001 1837 4818, ICO Girona Hospital Josep Trueta, ; Girona, Spain
                [28 ]GRID grid.411336.2, ISNI 0000 0004 1765 5855, Hospital Universitario Principe de Asturias, ; Alcalà de Henares, Madrid, Spain
                [29 ]GRID grid.1957.a, ISNI 0000 0001 0728 696X, Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, , RWTH Aachen University, ; Aachen, Germany
                [30 ]GRID grid.416303.3, ISNI 0000 0004 1758 2035, Ospedale San Bortolo, ; Vicenza, Italy
                [31 ]GRID grid.459669.1, Hospital Universitario de Burgos, ; Burgos, Spain
                [32 ]GRID grid.429003.c, Hospital Clinico Universitario, , INCLIVA, ; Valencia, Spain
                [33 ]GRID grid.411093.e, ISNI 0000 0004 0399 7977, Hospital General de Elche, Elche, ; Alicante, Spain
                [34 ]GRID grid.7080.f, Institut Català d’Oncologia-Hospital Germans Trias i Pujol, Joseo Carreras Leukemia Research Institute, Badalona (Barcelona) Spain, , Universitat Autònoma de Barcelona, ; Barcelona, Spain
                [35 ]GRID grid.8404.8, ISNI 0000 0004 1757 2304, Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Department of Experimental and Clinical Medicine, Azienda Ospedaliera Universitaria Careggi, , University of Florence, ; Florence, Italy
                [36 ]GRID grid.420545.2, Guy’s and St. Thomas’ NHS Foundation Trust, ; London, UK
                [37 ]ASST Papa Giovanni XXIII, Bergamo, Italy
                [38 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Università degli Studi di Milano, ; Milano, Italy
                Author information
                http://orcid.org/0000-0003-2747-6327
                http://orcid.org/0000-0002-5178-5827
                http://orcid.org/0000-0002-4401-0812
                http://orcid.org/0000-0001-9664-7084
                http://orcid.org/0000-0001-8367-5668
                http://orcid.org/0000-0003-4752-0815
                http://orcid.org/0000-0002-3511-0504
                http://orcid.org/0000-0002-7572-9504
                http://orcid.org/0000-0003-0716-1686
                http://orcid.org/0000-0001-8553-3524
                http://orcid.org/0000-0002-9570-5542
                http://orcid.org/0000-0002-1011-8171
                http://orcid.org/0000-0001-7555-3361
                http://orcid.org/0000-0002-4289-3113
                http://orcid.org/0000-0003-1809-284X
                http://orcid.org/0000-0002-3739-7502
                Article
                417
                10.1038/s41408-021-00417-3
                7871138
                33563901
                726a65ba-c0fa-4b9c-8b64-deba6b0b3517
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 23 November 2020
                : 15 December 2020
                : 19 January 2021
                Funding
                Funded by: Funder: Brembo SpA, grant: Brembo "3x1 project"
                Funded by: Funder: AIRC, Grant: MYNERVA project, #21267
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                Oncology & Radiotherapy
                risk factors,myeloproliferative disease,infectious diseases
                Oncology & Radiotherapy
                risk factors, myeloproliferative disease, infectious diseases

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