key: cord-0910265-7ykgsqwd authors: Dolhnikoff, Marisa; Duarte‐Neto, Amaro Nunes; de Almeida Monteiro, Renata Aparecida; Ferraz da Silva, Luiz Fernando; Pierre de Oliveira, Ellen; Nascimento Saldiva, Paulo Hilário; Mauad, Thais; Marcia Negri, Elnara title: Pathological evidence of pulmonary thrombotic phenomena in severe COVID‐19 date: 2020-04-15 journal: J Thromb Haemost DOI: 10.1111/jth.14844 sha: 38d7556a06315925f472b3ae73d04a9154d9518e doc_id: 910265 cord_uid: 7ykgsqwd Between February and March 2020, the Journal of Thrombosis and Hemosthasis has published four papers addressing the intricate, complex and still little understood relation between COVID‐19 and thrombogenesis (1‐4). ARS‐Cov‐2 induces in severe cases a cytokine storm that ultimately leads to the activation of the coagulation cascade, causing thrombotic phenomena (5). There is a further strong link between abnormal coagulation parameters (D‐dimer and fibrin degradation products) and mortality. Tang et al. described that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of disseminated intravascular coagulation (DIC), suggesting that DIC is a frequent occurrence in severe COVID‐19 (4). The frequency of DIC in these patients is much higher than that reported for severe SARS (6). SARS-Cov-2 induces in severe cases a cytokine storm that ultimately leads to the activation of the coagulation cascade, causing thrombotic phenomena (5) . There is a further strong link between abnormal coagulation parameters (D-dimer and fibrin degradation products) and mortality. Tang et al. described that 71.4% of nonsurvivors and 0.6% of survivors showed evidence of disseminated intravascular coagulation (DIC), suggesting that DIC is a frequent occurrence in severe COVID-19 (4). The frequency of DIC in these patients is much higher than that reported for severe SARS (6) . This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/JTH.14844 This article is protected by copyright. All rights reserved or more resulted in decreased mortality in severe cases, especially the ones with SIC score > 4 or D-dimer > 6 fold of upper normal limit (2) . A pathological substrate confirming the presence and frequency of pulmonary thrombi in severe COVID-19, to provide more rationale to therapeutic management, is missing. Although the number of fatalities is in the range of tens of thousands worldwide, the autopsy studies are scarce and limited to few organs (7, 8) . It is comprehensible that few autopsies descriptions have been cases, we analyze histological samples from lungs, kidneys, heart, liver, spleen, brain, skin and skeletal muscle. The procedure was approved by the institution's ethics board and was performed after informed consent from the next-of-kin. Here, we present some preliminary autopsy results that may provide new insights into the relation between COVID-19 and DIC. This article is protected by copyright. All rights reserved To date, we have studied 10 fatal cases, 5 men and 5 women, with a mean age of 67.8 years (33 to 83 years). Eight patients were over 60 years old and seven of them had comorbidities, including arterial hypertension, diabetes mellitus, ischemic heart disease and COPD. The average hospital stay was 5.4 days (0 to 15 days). The general pulmonary histological picture in fatal cases of COVID-19 is exsudative/proliferative diffuse alveolar damage, with intense epithelial viral cytopathic effects involving alveolar and small airway epithelium, and little lymphocytic infiltration ( Figure 1A ). We observed a variable number of small fibrinous thrombi in small pulmonary arterioles in areas of both damaged and more preserved lung parenchyma in 8 out of 10 cases ( Figure 1B to 1D) . Endothelial tumefaction and a large number of pulmonary megakaryocytes in the pulmonary capillaries are other indicators of activation of the coagulation cascade. In addition, small fibrinous thrombi were rarely found in the glomeruli and superficial dermal vessels. There were few and small foci of alveolar hemorrhage, and pulmonary infarctions were not observed. Signs of secondary bacterial pneumonia were observed in 6 cases. As these are post-mortem transthoracic biopsies, we do not have access to large vessels and, therefore, we cannot exclude or confirm pulmonary embolisms. In summary, our pathological observations support the current concept of hypercoagulative status in these critically ill patients, showing that the frequency of pulmonary microthrombosis is high. Hopefully, these findings may shed light on the complex therapeutic decisions on this subject. Legend for figure: This article is protected by copyright. All rights reserved Accepted Article The versatile heparin in COVID-19 Apr 2 epublished Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia COVID-19: consider cytokine storm syndromes and immunosuppression Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis Pathological findings of COVID-19 associated with acute respiratory distress syndrome A pathological report of three COVID-19 cases by minimally invasive autopsies Fluctuations in the rate of autopsy in China Ultrasound-guided minimally invasive autopsy as a tool for rapid post-mortem diagnosis in the 2018 Sao Paulo yellow fever epidemic: Correlation with conventional autopsy This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Accepted Article