Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease with thrombotic microangiopathy and aberrant immune response. The Mount Sinai COVID-19 autopsy experience
Authors: Bryce Clare , Grimes Zachary , Pujadas Elisabet , Ahuja Sadhna , Beasley Mary Beth , Albrecht Randy , Hernandez Tahyna , Stock Aryeh , Zhao Zhen , Al Rasheed Mohamed , Chen Joyce , Li Li , Wang Diane , Corben Adriana , Haines Kenneth , Westra William , Umphlett Melissa , Gordon Ronald E , Reidy Jason , Petersen Bruce , Salem Fadi , Fiel MariaIsabel , El Jamal Siraj M , Tsankova Nadejda M , Houldsworth Jane , Mussa Zarmeen , Liu Wen-Chun , Veremis Brandon , Sordillo Emilia , Gitman Melissa , Nowak Michael , Brody Rachel , Harpaz Noam , Merad Miriam , Gnjatic Sacha , Donnelly Ryan , Seigler Patricia , Keys Calvin , Cameron Jennifer , Moultrie Isaiah , Washington Kae-Lynn , Treatman Jacquelyn , Sebra Robert , Jhang Jeffrey , Firpo Adolfo , Lednicky John , Paniz-Mondolfi Alberto , Cordon-Cardo Carlos , Fowkes Mary 
Published: May 2020

BACKGROUND
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease process is still lacking.
METHODS
Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays.
RESULTS
Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNFα. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis and a secondary hemophagocytic lymphohistiocytosis-like syndrome in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples.
CONCLUSIONS
We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome, with hemophagocytosis and a hemophagocytic lymphohistiocytosis-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.