Steven J. Mentzer1, Maximilian Ackermann2 and Danny Jonigk3 1Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA 2Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten-Herdecke, 42283 Wuppertal, Germany; Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany 3Institute of Pathology, Hannover Medical School, 30625 Hanover, Germany; Member of the German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease Hannover, 30625 Hanover, Germany Correspondence: smentzerbwh.harvard.edu

COVID-19 has been associated with a range of illness severity—from minimal symptoms to life-threatening multisystem organ failure. The severe forms of COVID-19 appear to be associated with an angiocentric or vascular phase of the disease. In studying autopsy patients succumbing to COVID-19, we found alveolar capillary microthrombi were 9 times more common in COVID-19 than in comparable patients with influenza. Corrosion casting of the COVID-19 microcirculation has revealed microvascular distortion, enhanced bronchial circulation, and striking increases in intussusceptive angiogenesis. In patients with severe COVID-19, endothelial cells commonly demonstrate significant ultrastructural injury. High-resolution imaging suggests that microcirculation perturbations are linked to ischemic changes in microanatomic compartments of the lung (secondary lobules). NanoString profiling of these regions has confirmed a transcriptional signature compatible with microischemia. We conclude that irreversible tissue ischemia provides an explanation for the cystic and fibrotic changes associated with long-haul COVID-19 symptoms.