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      Autopsy Findings and Venous Thromboembolism in Patients With COVID-19 : A Prospective Cohort Study

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          Abstract

          Background:

          The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features.

          Objective:

          To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests.

          Design:

          Prospective cohort study.

          Setting:

          Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction–confirmed diagnosis of COVID-19.

          Patients:

          The first 12 consecutive COVID-19–positive deaths.

          Measurements:

          Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated.

          Results: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital ( n = 10) or outpatient sector ( n = 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS–CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart.

          Limitation:

          Limited sample size.

          Conclusion:

          The high incidence of thromboembolic events suggests an important role of COVID-19–induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19–related death, as well as possible therapeutic interventions to reduce it.

          Primary Funding Source:

          University Medical Center Hamburg-Eppendorf.

          Abstract

          Little is known of the pathologic changes that lead to death in patients with COVID-19. This study reports the autopsy findings of consecutive patients who died with a diagnosis of COVID-19.

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          Most cited references7

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          The stimulation of thrombosis by hypoxia

          Thrombus formation is increased under conditions of hypoxia in animal models of thrombosis and in human populations, but current therapies for thrombosis do not directly target hypoxia-responsive signaling pathways. The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs), whose target genes include several factors that regulate thrombus formation. In this article, we review the HIF-dependent and HIF-independent signaling pathways that regulate thrombus formation under hypoxic conditions. A better understanding of hypoxia-induced thrombus formation could lead to the development of novel prophylactic therapies for thrombosis.
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            Multiple roles of the coagulation protease cascade during virus infection.

            The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.
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              Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys.

              Organomegaly can be a sign of disease and pathologic abnormality, although standard tables defining organomegaly have yet to be established and universally accepted. This study was designed to address the issue and to determine a normal weight for the major organs in adult human males. A prospective study of healthy men aged 18 to 35 years who died of sudden, traumatic deaths was undertaken. Cases were excluded if there was a history of medical illness including illicit drug use, if prolonged medical treatment was performed, if there was a prolonged period between the time of injury and death, if body length and weight could not be accurately assessed, or if any illness or intoxication was identified after gross and microscopic analysis including evidence of systemic disease. Individual organs were excluded if there was significant injury to the organ, which could have affected the weight. A total of 232 cases met criteria for inclusion in the study during the approximately 6-year period of data collection from 2005 to 2011. The decedents had a mean age of 23.9 years and ranged in length from 146 to 193 cm, with a mean length of 173 cm. The weight ranged from 48.5 to 153 kg, with a mean weight of 76.4 kg. Most decedents (87%) died of either ballistic or blunt force (including craniocerebral) injuries. The mean weight of the brain was 1407 g (range, 1070-1767 g), that of the liver was 1561 g (range, 838-2584 g), that of the spleen was 139 g (range, 43-344 g), that of the right lung was 445 g (range, 185-967 g), that of the left lung was 395 g (range, 186-885 g), that of the right kidney was 129 g (range, 79-223 g), and that of the left kidney was 137 g (range, 74-235 g). Regression analysis was performed and showed that there were insufficient associations between organ weight and body length, body weight, and body mass index to allow for predictability. The authors, therefore, propose establishing a reference range for organ weights in men, much like those in use for other laboratory tests including hemoglobin, hematocrit, or glucose. The following reference ranges (95% inclusion) are proposed: brain, 1179-1621 g; liver, 968-1860 g; spleen, 28-226 g; right lung, 155-720 g; left lung, 112-675 g; right kidney, 81-160 g; and left kidney, 83-176 g.
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                Author and article information

                Journal
                Ann Intern Med
                Ann. Intern. Med
                aim
                Annals of Internal Medicine
                American College of Physicians
                0003-4819
                1539-3704
                6 May 2020
                6 May 2020
                : M20-2003
                Affiliations
                [1 ]University Medical Center Hamburg-Eppendorf, Hamburg, Germany (D.W., J.S., M.L., S.S., C.E., A.H., F.H., H.M., I.K., A.S.S., C.B., G.D., A.N., D.F., S.P., S.S., C.B., M.M.A., M.A., K.P., S.K.)
                [2 ]Asklepios Hospital Barmbek, Hamburg, Germany (H.B., A.S.)
                [3 ]Bethesda Hospital Bergedorf, Hamburg, Germany (H.B.)
                [4 ]Agaplesion Diakonie Hospital, Hamburg, Germany (A.D.)
                [5 ]Amalie Sieveking Hospital, Hamburg, Germany (H.P.)
                [6 ]Asklepios Hospital Saint Georg, Hamburg, Germany (S.S.)
                Article
                aim-olf-M202003
                10.7326/M20-2003
                7240772
                32374815
                a625f85e-dfc9-4ad8-b79d-116139c397e6
                Copyright @ 2020

                This article is made available via the PMC Open Access Subset for unrestricted re-use for research, analyses, and text and data mining through PubMed Central. Acknowledgement of the original source shall include a notice similar to the following: "© 2020 American College of Physicians. Some rights reserved. This work permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited." These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

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