key: cord-0735067-k18iylu8
authors: Fahmy, Omar H.; Daas, Farah M.; Salunkhe, Vidyulata; Petrey, Jessica L.; Cosar, Ediz F.; Ramirez, Julio; Akca, Ozan
title: Is Microthrombosis the Main Pathology in Coronavirus Disease 2019 Severity?—A Systematic Review of the Postmortem Pathologic Findings
date: 2021-05-20
journal: Crit Care Explor
DOI: 10.1097/cce.0000000000000427
sha: 41e398ded5aad7452ea04f15212e84e039921c62
doc_id: 735067
cord_uid: k18iylu8

OBJECTIVES: This systematic review attempts to retrieve and report the findings of postmortem studies including the histopathologic data of deceased coronavirus disease 2019 patients and to review the manifestations of coronavirus disease 2019–associated thrombotic pathologies reported in the recent literature. DATA SOURCES: PubMed, Excerpta Medica Database, and Cochrane library between December 1, 2019, and August 26, 2020. STUDY SELECTION: Investigators screened 360 unique references, retrieved published autopsy series, and report on the postmortem histopathologic information on patients who had died of coronavirus disease 2019. DATA EXTRACTION: Investigators independently abstracted all available data including study design, participant demographics, key histopathologic findings, disease severity markers, duration of hospital stay, and cause of death. DATA SYNTHESIS: From the 65 eligible studies, 691 total completed autopsies were included in evidence synthesis. Histopathologic evaluation of the lungs revealed presence of diffuse alveolar damage in 323 of 443 patients and pulmonary microthrombi in 242 of 326 patients. Deep venous thrombosis and pulmonary embolism were found in 41% and ~15%, respectively, of the cadavers examined for thromboembolic events. d-dimer levels were generally higher in patients with severe clinical course of coronavirus disease 2019. Plasma levels of ferritin, lactate dehydrogenase, interleukin-6, and C-reactive protein were higher in nonsurvivors when compared with survivors. Overall, microthrombi and extensive angiogenesis of lung vasculature were the most common pathologic findings in the lungs and microthrombi in most of the assessed organ-tissue. CONCLUSIONS: Diffuse alveolar damage was the most predominant feature in the lungs of coronavirus disease 2019 patients who underwent postmortem assessment. Widespread pulmonary microthrombosis and extensive pulmonary angiogenesis, in addition to frequent pulmonary and extrapulmonary microthrombotic and thromboembolic findings in patients with coronavirus disease 2019, appear to be consistent with the disease-specific hypercoagulability. Further discovery efforts in assessing the link between coronavirus disease 2019, hypercoagulable state, and immunothrombosis are warranted. In the interim, increased attention to anticoagulant treatment approaches in coronavirus disease 2019 patients is needed.

the hospitalized patients, about 20% developed critical pneumonia similar to acute respiratory distress syndrome (ARDS) (2) . Severe lung disease manifestation of COVID-19-whether true pneumonia, ARDS, or a distinct pneumonitis-has been serving as the main cause of the disease-related morbidity and mortality (3, 4) . Although at the beginning of the pandemic, critically ill COVID-19 patients' mortality was as high as 70%, as in our city's example, it mostly averaged less than 40% (5) .

To expand the medical knowledge about COVID-19 pneumonia, autopsy results of deceased COVID-19 patients were deemed to be crucial and of great interest in exploring the details of the disease pathogenesis. Knowing the pathology behind the severe illness and its postmortem findings will help to understand the disease process better and will likely lead to efforts of therapeutic discovery.

Diffuse alveolar damage (DAD) and thrombotic disease processes appear to contribute to the mortality of severe COVID-19. In this systematic review, we aimed to report the postmortem findings of deceased COVID-19 patients. Specific emphasis was given to pulmonary microthrombosis and widespread thrombotic manifestations in hospitalized COVID-19 patients.

Although similar systematic reviews have been published regarding postmortem pathologic manifestations of COVID-19 (6) (7) (8) , in the present analysis, we aimed to include a larger number of studies with fewer restrictions by biopsy site or manifestation type for a more comprehensive and generalizable picture of the disease. Additionally, published postmortem reviews did not direct the focus to critical illness. Providing all available postmortem pathologic evidence in an abstracted form to the physicians managing these patients will likely have potential treatment implications.

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Between December 1, 2019, and August 26, 2020, literature searches were conducted in PubMed, Cochrane, and Excerpta Medica Database. The following strategy was used in PubMed and adapted as appropriate for the other databases: ("COVID-19"[All Fields] OR "COVID-2019"[All Fields] OR "severe acute respiratory syndrome coronavirus 2"[Supplementary Concept] OR "severe acute respiratory syndrome coronavirus 2"[All Fields] OR "2019-nCoV"[All Fields] OR "SARS-CoV-2"[All Fields] OR "2019nCoV"[All Fields] OR (("Wuhan"[All Fields] AND ("coronavirus"[MeSH Terms] OR "coronavirus"[All Fields])) AND (2019/12 [PDAT] OR 2020[PDAT]))) AND ("autopsy"[MeSH Terms] OR "autopsy"[All Fields] OR "autopsies"[All Fields] OR "postmortem"[All Fields] OR "postmortems"[All Fields] OR "post-mortem"[All Fields]). Results were filtered to English-language human studies published after December 2019. Content experts also screened reference lists of included trials and relevant narrative reviews. A total of 549 references were retrieved. After duplicates were extracted, 360 unique records remained for screening. To reduce the risk of bias, two researchers (O.H.F., F.M.D.) screened these remaining references according to the following inclusion criteria: 1) Studies presenting pathology, histology and/or laboratory findings. 2) Patients with positive reverse transcriptase-polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3) Articles written in English or with an available translation. Narrative reviews, editorials, and other publications without original data were excluded, although publications with incomplete data were included if additional data were provided by corresponding authors upon request. Studies were excluded from the data synthesis if SARS-CoV-2 was not confirmed in the deceased patients. Any screening conflicts were discussed with a third content expert reviewer available for resolution as needed. Of the 360 distinct references identified through database searching, 58 studies were eligible for inclusion. Seven additional studies were identified through hand search, for a total of 65 studies included in the evidence synthesis (Fig. 1) . These studies were appraised for bias, methodological quality, and significance of results but were not excluded based on their individual limitations. Data were extracted and summarized in 

The 65 included studies reported pathologic and histological findings of a combined total of 691 patients, of which 677 were deceased due to COVID-19. Three of these studies (Edler et al [37] , Lindner et al [62] , and Wichmann et al [19] ) reported data from the same cohort of patients, although any duplicate data were counted only once in our analysis. Additionally, Varga et al (15) , Magro et al (14) , and Sharma et al (56) presented the histological findings of biopsies obtained from 14 alive COVID-19 patients during their hospital stay, and we included these data as they provided valuable information about the involvement of the endothelium, kidneys, and other organs in patients with As represented in the published clinical reports, the majority of pathologic findings were seen in the lungs (n = 443). However, many other histopathologic findings were reported from other organ systems, including heart (n = 262), brain (n = 129), liver (n = 263), kidneys (n = 281), prostate, testes, vascular system, and cutaneous tissue. Details related to the major organ systems were summarized below as well as in tables and figures (Tables 2-4 

Out of 443 patients with postmortem lung tissue samples evaluated histologically, 86% showed features of DAD in exudative and proliferative phases, characterized by alveolar edema, hyaline membrane (HM) formation, as well as some other changes such as intraalveolar fibrin deposition, and proliferation of pneumocytes and fibroblasts. DAD is a known hallmark feature of ARDS.

Another frequently observed key finding was the presence of vascular pathology including fibrin thrombi inside the pulmonary vasculature. Pulmonary thrombi were found in 242 of 326 autopsies examined (~74%). The thrombi were more often seen in the small and midsized vessels of the lung, in areas where DAD existed (40) . (Table 3) . Although these numbers are prevalent enough to be reported in here, they are less prevalent than expected when compared with the clinical reports from patients recovering from COVID-19 (74) .

Microthrombi were seen in postmortem brain tissue samples of 4.7% of the patients. Encephalitis was reported only in one study (38) . Encephalitis and/or meningitis were reported in 5.4% of evaluated patients. Hemorrhagic lesions were seen in six of 129 examined brains. Ischemic lesions and infarcts were reported in 9.3% of patients.

Microthrombi were reported in the kidney tissue samples of 12.1% of the patients.

Postmortem examination of the liver revealed thrombosis and microthrombosis in 27.4% of evaluated cases.

Intravascular thrombi were reported in various organ systems. We presented these findings for each organ system under the respective section in Tables 2-4 and reported endothelial and thrombotic changes under the vascular system section separately in Supplemental  Table S5 (http://links.lww.com/CCX/A620). In addition to the microthrombi, 41% of 110 postmortem assessments reported deep vein thrombosis (DVT). Wichmann et al (19) reported bilateral leg involvement in all patients who developed DVT. In total, pulmonary embolism (PM) was reported in 39 of 257 deceased COVID-19 patients. Interestingly, prostatic vein plexus thrombosis was observed in 15 male patients (37) . Three patients demonstrated cutaneous coagulopathy (14) .

Similarly with SARS-CoV and other viruses from the same family, major pathologic respiratory system finding of this COVID-19 cohort of autopsies was epithelial changes. Mainly, DAD and HM formation, which generally corresponds to the clinical course of ARDS. PEs were reported in 15% of the patients, but a coexisting DVT was not necessarily found in patients who had documented PE (24, 75) . Another peculiar finding was the type or observed shape of pulmonary emboli, which conformed to the walls of pulmonary arteries. This finding led many to hypothesize that these pulmonary emboli are in fact pulmonary thrombi, which were formed in the lung vasculature (24, 46, 75) .

Possibly, the most interesting finding of this report is the abundance of microvascular damage, which was reported as microvascular thrombi. Interestingly, microthrombi was not only reported in the lungs, but it was also shown in the other organ systems including brain, kidneys, spleen, heart, and liver at significant prevalence. In addition to interesting predominance of microthrombi, multiple reports presented various levels of endothelial injury. Endothelial injury may suggest a triggering mechanism, which may possibly being initiated by hypercoagulable and hyperinflammatory pathways. Patterns of endothelial injury and microthrombi formation may happen simultaneously, or one may follow the other (8) . Immunothrombotic dysregulation appears to strongly contribute to the disease severity in COVID-19 (76) .

Intravascular microthrombosis is not specific to COVID-19; it is seen in ARDS due to various other causes, such as sepsis and trauma. However, the prevalence and extensiveness of microthrombi in patients with COVID-19-associated DAD is more prominent compared with other severe disease states (27) . Microthrombi in the lungs were observed in up to 42% of evaluated patients with nontraumatic ARDS of other causes, whereas our review detected pulmonary (micro) thrombosis in 74% of patients with COVID-19 (77) . To shed more light on the difference of SARS-CoV-2 from other respiratory viruses, Ackermann et al (27) examined the lungs of deceased patients with COVID-19 and compared them with the lungs of patients who died of H1N1-associated ARDS as well as to the uninfected lungs that were donated but not transplanted. First, the mean lung weight was found to be much higher in patients who died of influenza compared with those who died of SARS-CoV-2 infection, and this was explained by the extensive interstitial edema and severe 

Cardiac System-Heart

Potential Mechanistic Biomarkers CRP, mg/L IL-6, pg/mL d-dimer, ng/mL fibrin deposition in the influenza lungs. Intravascular thrombi were found in pulmonary arteries and alveolar capillaries in all of the patients in both the COVID-19 and H1N1 groups. However, the thrombi were nine times more widespread in the COVID-19 cohort, and the extent of angiogenesis was nearly three times higher in the COVID-19 lungs. Possibly, the profound immunothrombosis in the lungs of COVID-19 patients is the cause of ischemia and subsequent angiogenesis (78) . Newly formed blood vessels will further increase inflammation. Pulmonary microthrombosis can justify the near-normal compliance, high-elastance phenotype of COVID-19, but with ventilation perfusion mismatch, and severe hypoxemia (79). This number includes organs that were examined and did not show significant histopathologic findings; however; those were counted toward the total number of organs examined.

Critically ill patients with COVID-19 were found to have elevated circulating markers of endothelial dysfunction (80) . Furthermore, higher levels of endothelial biomarkers, including interleukin (IL)-6, tumor necrosis factor-alpha, inter-cellular adhesion molecule 1, and caspase-1, were present in the lungs of deceased patients with COVID-19 compared with H1N1 lungs (81) . There is a number of possible explanations for the causes of observed endothelial dysfunction in the patients with severe COVID-19. First, SARS-CoV-2 was found in endothelial cells in several autopsies, where it caused diffuse endothelial inflammation and endotheliitis (15, 48) . This endothelial disruption activates the proinflammatory and procoagulant pathways (82) . COVID-19-related endotheliitis may serve as a trigger for generalized microcirculatory dysfunction and related microthrombi. Predisposing factors to endothelial dysfunction such as male sex, smoking, hypertension, diabetes, obesity, and cardiovascular disease are also associated with severe COVID-19, and these factors may contribute to profound endotheliitis (15) .

Significant proinflammatory state exhibited in patients with severe COVID-19, and the considerable cytokine production are evidenced by elevated IL-6, C-reactive protein (CRP), and ferritin as demonstrated by multiple retrospective cohort studies (Supplemental Table S6 , http://links.lww.com/CCX/A621). Five studies categorized patients with COVID-19 as survivors and nonsurvivors and reported their laboratory values and anticoagulant administration during the hospitalization (83) (84) (85) (86) (87) . A summary of these data is available in Supplemental Table S6 (http://links.lww.com/CCX/ A621). The significant inflammatory state and cytokine production activate the endothelium. This activation turns on the coagulation cascade and results in hypercoagulable state. IL-6, CRP, and d-dimer levels were significantly higher in nonsurvivors compared with survivors. IL-6 was reported in two studies (83, 85) , and the range of median IL-6 was 11-152.4 pg/mL in nonsurvivors compared with 6.3-45.8 in survivors. CRP, which was reported in two studies (84, 85) , ranged from 130 to 174.4 in nonsurvivors, compared with a range of 40.9-93.9 mg/L in survivors. d-dimer levels were significantly higher in the nonsurvivor group of COVID-19 patients; ranging from 1.74 to 5.2 µg/mL compared with the survivors where laboratory values were ranging from 0.6 to 1.47 µg/mL (83) (84) (85) (86) (87) .

Another factor that causes endothelial disruption is hyperviscosity (88) . Fibrinogen, a glycoprotein complex and clotting factor (Factor I), is a major contributor of plasma viscosity (89) . An elevation in plasma fibrinogen levels leads to higher blood viscosity and subsequent increase in thrombotic risk. Elevated fibrinogen levels in patients with COVID-19 cause hyperviscosity, which plays a significant factor in the pathophysiology of COVID-19-induced coagulopathy. Bowles et al (90) reported positive lupus anticoagulant test in 31 of 34 patients with COVID-19 who had prolonged activated partial thromboplastin time (with a mean of 35.5 s). Lupus anticoagulant is known to be associated with high risk of thrombosis. That is one more element that might be contributing to the profound hypercoagulability associated with COVID-19 (90) .

These elements can also explain the growing recognition of the extrapulmonary microthrombi and thromboemboli. Microthrombi were observed occasionally in the vasculature of the kidneys and the liver. The exclusion of these organs from many autopsy reports, as well as minimally invasive (biopsylike) autopsies of these organs, renders the histological evidence insufficient. More extensive open autopsies will likely lead to a better understanding behind the reported elevated liver biomarkers (55, 91) , as well as acute kidney injury, hematuria, and proteinuria in COVID-19 patients (56) . Although possible credible explanations are available such as direct viral injury and the considerable elevated cytokine production, determining the exact pathway is critical.

Despite one study reporting five patients under the age of 50 presenting with strokes and later found to be SARS-CoV-2 positive (92), our review of brain autopsies revealed infrequent thrombotic complications in brain. However, when compared with influenza, stroke risk was 7.6 times higher (0.2% vs 1.6%) in COVID-19 (93) . COVID-19 was recently reported as an independent risk factor for stroke and increased mortality in hospitalized patients (94) . Interestingly, nonspecific neurologic symptoms such as dizziness, headache, and impaired consciousness are common (~36%) in COVID-19, and even more common (~46%) in severe cases (95) . Overall, the incidence of meningoencephalopathy was reportedly very low.

Cardiac dysfunction and arrhythmias have been reported in patients with unfavorable COVID-19 course (96) (97) (98) . SARS-CoV-2 was reported to be present in myocardial cells, with a significant viral load of more than 1,000 copies per microgram RNA in 41% of the evaluated www.ccejournal.org May 2021 • Volume 3 • Number 5 patients (62) . None of these heart tissue samples revealed the expected inflammatory response to the viral presence in the myocardial tissue nor were the clinical signs and symptoms of myocarditis observed. There is a paucity of histological evidence of myocarditis in the autopsies that we compiled in our review in spite of the fact that myocardial cells highly express angiotensin-converting enzyme 2 receptors (99). Very few recent work reported lymphocytic infiltrate in the heart (20, 35, 37, 46, 57, 100) . However, a cardiovascular magnetic resonance assessment of 100 patients who recovered from COVID-19-related ARDS showed that 78% of patients had ongoing cardiac involvement, and 60% of the patients had ongoing myocardial inflammation (74) . These findings may suggest that some of the postmortem cardiac assessments possibly missed discovering an existing focal myocarditis site. Of note, troponin was found to be elevated in many patients with COVID-19, and it was associated with a poorer prognosis (96) (97) (98) . In light of the insufficient histological findings to support myocarditis, the elevated troponin can also be explained by mechanisms other than inflammation and myocarditis. For example, right ventricular strain due to PM and/or thrombosis or cardiac vein thrombosis (20, 101) . Limitations of this report need to be addressed. First, although this systematic review includes data from previously published postmortem reports of COVID-19 deaths, the systematic review protocols may have been insufficient to capture autopsy data published in other study types. More importantly, knowing that globally COVID-19-related deaths passed the one million mark, our total number of 691 postmortem reports may not necessarily accurately represent the complete pathology of severe disease. Second, a postmortem examination may bias results toward an exaggerated pathology, which may not be seen in an average patient experiencing a less severe course of the same disease process. Third, autopsy reports may not always be specifically focused on the clinical cause of death or the presumed clinical mechanisms behind it. Histopathologic examination of alive patients with a less severe course of COVID-19, albeit challenging, might reveal more in depth data that can provide comprehensive and plausible pathophysiologic explanation of the course of COVID-19.

In this systematic review, we aimed to abstract all available postmortem data from 65 studies representing a total of 691 patients. Postmortem findings of COVID-19 patients summarize the final stages of disease in critically ill. Understanding the pathology behind these cases is crucial for critical care professionals. Multiple studies demonstrated evidence supporting the importance of anticoagulation and antiplatelet therapy (86, (102) (103) (104) . In a large trial, Paranjpe et al (103) studied mechanically ventilated COVID-19 and reported nearly double number of deaths in patients who did not receive therapeutic-dose of anticoagulation. In an observational study by Chow et al (102) , aspirin use-defined as receiving aspirin within the 7 days prior to hospitalization and/or the 24 hours following admission-was associated with a significant reduction in ICU admission and invasive mechanical ventilation needs. It is possible that antiplatelet agents may have beneficial effect, but this is neither tested under prospective controlled studies at this point nor any significant effect of such therapy was assessed in the setting where anticoagulation therapy was applied.

Therefore, highlighting the impact of thrombotic pathology is paramount in extrapolating the mechanism of disease and will likely lead to potential therapeutic approaches. We believe that reporting widespread occurrence of thrombotic complications will draw attention to the urgent need of performing randomized controlled trials addressing the benefits of administering various doses of anticoagulant and-possibly-antiplatelet therapies in critically ill COVID-19 patients.

In this systematic review of postmortem data, we are reporting an association between widespread thrombotic process and mortality. Although microvascular thrombi were abundant in the lung tissue, they were observed at significant percentages in most tissue and organs including liver, kidneys, brain, and heart.

Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): A review

COVID-19 Lombardy ICU Network: Risk factors associated with mortality among patients with COVID-19 in intensive care units in

Short-term outcomes of patients with COVID-19 undergoing invasive mechanical ventilation: A retrospective observational study from Wuhan

Characteristics and outcomes of adults hospitalized with SARS-CoV-2 community-acquired pneumonia in

More than pneumonia: Distinctive features of SARS-Cov-2 infection. From autopsy findings to clinical implications: A systematic review

Lung histopathology in coronavirus disease 2019 as compared with severe acute respiratory sydrome and H1N1 influenza: A systematic review

A systematic review of pathological findings in COVID-19: A pathophysiological timeline and possible mechanisms of disease progression

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies

Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Endothelial cell infection and endotheliitis in COVID-19

Postmortem lung findings in a patient with asthma and coronavirus disease 2019

Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction

COVID-19 autopsies

Autopsy findings and venous thromboembolism in patients with COVID-19: A prospective cohort study

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

Autopsy findings from the first known death from severe acute respiratory syndrome SARS-CoV-2 in Spain

Fatal pulmonary thromboembolism in SARS-CoV-2-infection

Fatal eosinophilic myocarditis in a healthy 17-Year-Old male with severe acute rspiratory syndrome coronavirus 2 (SARS-CoV-2c)

Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series

Clinicopathologic and immunohistochemical findings from autopsy of patient with COVID-19

Autopsy report with clinical pathological correlation

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

Postmortem examination of patients with COVID-19

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

Pulmonary and systemic involvement of COVID-19 assessed by ultrasound-guided minimally invasive autopsy

The first COVID-19 autopsy in Spain performed during the early stages of the pandemic

Neuropathology of COVID-19: A spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Inside the lungs of COVID-19 disease

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Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series from New Orleans

Pathological findings in the testes of COVID-19 patients: Clinical implications

Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in

Early evidence of pronounced brain involvement in fatal COVID-19 outcomes

Gross and histopathological pulmonary findings in a COVID-19 associated death during self-isolation

Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: A twocentre descriptive study

Neuropathological features of Covid-19

Diffuse alveolar damage (DAD) from coronavirus disease 2019 infection is morphologically indistinguishable from other causes of DAD

Pathological findings of postmortem biopsies from lung, heart, and liver of 7 deceased COVID-19 patients

In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19

Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients

Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series

SARS-CoV-2-related deaths in routine forensic autopsy practice: Histopathological patterns

The evolution of pulmonary pathology in fatal COVID-19 disease: An autopsy study with clinical correlation

COVID-19 autopsy in people who died in community settings: The first series

Histiocytic hyperplasia with hemophagocytosis and acute alveolar damage in COVID-19 infection

Confirmed invasive pulmonary aspergillosis and COVID-19: The value of postmortem findings to support antemortem management

Tissue-specific tolerance in fatal Covid-19

Late histopathologic characteristics of critically ill COVID-19 patients: Different phenotypes without evidence of invasive aspergillosis, a case series

Case 23-2020: A 76-Year-Old woman who died from Covid-19

Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations

Northwell Nephrology COVID-19 Research Consortium: COVID-19-associated kidney injury: A case series of kidney biopsy findings

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: A case series

Analysis of cardiopulmonary findings in COVID-19 fatalities: High incidence of pulmonary artery thrombi and acute suppurative bronchopneumonia

SARS-CoV-2 infection-associated hemophagocytic lymphohistiocytosis

Histopathologic and ultrastructural findings in postmortem kidney biopsy material in 12 patients with AKI and COVID-19

Cerebral microvascular injury in severe COVID-19

Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases

Fatal pulmonary fibrosis: A post-COVID-19 autopsy case

Postmortem kidney pathology findings in patients with COVID-19

Histopathological findings in the advanced natural evolution of the SARS-CoV-2 infection

Complete post-mortem data in a fatal case of COVID-19: Clinical, radiological and pathological correlations

Neuropathologic features of four autopsied COVID-19 patients

Preliminary post-mortem COVID-19 evidence of endothelial injury and factor VIII hyperexpression

Unspecific post-mortem findings despite multiorgan viral spread in COVID-19 patients

A Japanese case of COVID-19: An autopsy report

Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage

The spectrum of histopathologic findings in lungs of patients with fatal COVID-19 infection

Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19

Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19)

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Immunothrombotic dysregulation in COVID-19 pneumonia is associated with respiratory failure and coagulopathy

Pulmonary microthrombosis in severe adult respiratory distress syndrome

COVID-19: The vasculature unleashed

COVID-19 pneumonia: ARDS or not?

Circulating markers of angiogenesis and endotheliopathy in COVID-19

Endothelial dysfunction and thrombosis in patients with COVID-19

Endothelial dysfunction: A marker of atherosclerotic risk

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study

30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: A prospective cohort study

Risk factors for mortality in patients with COVID-19 in New York City

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

COVID-19-associated hyperviscosity: A link between inflammation and thrombophilia?

Role of plasma proteins in whole blood viscosity: A brief clinical review

Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19

Clinical features of COVID-19 related liver damage

Large-vessel stroke as a presenting feature of Covid-19 in the young

Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza

Cerebrovascular complications of COVID-19

Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China

COVID-19 and relative angiotensinconverting enzyme 2 deficiency: Role in disease severity and therapeutic response

Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection

Spectrum of cardiac manifestations in COVID-19: A Systematic Echocardiographic Study

Aspirin use is associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality in hospitalized patients with COVID-19

Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19

Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study

We very much appreciate the extreme hard work of all members of the Center of Excellence for Research in Infectious Diseases.The authors have disclosed that they do not have any potential conflicts of interest.