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    Cerebral Microvascular Injury in Severe COVID-19

    Authors: John Conklin; Matthew P. Frosch; Shibani Mukerji; Otto Rapalino; Mary Maher; Pamela W. Schaefer; Michael H. Lev; Ramon G. Gonzalez; Sudeshna Das; Samantha N. Champion; Colin Magdamo; Pritha Sen; George Kyle Harrold; Haitham Alabsi; Erica Normandin; Bennett Shaw; Jacob Lemieux; Pardis Sabeti; John A. Branda; Emery N. Brown; M. Brandon Westover; Susie Y. Huang; Brian L Edlow

    doi:10.1101/2020.07.21.20159376 Date: 2020-07-24 Source: medRxiv

    IMPORTANCE: Microvascular lesions are common in patients with severe COVID-19. Radiologic-pathologic correlation in one case suggests a combination of microvascular hemorrhagic and ischemic lesions that may reflect an underlying hypoxic mechanism of injury, which requires validation in larger studies. OBJECTIVE: To determine the incidence, distribution, and clinical and histopathologic correlates of microvascular lesions in patients with severe COVID-19. DESIGN: Observational, retrospective cohort study: March to May 2020. SETTING: Single academic medical center. PARTICIPANTS: Consecutive patients (16) admitted to the intensive care unit with severe COVID-19, undergoing brain MRI for evaluation of coma MESHD coma HP or focal neurologic deficits. EXPOSURES: Not applicable. MAIN OUTCOME AND MEASURES: Hypointense microvascular lesions identified by a prototype ultrafast high-resolution susceptibility-weighted imaging (SWI) MRI sequence, counted by two neuroradiologists and categorized by neuroanatomic location. Clinical and laboratory data (most recent measurements before brain MRI). Brain autopsy and cerebrospinal fluid PCR for SARS-CoV 2 in one patient who died from severe COVID-19. RESULTS: Eleven of 16 patients (69%) had punctate and linear SWI lesions in the subcortical and deep white matter, and eight patients (50%) had >10 SWI lesions. In 4/16 patients (25%), lesions involved the corpus callosum. Brain autopsy in one patient revealed that SWI lesions corresponded to widespread microvascular injury, characterized by perivascular and parenchymal petechial hemorrhages MESHD and microscopic ischemic lesions. CONCLUSIONS AND RELEVANCE: SWI lesions are common in patients with neurological manifestations of severe COVID-19 ( coma MESHD coma HP and focal neurologic deficits). The distribution of lesions is similar to that seen in patients with hypoxic respiratory failure HP, sepsis MESHD sepsis HP, and disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP. Collectively, these radiologic and histopathologic findings suggest that patients with severe COVID-19 are at risk for multifocal microvascular hemorrhagic and ischemic lesions in the subcortical and deep white matter.

    Clinical characteristics and risk factors for mortality in patients with coronavirus disease MESHD 2019 in intensive care unit: a single-center, retrospective, observational study in China

    Authors: Fangfang Sai; Xiaolei Liu; Lanyu Li; Yan Ye; Changqing Zhu; Ying Hang; Conghua Huang; Lei Tian; Xinhui Xu; Huan Huang

    doi:10.21203/rs.3.rs-46078/v1 Date: 2020-07-20 Source: ResearchSquare

    Background: Coronavirus disease MESHD 2019 (COVID-19) is a potentially life-threatening contagious disease MESHD disease which has spread TRANS which has spread all over the world. Risk factors for the clinical outcomes of COVID-19 pneumonia MESHD pneumonia HP in intensive care unit (ICU) have not yet been well determined. Methods: In this retrospective, single-centered, observational study, we consecutively included 47 patients with confirmed COVID-19 who were admitted to the ICU of Leishenshan Hospital in Wuhan, China, from February 24 to April 5, 2020. Clinical characteristics and outcomes were collected and compared between survivors and non-survivors. Multivariable logistic regression was used to explore the risk factors associated with death MESHD in patients of COVID-19.Results: The study cohort included 47 adult TRANS patients with a median age TRANS of 70.55±12.52 years, and 30 (63.8%) patients were men. Totally 15 (31.9%) patients died. Compared with survivors, non-survivors were more likely to develop septic shock MESHD shock HP (6 [40%] patients vs 3 [9.4%] patients ), disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP (3 [21.4%] vs 0), and had higher score of APACHE II (25.07±8.03 vs 15.56±5.95), CURB-65 (3[2-4] vs 2[1-3]), Sequential Organ Failure Assessment (SOFA) (7[5-9] vs 3[1-6]), higher level of D-dimer (5.74 [2.32-18] vs 2.05 [1.09-4.00] ) and neutrophil count (9.4[7.68-14.54] vs 5.32[3.85-9.34] ). SOFA score (OR 1.47, 1.01–2.13; p=0.0042) and lymphocyte count (OR 0.02, 0.00–0.86; p=0.042) on admission were independently risk factors for mortality. Patients with higher lymphocyte count (>0.63×109/L) and lower SOFA score ≤4 on admission had a significantly well prognosis than those with lower lymphocyte count (≤0.63×109/L) and higher SOFA score >4 in overall survival.Conclusions: Higher SOFA score and lower lymphocyte count on admission were associated with poor prognosis of patients with COVID-19 in ICU. Lymphocyte count may serve as a promising prognostic biomarker.

    Clot Waveform of APTT Has Abnormal Patterns in Subjects with COVID-19

    Authors: Takuya Shimura; Makoto Kurano; Yoshiaki Kanno; Mahoko Ikeda; Koh Okamoto; Daisuke Jubishi; Sohei Harada; Shu Okugawa; Kyoji Moriya; Yutaka Yatomi

    doi:10.21203/rs.3.rs-43405/v1 Date: 2020-07-15 Source: ResearchSquare

    In Coronavirus disease MESHD 2019 (COVID-19) subjects, recent evidence suggests the presence of unique coagulation abnormalities HP. In this study, we performed clot waveform analyses to investigate whether specific modulations are observed in COVID-19 subjects. We analyzed the second derivative of the absorbance in routine APTT tests performed using an ACL-TOP system. We observed high frequencies of abnormal patterns in APTT second-derivative curves that could be classified into an early shoulder type, a late shoulder type, or a biphasic type, high maximum first-derivative and second-derivative peak levels, and a low minimum second-derivative peak level in COVID-19 subjects. These modulations were not observed in subjects with disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP. These abnormal patterns are also observed in patients with lupus anticoagulant HP, hemophilia MESHD, or factor IX deficiency. The plasma SERO fibrinogen levels might also be involved in the abnormal APTT waveforms, especially the high maximum first-derivative and second-derivative peak levels. The abnormal patterns in the APTT second-derivative curves appear with highest frequency at around 2 weeks after the onset of COVID-19 and were not associated with the severity of COVID-19. These results suggest the possible presence of a specific abnormal coagulopathy in COVID-19.

    In vivo demonstration of microvascular thrombosis MESHD in severe Covid-19

    Authors: Douglas Alexandre Espirito Santo; Anna Cristina Bertoldi Lemos; Carlos Henrique Miranda

    doi:10.1101/2020.07.09.20149971 Date: 2020-07-11 Source: medRxiv

    Several autopsies studies showed the presence of microthrombi in the pulmonary circulation of the severe COVID-19. The major limitation of these investigations is that the autopsy provided static information. Some of these alterations could be secondary to the disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP (DIC) observed as the final common pathway of the multisystem organ failure exhibited in the critical patient. We report the preliminary results of an in vivo evaluation of the sublingual microcirculation in thirteen patients with severe COVID-19 requiring mechanical ventilation at the beginning of the hospitalization. They did not have any laboratorial DIC evidence. We observed multiple filling defects moving within the sublingual microvessels indicative of microthrombi in 11 (85%) patients. This is the first imaging documentation of microvascular thrombosis MESHD in living patients with severe COVID-19. The clinical relevance of microvascular thrombosis MESHD in this disease MESHD requires further research.

    COVID-19-related coagulopathy, is transferrin a missing link?

    Authors: Katie-May McLaughlin; Marco Bechtel; Denisa Bojkova; Sandra Ciesek; Mark N Wass; Martin Michaelis; Jindrich N Cinatl Jr.

    doi:10.1101/2020.06.11.147025 Date: 2020-06-16 Source: bioRxiv

    SARS-CoV-2 is the causative agent of COVID-19. Severe COVID-19 disease MESHD has been associated with disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP and thrombosis MESHD, but the mechanisms underlying COVID-19-related coagulopathy remain unknown. Since the risk of severe COVID-19 disease MESHD is higher in males TRANS than in females TRANS and increases with age TRANS, we combined proteomics data from SARS-CoV-2-infected cells with human gene expression data from the Genotype-Tissue Expression (GTEx) database to identify gene products involved in coagulation that change with age TRANS, differ in their levels between females TRANS and males TRANS, and are regulated in response to SARS-CoV-2 infection MESHD. This resulted in the identification of transferrin as a candidate coagulation promoter, whose levels increases with age TRANS and are higher in males TRANS than in females TRANS and that is increased upon SARS-CoV-2 infection MESHD. A systematic investigation of gene products associated with the GO term " blood SERO coagulation" did not reveal further high confidence candidates, which are likely to contribute to COVID-19-related coagulopathy. In conclusion, the role of transferrin should be considered in the course of COVID-19 disease MESHD and further examined in ongoing clinic-pathological investigations.

    Severe colon ischemia MESHD in patients with severe COVID-2019 infection MESHD: a report of three cases

    Authors: Ana Almeida; Víctor Valentí Azcárate; Carlos Sánchez Justicia; Fernando Martínez Regueira; Pablo Martí-Cruchaga; Javier A. Cienfuegos; Fernando Rotellar

    doi:10.21203/rs.3.rs-31237/v1 Date: 2020-05-25 Source: ResearchSquare

    Severe disease MESHD caused by the SARS-CoV coronavirus is characterized by patients presenting with respiratory distress HP associated with a systemic inflammatory response syndrome MESHD (cytokine storm). Sixteen to thirty percent of COVID-19 patients also have gastrointestinal symptoms. Here we present three cases of COVID-19 who developed colonic ischemia MESHD. Three males TRANS aged TRANS 76, 68 and 56 with respiratory distress HP and receiving mechanical ventilation presented episodes of rectal bleeding, abdominal distension and signs of peritoneal irritation. Endoscopy (case 1) and computed tomography angiography revealed colonic ischemia MESHD and pneumoperitoneum MESHD.One patient (case 2) underwent surgery in which perforation of the gangrenous cecum and colonic ischemia MESHD was confirmed.In all three patients D-dimer levels were markedly increased (2170, 2100 and 7360 ng/mL). All three patients died shortly after diagnosis.In severe COVID-19 disease MESHD, the pathogenic cause has increasingly become attributed to the development of disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP secondary to the systemic inflammatory response.


    Authors: Giulia Previtali; Michela Seghezzi; Valentina Moioli; Aurelio Sonzogni; Roberto Marozzi; Lorenzo Cerutti; Rudi Ravasio; Andrea Gianatti; Giovanni Guerra; Maria Grazia Alessio

    doi:10.1101/2020.04.30.20086397 Date: 2020-05-06 Source: medRxiv

    Background The most severely COVID-19 patients need intensive care and show increased risk of thromboembolic events. Although some patients meet the diagnostic criteria for the Disseminated Intravascular Coagulation MESHD Disseminated Intravascular Coagulation HP, the pathogenesis of the diffuse thrombotic status remains unclear. The aim of the present study is to evaluate the presence of antiphospholipid antibodies SERO (aPL) in sera of deceased patients with autoptic proven thrombotic microangiopathy MESHD to evaluate if some patients may have developed Catastrophic Antiphospholipid Syndrome MESHD (CAPS). Methods Thirty-five patients were enrolled. The available medical history, comorbidities, therapies, laboratory and autopsy findings were collected post-mortem from clinical records. IgA, IgG and IgM anti cardiolipin (ACA) and anti {beta}2 glycoprotein 1 ({beta}2GP1) antibodies, IgG and IgM SERO anti phosphatidylserine/prothrombin (PS/PT) antibodies were tested SERO for all the patients. Results 3/35 (8.6%) patients were slightly positive for aPL: one for ACA IgG and two for ACA IgM but values were low (< 3X the cut off). No patients tested positive for ACA IgA neither for {beta}2GP1 isotypes. 3/35 (8.6%) patients were positive for PS/PT, one for IgG and two for IgM, but values were less than 2X the cut off. No patients showed simultaneous positivity for ACA and PS/ PT. Conclusions It is difficult to categorize the vascular events into a conventional disease MESHD: we did not find significant association with anti-phospholipid antibodies SERO. It is most likely that several factors contribute to trigger the hypercoagulability HP status and the thromboembolism MESHD thromboembolism HP but, on the basis our results, CAPS is probably not involved into the pathogenesis of these phenomena.

    TEG Max Clot Strength is Consistently Elevated and May Be Predictive of COVID-19 Status at the Time of ICU Admission

    Authors: Shaun D Lawicki; Katherine V Wang; Bing Han; Gordon L Love

    doi:10.1101/2020.04.30.20076703 Date: 2020-05-05 Source: medRxiv

    Background: Hypercoagulability HP is becoming widely recognized as a major complication of COVID-19 infection MESHD as evidenced by high levels of fibrinogen degradation products and microthrombi identified within the lungs and kidneys of autopsy specimens from these patients. We report thromboelastography (TEG) testing on a cohort of patients with suspected COVID-19 infection MESHD at the time of admission to the intensive care unit. Methods: TEG testing was performed using the TEG 6s analyzer near or at the time of ICU admission. We also report the results of other coagulation or inflammatory related indices such as platelet count, prothrombin time, fibrinogen, D-dimer, C-reactive protein, ferritin, and procalcitonin. All laboratory testing was performed at the discretion of the attending physician in the course of normal patient care and retrospectively reviewed. Results: We found that maximum clot strength was consistently elevated in COVID-19 patients while normal in all patients found to be negative. We did not encounter significant prolongations of coagulation assays outside of those expectedly prolonged by heparin therapy nor was meeting the criteria for disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP encountered. Conclusions: We postulate that elevated maximum clot strength by TEG testing is predictive of COVID-19 status as within our cohort this perfectly predicted patients COVID-19 status despite a high level of suspicion in negative patients with normal TEG results. While these results require a larger cohort for confirmation, we feel that TEG testing could improve confidence in negative COVID-19 testing results in suspected patients possibly allowing for earlier de-escalation of infectious precautions and personal protective equipment utilization.

    The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection MESHD in vitro: an existing drug with multiple possible therapeutic effects

    Authors: Mizuki Yamamoto; Maki Kiso; Yuko Sakai-Tagawa; Kiyoko Iwatsuki-Horimoto; Masaki Imai; Makoto Takeda; Noriko Kinoshita; Norio Ohmagari; Jin Gohda; Kentaro Semba; Zene Matsuda; Yasushi Kawaguchi; Yoshihiro Kawaoka; Jun-ichiro Inoue

    doi:10.1101/2020.04.22.054981 Date: 2020-04-23 Source: bioRxiv

    Although infection MESHD by SARS-CoV-2, the causative agent of COVID-19, is spreading rapidly worldwide, no drug has been shown to be sufficiently effective for treating COVID-19. We previously found that nafamostat mesylate, an existing drug used for disseminated intravascular coagulation MESHD disseminated intravascular coagulation HP (DIC), effectively blocked MERS-CoV S protein-initiated cell fusion by targeting TMPRSS2, and inhibited MERS-CoV infection MESHD of human lung epithelium-derived Calu-3 cells. Here we established a quantitative fusion assay dependent on SARS-CoV-2 S protein, ACE2 and TMPRSS2, and found that nafamostat mesylate potently inhibited the fusion while camostat mesylate was about 10-fold less active. Furthermore, nafamostat mesylate blocked SARS-CoV-2 infection MESHD of Calu-3 cells with an EC50 around 10 nM, which is below its average blood SERO concentration after intravenous administration through continuous infusion. These findings, together with accumulated clinical data regarding its safety, make nafamostat a likely candidate drug to treat COVID-19.

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MeSH Disease
Human Phenotype

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