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1.
Blood Coagul Fibrinolysis ; 32(8): 544-549, 2021 Dec 01.
Article in English | MEDLINE | ID: covidwho-1526211

ABSTRACT

Standard biomarkers have been widely used for COVID-19 diagnosis and prognosis. We hypothesize that thrombogenicity metrics measured by thromboelastography will provide better diagnostic and prognostic utility versus standard biomarkers in COVID-19 positive patients. In this observational prospective study, we included 119 hospitalized COVID-19 positive patients and 15 COVID-19 negative patients. On admission, we measured standard biomarkers and thrombogenicity using a novel thromboelastography assay (TEG-6s). In-hospital all-cause death and thrombotic occurrences (thromboembolism, myocardial infarction and stroke) were recorded. Most COVID-19 patients were African--Americans (68%). COVID-19 patients versus COVID-19 negative patients had higher platelet-fibrin clot strength (P-FCS), fibrin clot strength (FCS) and functional fibrinogen level (FLEV) (P ≤ 0.003 for all). The presence of high TEG-6 s metrics better discriminated COVID-19 positive from negative patients. COVID-19 positive patients with sequential organ failure assessment (SOFA) score at least 3 had higher P-FCS, FCS and FLEV than patients with scores less than 3 (P ≤ 0.001 for all comparisons). By multivariate analysis, the in-hospital composite endpoint occurrence of death and thrombotic events was independently associated with SOFA score more than 3 [odds ratio (OR) = 2.9, P = 0.03], diabetes (OR = 3.3, P = 0.02) and FCS > 40 mm (OR = 3.4, P = 0.02). This largest observational study suggested the early diagnostic and prognostic utility of thromboelastography to identify COVID-19 and should be considered hypothesis generating. Our results also support the recent FDA guidance regarding the importance of measurement of whole blood viscoelastic properties in COVID-19 patients. Our findings are consistent with the observation of higher hospitalization rates and poorer outcomes for African--Americans with COVID-19.


Subject(s)
COVID-19/blood , SARS-CoV-2 , Thrombophilia/diagnosis , Adult , African Americans/statistics & numerical data , Aged , Aged, 80 and over , Biomarkers , COVID-19/complications , COVID-19/epidemiology , COVID-19 Testing , Cardiovascular Diseases/epidemiology , Comorbidity , Diabetes Mellitus/epidemiology , Early Diagnosis , Female , Fibrin/analysis , Fibrin Clot Lysis Time , Fibrinogen/analysis , Hospitalization , Humans , Hyperlipidemias/epidemiology , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Obesity/epidemiology , Organ Dysfunction Scores , Prognosis , Prospective Studies , Thrombelastography , Thrombophilia/blood , Thrombophilia/drug therapy , Thrombophilia/etiology , Treatment Outcome , /statistics & numerical data
2.
Eur Rev Med Pharmacol Sci ; 25(19): 5904-5912, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1478932

ABSTRACT

OBJECTIVE: Liver injury has been reported in patients with COVID-19. This condition is characterized by severe outcome and could be related with the ability of SARS-CoV-2 to activate cytotoxic T cells. The purpose of this study is to show the histological and scanning electron microscopy features of liver involvement in COVID-19 to characterize the liver changes caused by the activation of multiple molecular pathways following this infection. PATIENTS AND METHODS: Liver biopsies from 4 patients (3 post-mortems and 1 in vivo) with COVID-19 were analyzed with histology and by scanning electron microscopy. RESULTS: The liver changes showed significant heterogeneity. The first case showed ground glass hepatocytes and scattered fibrin aggregates in the sinusoidal lumen. The second evidenced intra-sinusoidal thrombi. The third was characterized by sinusoidal dilatation, atrophy of hepatocytes, Disse's spaces dilatation and intra-sinusoidal aggregates of fibrin and red blood cells. The fourth case exhibited diffuse fibrin aggregates in the dilated Disse spaces and microthrombi in the sinusoidal lumen. CONCLUSIONS: In COVID-19-related liver injury, a large spectrum of pathological changes was observed. The most peculiar features were very mild inflammation, intra-sinusoidal changes, including sinusoidal dilatation, thrombotic sinusoiditis and diffuse intra-sinusoidal fibrin deposition. These findings suggested that a thrombotic sinusoiditis followed by a local diffuse intra-vascular (intra-sinusoidal) coagulation could be the typical features of the SARS-CoV-2-related liver injury.


Subject(s)
Blood Coagulation Disorders/pathology , COVID-19/pathology , Liver Diseases/pathology , Liver/pathology , Thrombosis/pathology , Aged , Autopsy , Biopsy , Erythrocytes/pathology , Fibrin , Hepatocytes/pathology , Humans , Male , Microscopy, Electron, Scanning , Middle Aged , Thrombosis/complications , Young Adult
3.
Ophthalmic Res ; 64(5): 785-792, 2021.
Article in English | MEDLINE | ID: covidwho-1443682

ABSTRACT

INTRODUCTION: In December 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic broke out. The virus rapidly spread globally, resulting in a major world public-health crisis. The major disease manifestation occurs in the respiratory tract. However, further studies documented other systemic involvement. This study investigates histopathologic eye changes in postmortem material of coronavirus disease 2019 (COVID-19) patients. METHODS: Sections of formalin-fixed, paraffin-embedded eyes from 5 patients (10 eyes) who died of COVID-19 at the University Hospital in Basel were included. Gross examination and histological evaluation were performed by 3 independent ophthalmopathologists. Immunohistochemical staining was performed using antibodies against fibrin, cleaved caspase 3, and ACE-2. Five enucleated eyes of patients not infected with SARS-CoV-2 served as control group. All cases have been studied for presence of SARS-CoV-2 RNA by means of reverse transcription PCR and RNA in situ hybridization (ISH). The choroidal vessels of one case were analyzed with electron microscope. RESULTS: Ophthalmopathologically, 8 eyes from 4 patients displayed swollen endothelial cells in congested choroidal vessels. No further evidence of specific eye involvement of SARS-CoV-2 was found in any of the patients. In the 8 eyes with evidence of changes due to SARS-CoV-2, immunohistochemical staining demonstrated fibrin microthrombi, apoptotic changes of endothelial and inflammatory cells. In control eyes, ACE-2 was detectable in the conjunctiva, cornea, retina, and choroidea and displayed significantly lower amounts of stained cells as in COVID-19 eyes. SARS-CoV-2 RNA was detectable in both bulbi of 2/5 patients, yet ISH failed to visualize viruses. Electron microscopy showed no significant results due to the artifacts. DISCUSSION/CONCLUSION: As already described in other organs of COVID-19 patients, the ophthalmological examination revealed-microthrombi, that is, hypercoagulation and vasculopathy most probably due to endothelial damage. A possible viral spread to the endothelial cells via ACE-2 provides one pathophysiological explanation. The expression of ACE-2 receptors in the conjunctiva hints toward its susceptibility to infection. To what extend eyes, function is disrupted by SARS-CoV-2 is subject to further studies, especially in the clinic.


Subject(s)
COVID-19/pathology , Choroid Diseases/pathology , Eye Infections, Viral/pathology , RNA, Viral/genetics , Retinal Diseases/pathology , SARS-CoV-2/genetics , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Nucleic Acid Testing , Caspase 3/metabolism , Choroid/blood supply , Choroid/pathology , Choroid Diseases/virology , Ciliary Body/blood supply , Ciliary Body/pathology , Conjunctiva/metabolism , Cornea/metabolism , Endothelial Cells/metabolism , Eye Infections, Viral/virology , Female , Fibrin/metabolism , Humans , Immunohistochemistry , In Situ Hybridization , Male , Real-Time Polymerase Chain Reaction , Retinal Diseases/virology , Retinal Vessels/pathology , Thrombosis/metabolism , Thrombosis/pathology
4.
Biosci Rep ; 41(8)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1334001

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet-poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to ß and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.


Subject(s)
COVID-19/pathology , Fibrin/metabolism , Fibrinolysis/physiology , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Adult , Aged , Amyloid/metabolism , Blood Platelets/metabolism , Complement C3/metabolism , Female , Fibrinogen/metabolism , Humans , Lung/pathology , Male , Microfluidic Analytical Techniques , Middle Aged , Prothrombin/metabolism , SARS-CoV-2/metabolism , Thrombosis/virology , Trypsin/metabolism
5.
Pediatr Dev Pathol ; 24(5): 450-454, 2021.
Article in English | MEDLINE | ID: covidwho-1259128

ABSTRACT

An emerging complication of COVID-19 (SARS-CoV-2) infection is reported. A 23-year-old patient presented with high temperature and reduced fetal movements at 25 + 5/40 weeks of gestation. RT-PCR proved maternal COVID-19 infection. Ultrasound examination confirmed intrauterine death. Placenta histology showed necrosis of the villous trophoblast, associated with Chronic Histiocytic Intervillositis (CHI) and Massive Perivillous Fibrin Deposition (MPFD) with up to 90% - of the intervillous spaces being involved. Immunohistochemistry showed CD68 positive histiocytes in the intervillous spaces and the villous trophoblast was positive for the COVID-19 spike protein. RNA scope signal was indicative of the presence of the viral genome and active viral replication in the villous trophoblastic cells, respectively. MPFD is a gradually developing end-stage disease with various etiology, including autoimmune and alloimmune maternal response to antigens expressed at the feto-maternal interface and frequently accompanies chronic alloimmune villitis or histiocytic intervillositis. Covid-19 infection is associated with similar pattern of histological changes of the placenta leading to placental insufficiency and fetal death. This case report supports maternal- fetal vertical transmission of SARS-CoV-2 virus leading to placental insufficiency and fetal demise. MPFD and CHI appear to be the typical placental histology for SARS-CoV-2 virus infection associated fetal demise.


Subject(s)
COVID-19/virology , Chorionic Villi/virology , Fibrin/metabolism , Pregnancy Complications, Infectious/virology , SARS-CoV-2/pathogenicity , Adult , Chorionic Villi/pathology , Female , Fetal Death/etiology , Histiocytes/virology , Humans , Placenta/pathology , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/pathology , RNA, Viral
6.
Stroke ; 52(5): 1895-1904, 2021 05.
Article in English | MEDLINE | ID: covidwho-1166638

ABSTRACT

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.


Subject(s)
Brain Ischemia/complications , Brain/physiopathology , COVID-19/complications , Endothelial Cells/cytology , Ischemic Stroke/complications , Angiotensin-Converting Enzyme 2/metabolism , Blood Coagulation , Brain Ischemia/physiopathology , COVID-19/physiopathology , Cytokines/metabolism , Fibrin/chemistry , Fibrin Fibrinogen Degradation Products/chemistry , Hemostasis , Humans , Hypoxia , Incidence , Inflammation , Ischemic Stroke/physiopathology , Myocardial Infarction/physiopathology , Pandemics , Prognosis
7.
Int J Mol Sci ; 22(5)2021 Mar 09.
Article in English | MEDLINE | ID: covidwho-1134169

ABSTRACT

Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.


Subject(s)
Blood Chemical Analysis/methods , Disease , Fibrinolysin/analysis , Fibrinolysin/metabolism , Animals , Antifibrinolytic Agents/blood , Fibrin/analysis , Fibrin/chemistry , Fibrinolytic Agents/blood , Humans , Plasminogen/analysis , Plasminogen/chemistry , Plasminogen/metabolism
8.
Elife ; 102021 03 08.
Article in English | MEDLINE | ID: covidwho-1122117

ABSTRACT

Extensive fibrin deposition in the lungs and altered levels of circulating blood coagulation proteins in COVID-19 patients imply local derangement of pathways that limit fibrin formation and/or promote its clearance. We examined transcriptional profiles of bronchoalveolar lavage fluid (BALF) samples to identify molecular mechanisms underlying these coagulopathies. mRNA levels for regulators of the kallikrein-kinin (C1-inhibitor), coagulation (thrombomodulin, endothelial protein C receptor), and fibrinolytic (urokinase and urokinase receptor) pathways were significantly reduced in COVID-19 patients. While transcripts for several coagulation proteins were increased, those encoding tissue factor, the protein that initiates coagulation and whose expression is frequently increased in inflammatory disorders, were not increased in BALF from COVID-19 patients. Our analysis implicates enhanced propagation of coagulation and decreased fibrinolysis as drivers of the coagulopathy in the lungs of COVID-19 patients.


Subject(s)
Blood Coagulation/genetics , COVID-19/pathology , Fibrin/genetics , Lung/pathology , SARS-CoV-2 , Anticoagulants/metabolism , Bronchoalveolar Lavage Fluid , COVID-19/genetics , COVID-19/metabolism , Endothelial Protein C Receptor/genetics , Endothelial Protein C Receptor/metabolism , Fibrin/metabolism , Gene Expression , Humans , Kallikrein-Kinin System/genetics , Kallikreins/genetics , Kallikreins/metabolism , Kinins/genetics , Kinins/metabolism , Lung/metabolism , RNA, Messenger/metabolism , Sequence Analysis, RNA , Thrombomodulin/genetics , Thrombomodulin/metabolism , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolism
9.
J Thromb Haemost ; 18(9): 2103-2109, 2020 09.
Article in English | MEDLINE | ID: covidwho-1096903

ABSTRACT

The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain.


Subject(s)
Blood Coagulation Disorders/blood , COVID-19/epidemiology , Disseminated Intravascular Coagulation/blood , Anticoagulants , Blood Coagulation , Blood Coagulation Disorders/complications , Blood Coagulation Tests , COVID-19/complications , Cytokines/metabolism , Disseminated Intravascular Coagulation/complications , Fibrin/chemistry , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/chemistry , Fibrinolysis , Hemorrhage , Hemostasis , Humans , Inflammation , Lung/metabolism , Lung/virology , Lymphocytes/metabolism , Partial Thromboplastin Time , Protease Inhibitors , Prothrombin Time , Sepsis , Thrombosis/metabolism
10.
Circulation ; 143(3): 230-243, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-1039948

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. METHODS: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. RESULTS: Male sex was more common in the COVID-19 group (P=0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort (P=0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls (P=0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities (P=0.69, P=1.00, P=0.46, P=0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. CONCLUSIONS: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.


Subject(s)
COVID-19 , Coronary Thrombosis , Fibrin/metabolism , Myocardium , SARS-CoV-2/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/metabolism , COVID-19/mortality , COVID-19/pathology , Child , Child, Preschool , Coronary Thrombosis/metabolism , Coronary Thrombosis/mortality , Coronary Thrombosis/pathology , Female , Gene Expression Regulation, Enzymologic , Humans , Immunohistochemistry , Infant , Male , Middle Aged , Myocardium/metabolism , Myocardium/pathology
11.
Int J Lab Hematol ; 43(4): 813-820, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-967575

ABSTRACT

INTRODUCTION: Fibrin/fibrinogen degradation products (FDP) values reflect coagulation and fibrinolysis status, and FDP levels are helpful for diagnosis and classification of disseminated intravascular coagulation (DIC). FDP measurement has always played a key role in diagnosing DIC, a phenomenon that has recently gained renewed attention because of its occurrence in coronavirus disease 2019 (COVID-19) patients. Although the evaluation of FDP is crucial for the management of critical care, the variability among FDP reagents is unclear. In this study, we aimed to compare LIASAUTO P-FDP with three FDP reagents and investigate their characteristics. METHODS: In total, 172 plasmas samples were used in the correlation. The sample data were divided into three groups including negative, no and positive discrepancy based on the discrepancy percentages calculated from each correlation between LIASAUTO P-FDP and other three reagents. D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), fibrin monomer complex (FMC), fibrinogen (Fbg) and Plasmin-α2 Plasmin Inhibitor (α2 PI) were measured and included in data analysis. RESULTS: The positive discrepancy groups showed higher D-dimer, PIC and FMC values than the negative discrepancy groups. The data indicated that LIASAUTO P-FDP had higher reactivity to D-dimer than other reagents and the values were elevated in the fibrinolysis-enhanced samples with various FDP fragments. CONCLUSION: LIASAUTO P-FDP displayed the reactivity towards various fibrin/fibrinogen degradation products, and it might be useful for DIC diagnosis because the fibrinolytic status differed in the DIC types and stages.


Subject(s)
COVID-19/blood , Fibrin/analysis , Fibrinogen/analysis , Fibrinolysis , COVID-19/diagnosis , Critical Care , Fibrin Fibrinogen Degradation Products/analysis , Fibrinolysin/analysis , Humans , SARS-CoV-2/isolation & purification , alpha-2-Antiplasmin/analysis
12.
Forensic Sci Med Pathol ; 17(2): 279-296, 2021 06.
Article in English | MEDLINE | ID: covidwho-834059

ABSTRACT

Although many clinical reports have been published, little is known about the pathological post-mortem findings from people who have died of the novel coronavirus disease. The need for postmortem information is urgent to improve patient management of mild and severe illness, and treatment strategies. The present systematic review was carried out according to the Preferred Reporting Items for Systematic Review (PRISMA) standards. A systematic literature search and a critical review of the collected studies were conducted. An electronic search of PubMed, Science Direct Scopus, Google Scholar, and Excerpta Medica Database (EMBASE) from database inception to June 2020 was performed. We found 28 scientific papers; the total amount of cases is 341. The major histological feature in the lung is diffuse alveolar damage with hyaline membrane formation, alongside microthrombi in small pulmonary vessels. It appears that there is a high incidence of deep vein thrombosis and pulmonary embolism among COVID-19 decedents, suggesting endothelial involvement, but more studies are needed. A uniform COVID-19 post-mortem diagnostic protocol has not yet been developed. In a time in which international collaboration is essential, standardized diagnostic criteria are fundamental requirements.


Subject(s)
Autopsy , COVID-19/pathology , Lung/pathology , Alveolar Epithelial Cells/pathology , Brain/pathology , Fibrin/metabolism , Fibroblasts/pathology , Humans , Kidney/pathology , Leukocytes, Mononuclear/pathology , Myositis/pathology , Respiratory Mucosa/pathology , Thrombosis/pathology
13.
Int J Legal Med ; 134(6): 2209-2214, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-695582

ABSTRACT

A 75-year-old man presented to a French hospital with a 4-day fever after returning from a coronavirus disease-19 (COVID-19) cluster region. A reverse-transcription polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) using a nasopharyngeal swab sample. After he returned home and a telephone follow-up, he was found deceased 9 days after first showing symptoms. Whole-body, non-enhanced, post-mortem computed tomography (PMCT) and a forensic autopsy were performed approximately 48 h after death, with sanitary precautions. The PMCT showed bilateral and diffuse crazy-paving lung opacities, with bilateral pleural effusions. Post-mortem virology studies detected the presence of SARS-CoV-2 (B.1 lineage) in the nasopharynx, plasma, lung biopsies, pleural effusion and faeces confirming the persistence of viral ribonucleic acid 48 h after death. Microscopic examination showed that severe lung damage was responsible for his death. The main abnormality was diffuse alveolar damage, associated with different stages of inflammation and fibrosis. This case is one of the first to describe complete post-mortem data for a COVID-19 death and highlights the ability of PMCT to detect severe involvement of the lungs before autopsy in an apparently natural death. The present pathology results are concordant with previously reported findings and reinforce the disease pathogenesis hypothesis of combined viral replication with an inappropriate immune response.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Lung/diagnostic imaging , Lung/pathology , Pneumonia, Viral/pathology , Aged , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Fibrin/metabolism , Humans , Hyperplasia , Male , Pandemics , Pleural Effusion/diagnostic imaging , Pleural Effusion/pathology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , SARS-CoV-2 , Tomography, X-Ray Computed
14.
J Thromb Thrombolysis ; 51(1): 226-231, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-648995

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.


Subject(s)
Blood Coagulation , COVID-19/therapy , Cytokine Release Syndrome , Fibrin , Inflammation , Blood Coagulation/drug effects , Blood Coagulation/immunology , COVID-19/blood , COVID-19/drug therapy , COVID-19/immunology , Cells, Cultured , Chemokines/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Dose-Response Relationship, Drug , Fibrin/immunology , Fibrin/pharmacology , Fibrinolytic Agents/pharmacology , Heparin/pharmacology , Humans , Immunization, Passive , Inflammation/blood , Inflammation/therapy , Leukocytes, Mononuclear/drug effects , SARS-CoV-2
15.
J Thromb Haemost ; 18(9): 2118-2122, 2020 09.
Article in English | MEDLINE | ID: covidwho-599236

ABSTRACT

The COVID-19 pandemic has provided many challenges in the field of thrombosis and hemostasis. Among these is a novel form of coagulopathy that includes exceptionally high levels of D-dimer. D-dimer is a marker of poor prognosis, but does this also imply a causal relationship? These spectacularly raised D-dimer levels may actually signify the failing attempt of the fibrinolytic system to remove fibrin and necrotic tissue from the lung parenchyma, being consumed or overwhelmed in the process. Indeed, recent studies suggest that increasing fibrinolytic activity might offer hope for patients with critical disease and severe respiratory failure. However, the fibrinolytic system can also be harnessed by coronavirus to promote infectivity and where antifibrinolytic measures would also seem appropriate. Hence, there is a clinical paradox where plasmin formation can be either deleterious or beneficial in COVID-19, but not at the same time. Hence, it all comes down to timing.


Subject(s)
COVID-19/blood , COVID-19/complications , COVID-19/drug therapy , Fibrinolysis/drug effects , Acute Lung Injury , Animals , Antifibrinolytic Agents/pharmacology , Fibrin/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinolysin/metabolism , Humans , Immune System , Lung/metabolism , Necrosis , Prognosis , Thrombolytic Therapy , Tissue Plasminogen Activator/pharmacology
16.
Int J Legal Med ; 134(4): 1285-1290, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-544132

ABSTRACT

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.


Subject(s)
Betacoronavirus , Coronavirus Infections/pathology , Lung/pathology , Pneumonia, Viral/pathology , Alveolar Epithelial Cells/pathology , Autopsy , COVID-19 , Cough/virology , Diabetes Mellitus, Type 2 , Fever/virology , Fibrin/metabolism , Fibrosis/pathology , Humans , Hyperplasia/pathology , Hypertension , Lung/metabolism , Lymphocytes/pathology , Macrophages/pathology , Male , Megakaryocytes/pathology , Metaplasia/pathology , Middle Aged , Neutrophils/pathology , Pandemics , Quarantine , SARS-CoV-2 , Tachycardia/virology , Thrombosis/pathology
17.
Thromb Haemost ; 120(6): 998-1000, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-102182

ABSTRACT

In late December 2019 an outbreak of a novel coronavirus (SARS-CoV-2) causing severe pneumonia (COVID-19) was reported in Wuhan, Hubei Province, China. A common finding in most COVID-19 patients is high D-dimer levels which are associated with a worse prognosis. We aimed to evaluate coagulation abnormalities via traditional tests and whole blood thromboelastometry profiles in a group of 22 (mean age 67 ± 8 years, M:F 20:2) consecutive patients admitted to the Intensive Care Unit of Padova University Hospital for acute respiratory failure due to COVID-19. Cases showed significantly higher fibrinogen and D-dimer plasma levels versus healthy controls (p < 0.0001 in both comparisons). Interestingly enough, markedly hypercoagulable thromboelastometry profiles were observed in COVID-19 patients, as reflected by shorter Clot Formation Time (CFT) in INTEM (p = 0.0002) and EXTEM (p = 0.01) and higher Maximum Clot Firmness (MCF) in INTEM, EXTEM and FIBTEM (p < 0.001 in all comparisons). In conclusion, COVID-19 patients with acute respiratory failure present a severe hypercoagulability rather than consumptive coagulopathy. Fibrin formation and polymerization may predispose to thrombosis and correlate with a worse outcome.


Subject(s)
Blood Coagulation , Coronavirus Infections/blood , Coronavirus Infections/therapy , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Respiration Disorders/complications , Respiration Disorders/therapy , Thrombophilia/complications , Acute Disease , Aged , Area Under Curve , Betacoronavirus , Blood Coagulation Tests , COVID-19 , Coronavirus Infections/complications , Critical Care , Female , Fibrin/analysis , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Humans , Intensive Care Units , Italy/epidemiology , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Prognosis , SARS-CoV-2 , Thrombelastography , Treatment Outcome
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