COVID-19 Bimodal Clinical and Pathological Phenotypes

Background Patients with coronavirus disease-2019 (COVID-19) present varying clinical complications. Different viral load and host response related to genetic and immune background are probably the reasons for these differences. We aimed to sought clinical and pathological correlation that justifies the different clinical outcomes among COVID-19 autopsies cases. Methods Minimally invasive autopsy was performed on forty-seven confirmed COVID-19 patients from May-July, 2020. Electronic medical record of all patients was collected and a comprehensive histopathological evaluation was performed. Immunohistochemistry, immunofluorescence, special stain, western blotting and post-mortem real-time reverse transcriptase polymerase chain reaction on fresh lung tissue were performed. Resultss We show that 5/47 (10,6%) patients present a progressive decline in oxygenation index for acute respiratory distress syndrome (PaO2/FiO2 ratio), low compliance levels, interstitial fibrosis, high α-SMA+ cells/protein expression, high collagens I/III deposition and NETs(P<0.05), named as fibrotic phenotype (N=5). Conversely, 10/47 (21,2%) patients demonstrated progressive increase in PaO2/FiO2 ratio, high pulmonary compliance levels, preserved elastic framework, increase thrombus formation and high platelets and D-dimer levels at admission (P<0.05), named as thrombotic phenotype. While 32/47 (68,1%) had a mixed phenotypes between both ones. Conclusions We believe that categorization of patients based on these two phenotypes can be used to develop prognostic tools and potential therapies since the PaO2/FiO2 ratio variation and D-dimer levels correlate with the underlying fibrotic or thrombotic pathologic process, respectively; which may indicate possible clinical outcome of the patient.

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Significantly enlarged varix in the free-loop of the umbilical cord during the second trimester

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2019-0006 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Akiko Kurasaki ◽

Junichi Hasegawa ◽

Natsumi Furuya ◽

Chika Homma ◽

Satoshi Harada ◽

...

Keyword(s):

Umbilical Cord ◽

Thrombus Formation ◽

Umbilical Vein ◽

Second Trimester ◽

Venous Flow ◽

Case Presentation ◽

Neonatal Blood ◽

High Concentrations ◽

Venous Varix ◽

D Dimer

Abstract Objectives Umbilical cord varix is an abnormal dilatation of the umbilical vein. There are two types of umbilical venous varix, of which the free-loop type is extremely rare, and the prognosis and etiology are unclear. In this report, we present a case of a significantly enlarged varix in the free loop of the umbilical cord found in the second trimester. Case presentation Cesarean section was performed at 28 weeks’ gestation due to enlargement of the varix and rapidly increased umbilical venous velocity at the outlet of the varix. Neonatal blood tests revealed anemia and high concentrations of D-dimer, and they were considered to be due to clot formation inside the umbilical cord venous varix. The neonate received blood transfusion but other neonatal course was generally favorable. Thrombus formation in the enlarged varix was due to the constriction of the umbilical cord. Conclusions This case showed that the assessment of umbilical venous flow velocity can be used for estimating the constriction of the umbilical vein and for determining the timing of delivery.

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Left atrial appendage occlusion

Oxford Textbook of Interventional Cardiology ◽

10.1093/med/9780198754152.003.0047 ◽

2018 ◽

pp. 703-714

Author(s):

Sandeep Panikker ◽

Tim Betts ◽

Milena Leo

Keyword(s):

Transient Ischaemic Attack ◽

Left Atrial ◽

Thrombus Formation ◽

Blood Stasis ◽

Progressive Increase ◽

Thromboembolic Events ◽

Mortality And Morbidity ◽

Left Atrial Appendage Occlusion ◽

Ischaemic Attack ◽

Prior Stroke

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting 1.5–2% of the general population and more than 8% of those older than 80 years. Because of the progressive ageing of our population, an exponential increase in incidence is expected over the next few decades. Patients with AF have an increased mortality and morbidity, particularly owing to fatal or disabling stroke. The risk of embolic stroke is five times higher in the presence of AF, with an average annual rate around 5%, but there is a progressive increase with age and the presence of other risk factors, such as prior stroke or transient ischaemic attack, hypertension, diabetes mellitus, congestive heart failure, female sex, and vascular disease, as predicted by the CHADS2 and the CHA2DS2-VASc scores. Moreover, strokes associated with AF are more severe, with a 50% greater likelihood of becoming disabled or handicapped and more than 50% likelihood of death. Intracardiac thrombus formation due to the Virchow triad of events (endothelial or endocardial damage or dysfunction, abnormal blood stasis, and altered haemostasis, platelet function, and fibrinolysis) followed by distal embolization leads to thromboembolic events manifest as transient ischaemic attack, ischaemic stroke, and peripheral embolism in patients with AF.

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Importance of platelets in experimental venous thrombosis in the rat

Blood ◽

10.1182/blood.v80.9.2281.2281 ◽

1992 ◽

Vol 80 (9) ◽

pp. 2281-2286 ◽

Cited By ~ 4

Author(s):

JM Herbert ◽

A Bernat ◽

JP Maffrand

Keyword(s):

Venous Thrombosis ◽

Thrombus Formation ◽

Vena Cava ◽

Progressive Increase ◽

High Dose ◽

Experimental Conditions ◽

Dependent Inhibition ◽

Dose Dependent Inhibition ◽

Tissue Thromboplastin ◽

Dose Dependent

Abstract Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

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Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.2020040523 ◽

2020 ◽

Vol 31 (12) ◽

pp. 2773-2792

Author(s):

Markus Sellmayr ◽

Moritz Roman Hernandez Petzsche ◽

Qiuyue Ma ◽

Nils Krüger ◽

Helen Liapis ◽

...

Keyword(s):

Mass Spectrometry ◽

Aristolochic Acid ◽

Interstitial Fibrosis ◽

Ckd Progression ◽

Fticr Mass Spectrometry ◽

Progressive Decline ◽

Granulomatous Interstitial Nephritis ◽

Crystal Nephropathy ◽

Aristolochic Acid I

BackgroundThe roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression.MethodsMALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD.ResultsAsymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective.ConclusionsAsymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.

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Operant control of ambient temperature during sleep deprivation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.2.r682 ◽

1997 ◽

Vol 272 (2) ◽

pp. R682-R690 ◽

Cited By ~ 3

Author(s):

P. J. Shaw ◽

B. M. Bergmann ◽

A. Rechtschaffen

Keyword(s):

Energy Expenditure ◽

Sleep Deprivation ◽

Ambient Temperature ◽

Thermal Gradient ◽

Progressive Increase ◽

Thermal Preference ◽

Body Temperatures ◽

Progressive Decline ◽

Baseline Levels ◽

Almost All

Rats subjected to total sleep deprivation (TSD) by the disk-over-water method were provided with a continuously available operant by which they could increase ambient temperature (T(amb)). TSD rats progressively increased operant responses for heat to 700% of baseline levels. During the last quarter of sleep deprivation, they maintained mean T(amb) at 9 degrees C above baseline and held T(amb) over 40 degrees C for 35% of the day. In contrast, yoked control rats (TSC) did not change mean T(amb). Although both TSD and TSC rats showed a progressive decline in intraperitoneal temperature (T(ip)), TSD rats maintained an elevated T(amb) even during periods when T(ip) and brain temperatures (T(br)) were above baseline levels. Thus these results confirm and extend earlier findings that rats subjected to TSD show an increase in temperature set point (T(set)). The earlier studies, which utilized short daily trials in a thermal gradient, demonstrated an increase in T(set) early in the deprivation period. The present study, which obtained more extensive data on thermal preference at a range of body temperatures demonstrated an increasing T(amb) for almost all T(ip) and T(br) values, suggesting a progressive increase in T(set) over the course of sleep deprivation. Surprisingly, survival time was shorter than in previous TSD studies. Reduced survival could not be attributed to differences in T(br), T(ip), energy expenditure, or sleep loss from previous studies.

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Effect of AR-H067637, the Active Metabolite of the Oral Anticoagulant AZD0837, on Thrombus Formation Using Human Whole Blood in an In Vitro Flow Chamber Model

Blood ◽

10.1182/blood.v112.11.4049.4049 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4049-4049

Author(s):

Margareta Elg ◽

Helen Zachrisson

Keyword(s):

Active Metabolite ◽

Thrombus Formation ◽

Plasma Concentrations ◽

Flow Chamber ◽

Direct Thrombin Inhibitor ◽

Thrombin Inhibitor ◽

Antithrombotic Effect ◽

Chamber Model ◽

Platelet Content ◽

D Dimer

Abstract AR-H067637 is a direct thrombin inhibitor derived in vivo from the orally available prodrug AZD0837. AR-H067637 is a reversible and selective direct thrombin inhibitor, which has an inhibition constant, Ki, of 2–4 nmol/L against human alpha-thrombin. During early development of a new anticoagulant drug, data on antithrombotic doses from animal studies may help guide selection of the dose to use in initial human studies. In the present study, using a flow chamber model developed by Badimon and colleagues (Badimon L, et al. J Lab Clin Med1987;110:706–718), the antithrombotic effect of AR-H067637 was evaluated using pig aorta and human whole blood. Following collection of informed consent, blood was taken from 11 healthy subjects into citrate-containing (10%, 0.109 M) tubes. Subjects were not permitted to receive medication for 7 days prior to blood collection. Blood was also collected in EDTA-containing tubes for cell counting. Denuded pig aorta pieces were used as the thrombogenic surface in the flow chamber. AR-H067637 was added to the blood at final blood concentrations ranging from 0.01 to 10 μmol/L, corresponding to plasma concentrations of 0.02 to 16 μmol/L. The blood was drawn for 5 minutes through the flow chamber with a shear of 220−s which is comparable with venous flow rate. The thrombus formed inside the chamber was degraded by plasmin, and platelets attached to the thrombus were lysed. The degradation product of fibrin, D-dimer, and the expression of the platelet cell adhesion molecule P-selectin were used as indirect measures of fibrin and platelet content in the thrombus, respectively. The anticoagulant effect of AR-H067637 was determined using the activated partial thromboplastin time (APTT) and prothrombin time (PT) assays. When using D-dimer levels as a measure of thrombus size, 25%, 50% and 75% thrombus inhibition was estimated to occur at AR-H067637 plasma concentrations of 0.21, 0.48 and 1.32 μmol/L, respectively. A significant inhibition of P-selectin expression by AR-H067637 was seen only at the highest concentration. APTT and PT were shown to be prolonged in a concentration-dependent manner; 50% inhibition of thrombus formation on the pig aorta was obtained at 1.8 and 1.2 times prolongations of APTT and PT, respectively. Hematological parameters such as WBC, RBC, HCT and platelets were all within the normal range. In conclusion, this study demonstrates that AR-H067637, the active metabolite of the oral prodrug AZD0837, has antithrombotic effects, causing concentration-dependent inhibition of thrombus formation measured as fibrin degradation products on the denuded pig aorta. Only a small effect at the highest concentration was observed on inhibition of platelet content in the thrombus, measured by P-selectin. This is in accordance with thrombin being a very potent platelet agonist. Therefore, higher concentrations of a thrombin inhibitor are needed to totally prevent platelet activation and aggregation, compared to those needed to prevent fibrin formation. APTT and PT prolongation correlated with the antithrombotic effect of AR-H067637 with >75% inhibition of fibrin formation at APTT and PT prolongations of 2.4 and 1.7, respectively.

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Health and aging: does retirement transition make any difference?

Reviews in Clinical Gerontology ◽

10.1017/s0959259804001078 ◽

2003 ◽

Vol 13 (3) ◽

pp. 257-260 ◽

Cited By ~ 3

Author(s):

António M. Fonseca ◽

Constança Paúl

Keyword(s):

Individual Differences ◽

Old Age ◽

Good Health ◽

Progressive Increase ◽

Psychological Wellbeing ◽

Basic Notion ◽

Progressive Decline ◽

Elderly Individuals ◽

Health Trajectories ◽

Health Decline

A basic notion relating to development during adulthood and old age, according to a lifespan perspective, refers to the progressive increase in individual differences in psychological wellbeing. It is possible to find diverse ‘health trajectories’, shaping patterns of evolution regarding the general health of adult and elderly individuals, such as (1) permanent good health (2) good health most of the time and decline by the end of life (3) health decline and recovery (4) permanent poor health, (5) progressive decline and (6) irregular health.

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D-Dimer Concentrations in Normal Pregnancy: New Diagnostic Thresholds Are Needed

Clinical Chemistry ◽

10.1373/clinchem.2004.044883 ◽

2005 ◽

Vol 51 (5) ◽

pp. 825-829 ◽

Cited By ~ 130

Author(s):

Jeffrey A Kline ◽

Ginger W Williams ◽

Jackeline Hernandez-Nino

Keyword(s):

Fetal Loss ◽

Pregnant Patient ◽

Normal Pregnancy ◽

Progressive Increase ◽

Third Trimester ◽

The Third ◽

Diagnostic Thresholds ◽

Turbidimetric Assay ◽

D Dimer ◽

Rule Out

Abstract Background: Pregnancy is known to increase the D-dimer concentration above the conventional normal threshold of 0.50 mg/L, leading to an increased false-positive D-dimer test when venous thromboembolism (VTE) is clinically suspected in a pregnant patient. Our aim was to determine the effect of normal pregnancy on the D-dimer concentration. Methods: Healthy women who were seeking to become pregnant and had no preexisting condition known to increase the D-dimer concentration were identified. Quantitative D-dimer measurements (MDA turbidimetric assay) and fibrinogen assays were performed before conception, at each trimester, and at 4 weeks postpartum. Patients were excluded for fetal loss or preeclampsia. Results: A total of 50 women were enrolled in the study, and blood samples were obtained at preconception and all trimesters from 23 women. The mean (SD) preconception D-dimer concentration was 0.43 (0.49) mg/L, and 79% of women had a D-dimer concentration <0.50 mg/L. D-Dimer increased with each trimester such that only 22% of women in the second trimester and none (of 23) in the third trimester (95% confidence interval, 0–14%) had a D-dimer concentration <0.50 mg/L. We found no correlation between either the D-dimer and fibrinogen concentrations or between the increases in D-dimer and fibrinogen with pregnancy. Conclusions: Normal pregnancy causes a progressive increase in circulating D-dimer. The D-dimer test has no use in ruling out VTE in the third trimester if a cutoff of 0.50 mg/L is used. A large management study is needed to establish new thresholds for the D-dimer to rule out VTE in each trimester.

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Comprehensive analyses of immunoglobulin proteome and clinical variables identify biomarkers to predict mortality in patients with influenza-associated lower respiratory tract infection

10.21203/rs.2.20903/v1 ◽

2020 ◽

Author(s):

Fei Teng ◽

Dan Wang ◽

Xiao-Mei Zhang ◽

Jian-Hua Liu ◽

Jia-Yu Dai ◽

...

Keyword(s):

T Cell ◽

Tract Infection ◽

Respiratory Tract ◽

Prediction Model ◽

Respiratory Tract Infection ◽

Lower Respiratory Tract Infection ◽

Lower Respiratory Tract ◽

Oxygenation Index ◽

Clinical Variables ◽

D Dimer

Abstract Background: Influenza-associated lower respiratory tract infection (I-LRTI) brings a heavy clinical burden, and clinicians lack an effective prognostic evaluation system to control disease progression. Methods: This was a prospective, observational study, and the endpoint was 28-day mortality. Plasma microarrays were used for quantitative analysis of immunoglobulin (Ig) and its subclasses. Prognostic factors from Ig and clinical variables in the patients with I-LRTI were identified to create a prediction model. Results: To address this issue, we prospectively and observationally studied the difference of immunoglobulin proteome and clinical variables between survivors and non-survivals in 107 patients with influenza-associated lower respiratory tract infection (I-LRTI) selected from four hospitals affiliated to Capital Medical University. The results identified 17 variables with significant or marginally statistical differences by univariate analysis, including lymphocyte count (LY), monocytes count (MO), CD3 + CD4 + T-cell count, CD3 + CD8 + T-cell count, IgA, IgA1, IgG2, IgG4, CRP, PCT, D-dimer, oxygenation index, glycosylated hemoglobin, lactic acid (LAC), base excess of blood, lactic dehydrogenase, and α-hydroxybutyrate dehydrogenase. Furthermore, we analyzed the correlations of all the variables by hierarchical clustering analysis in which different functional modules were formed between survival and non-survival groups that are associated with the immunity and severe infection. At last, we built a prediction model with nine variables (D-dimer, days from onset to ED, IgA, IgG2, LAC, LY, MO, Staphylococcus aureus co-infection and age), with which the AUC value of 0.810 (95% CI 0.755-0.839) was achieved with the evaluation of LOO cross validation. The predictive model was further validated by disease severity evaluation. Conclusion: Lethal bacterial (especially S. aureus ) co-infection was associated with cellular immunity, oxygenation index, HbA1C and age. The combined prediction model with D-dimer, Days from onset to ED, IgA, IgG2, LAC, LY, MO, S.aureus co-infection and age demonstrate the predictive mortality powerfully in patients with I-LRTI.

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Associated risk factors with disease severity and antiviral drug therapy in patients with COVID-19

10.21203/rs.3.rs-70914/v2 ◽

2020 ◽

Author(s):

Xiaowei Gong ◽

Xianfeng Guo ◽

Shiwei Kang ◽

Yan Li ◽

Haixiang Gao ◽

...

Keyword(s):

Risk Factors ◽

Clinical Symptoms ◽

Discharge Rate ◽

Antiviral Drug ◽

Oxygenation Index ◽

Multivariable Logistic Regression Analysis ◽

Common Symptom ◽

Clinical Benefits ◽

Novel Coronavirus ◽

D Dimer

Abstract Background: Due to the latent onset of novel coronavirus disease 2019 (COVID-19), it is important to identify patients with increased probabilities for disease progression early in order to implement timely medical strategies. This study aimed to identify the factors associated with increased COVID-19 severity and evaluate the current antiviral drugs, especially in severe patients. Methods: This was a retrospective observational study performed at the No. 7 Hospital of Wuhan (Wuhan, China) with hospitalized patients confirmed with COVID-19 from January 11 to March 13, 2020. Multivariable logistic regression analysis was used to identify the associated factors of severe COVID. Treatments of antivirus drugs were collected and evaluated.Results: Of the 550 patients, 292 (53.1%) were female and 277 (50.4%) were >60 years old. The most common symptom was fever (n=372, 67.7%), followed by dry cough (n=257, 46.7%), and dyspnea (n=237, 43.1%), and fatigue (n=224, 40.7%). Among the severe patients, 20.2% required invasive ventilator support and 18.0% required non-invasive ventilator. The identified risk factors for severe cases were: age ≥60 years (odds ratio (OR) =3.02, 95% confidence interval (CI): 1.13-8.08, P=0.028), D-dimer >0.243 μg/ml (OR=2.734, 95%CI: 1.012-7.387, P=0.047), and low oxygenation index (OR=0.984, 95%CI: 0.980-0.989, P<0.001). In severe cases, the benefits (relief of clinical symptoms, clinical outcome, and discharge rate) of arbidol alone was 73.3%, which was better than ribavirin (7/17, 41.2%, P=0.029).Conclusions: Age >60 years, D-dimer >0.243 µg/ml, and lower oxygenation index were associated with severe COVID-19. Arbidol might provide more clinical benefits in treating patients with severe COVID-19 compared with ribavirin.

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