Posts tonen met het label COVID-19. Alle posts tonen
Posts tonen met het label COVID-19. Alle posts tonen

woensdag 3 februari 2021

Kinderen en verspreiding van het coronavirus (SARS-CoV-2)

Het RIVM heeft sinds medio 2020 stellig volgehouden dat "Kinderen geen tot nauwelijks een rol van betekenis spelen in de verspreiding van het coronavirus" en dat "Kinderen niet of bijna nooit ziek worden van besmetting met SARS-CoV-2". Het is van belang te onderscheiden tussen cytotoxiciteit van SARS-CoV-2 en virulentie, ofwel: hoe ziek een kind kan worden van COVID-19 enerzijds en het aandeel van het kind in de verspreiding van het coronavirus anderzijds. Dat kinderen over het algemeen minder ziek worden van COVID, kan niet als argument worden gebruikt om "aan te tonen" dat kinderen het virus minder vaak zouden verspreiden.

De richtlijn "Kinderen, school en COVID-19": onderzoek als fundament voor het beleid moet nog worden gestart
De volksmond verspreidt inmiddels de bewering dat het RIVM onderzoek heeft gedaan naar de verspreiding van het coronavirus door kinderen. Ik raadpleeg de meest recente richtlijn van het RIVM, "Kinderen, school en COVID-19", gepubliceerd op 3 februari 2021. Wat blijkt? De aannames, dat kinderen geen rol of een geringe rol van betekenis spelen in de verspreiding van SARS-CoV-2 en dat kinderen minder ziek worden van COVID-19, worden niet onderbouwd met onderzoeken. Het probleem is fundamenteel: aannames waarop het overheidsbeleid inzake kinderen en corona wordt gegrond, worden niet onderbouwd door wetenschappelijk onderzoek. Een aanname kan immers niet worden gebruikt als "bewijs" voor de stelling, dat kinderen geen rol van betekenis spelen. Kijk naar de "onderbouwing" van het beleid: daar staat aangegeven dat het onderzoek naar de verspreiding van het virus door kinderen nog moet worden gestart op het moment van dit schrijven.

Kinderen en de ernst van COVID, virale lading, infectiviteit en presymptomatische verspreiding en indexgevallen

1. Ernst van COVID-19 bij kinderen
Aangenomen wordt dat kinderen minder vaak ernstige COVID-19 ontwikkelen, omdat zij een lagere expressie van de ACE2-receptor hebben. De ACE2-receptor is de receptor waaraan het virus, SARS-CoV-2, hecht om zich in het lichaam van de gastheer te verspreiden. Een minder sterke expressie van ACE2 kan tevens verklaren waarom kinderen minder vaak geïnfecteerd zouden worden dan andere leeftijdscategorieën, hoewel een preprint van de MedRxiv concludeert dat de vatbaarheid van kinderen 43% van de vatbaarheid van volwassenen beloopt en dat de infectiviteit van kinderen gemiddeld 63% van de infectiviteit van volwassenen beloopt. De preprint toont dat kinderen tussen de 0-1 jaar oud vatbaarder zijn voor infectie met SARS-CoV-2 dan kinderen van andere leeftijden, omdat hun immuunsysteem nog "naïef"/ongetraind is (The role of children in the spread of COVID-19: Using household data from Bneik Brak, Israel, to estimate the relative susceptibility and infectivity of children, MedRxiv, 11 oktober 2020). Duidelijk is dat de ernst van COVID-19 onder kinderen niet moet worden onderschat. Daar komt bij dat de American Academy of Pediatrics in de afgelopen 2 weken een toename van 12% van het aantal besmettingsgevallen onder kinderen heeft geconstateerd (Children and COVID-19: State Data Report, 28 januari 2021). Deze trend, die in 49 staten in de VS is waargenomen, kan indicatief zijn voor de internationale gemeenschap.

Het is bekend dat COVID-19 onder kinderen gedurende de infectieperiode of ná herstel van het virus een hyperinflammatoir syndroom kan veroorzaken, dat wordt gekenmerkt door symptomen die gelijkenis hebben met Kawasaki (SARS-CoV-2-Induced Kawasaki-Like Hyperinflammatory Syndrome: A Novel COVID Phenotype in Children, Pediatrics Vol. 146, Issue 2, 1 Augustus 2020; zie ook “An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study, Lancet Vol. 395, Issue 10239, P1171-1178, 6 Juni 2020”).

Internationale studies melden dat bij voordien gezonde kinderen en jongeren Multisystemische Inflammatoire Syndromen met kenmerken van Kawasaki of Toxic Shock Syndrome geassocieerd met COVID-19 werden gerapporteerd (Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City, JAMA 2020;324(3):294-296; zie ook "Autoimmune and inflammatory diseases following COVID-19, Nature Reviews Rheumatology2020, 4 Juni 2020: 1-2"). Dit syndroom, Multisystem Inflammatory Syndrome in Children (MIS-C) is thans onderwerp van intensief internationaal onderzoek; in de Verenigde Staten zijn op dit moment 1659 gevallen van MIS-C gemeld, waarvan 26 kinderen zijn overleden (Health Department, Reported Cases of Multisystem Inflammatory Syndrome in Children in the United States, CDC, 8 januari 2021).

In november 2020 werd een schokkend bericht geplaatst over een driejarig kind dat lymfatische leukemie heeft opgelopen als gevolg van een coronavirus-infectie (Acute lymphoblastic leukemia onset in a 3-year-old-child with COVID-19, Pediatric Blood & Cancer Vol. 67, Issue 11 , November 2020). Dit kind had geen onderliggende medische aandoening, wat erop duidt dat de toxiciteit van het coronavirus zodanig is dat het ernstige aandoeningen bij kinderen kan veroorzaken. Een Frans onderzoek meldt twee casus van een 16-jarige jongen en een 6-jarig kind zonder medische aandoening, gediagnosticeerd met COVID-gerelateerde hersendood (Severe and fatal forms of COVID-19 in children, Archives de Pédiatrie Vol. 27, Issue 5, July 2020 , P235-238). 

COVID-19 wordt gekenmerkt door het optreden van (micro)trombose bij alle leeftijdscategorieën. Een studie die is gepubliceerd in december 2020, toont aan dat trombotische microangiopathie (TMA) kan optreden bij met SARS-CoV-2 geïnfecteerde kinderen, zelfs als het kind géén ernstige COVID-19 heeft. Bij zowel kinderen met minimale COVID als ernstige COVID en bij kinderen met MIS-C bleken markers voor trombose significant verhoogd te zijn. Complementactivering is een belangrijke marker  voor trombotische microangiopathie bij kinderen. In het bijzonder worden complementfactoren C5b-9 (MAC), die door het lichaam worden afgegeven om het coronavirus te bestrijden, geassocieerd met trombose bij kinderen met COVID-19. Kortom: ook bij kinderen die niet of nauwelijks last hebben van COVID-klachten, kan trombose optreden (Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations, Blood Advances Vol. 4, Issue 23, December 08 2020).

2. Virale lading van SARS-CoV-2 bij kinderen
Een studie die is gepubliceerd op 1 december 2020, toont dat de virale lading van het coronavirus (SARS-CoV-2) in de nasopharyngeale holte (keelneusholte) bij kinderen gelijk is aan de virale lading in de keelneusholte van volwassenen die moeten worden geïntubeerd vanwege COVID-19. De virale lading bij asymptomatische kinderen met een coronavirusinfectie is hoger dan de virale lading bij volwassenen die vanwege COVID-19 in het ziekenhuis zijn opgenomen en reeds 7 dagen symptomatisch zijn. Dat kinderen het coronavirus asymptomatisch verspreiden, moet dringend worden erkend en met adequate maatregelen (afstand, mondneusmaskers, adequate ventilatie en onderwijs op afstand) worden beantwoord om de SARS-CoV-2-pandemie te kunnen bestrijden (Pediatric Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Clinical Presentation, Infectivity and Immune Responses, Journal of Pediatrics Vol. 227, P45-52, 1 december 2020).

3. Infectiviteit en presymptomatische verspreiding door kinderen
Recentelijk is een grote cohortstudie die een periode van zes maanden aan onderzoek bestrijkt, gepubliceerd. Het gaat om een analyse van meer dan 27.000 huishoudens. Hoewel kinderen ook volgens deze studie minder vatbaar zijn voor het ontwikkelen van COVID-19, blijken kinderen tussen de 0-20 jaar, 60% meer bij te dragen aan verspreiding van het virus binnen gezinsverband, dan volwassenen boven de 60 jaar. Het in speciale quarantainevoorzieningen plaatsen van gezinnen met geïnfecteerde kinderen heeft de verspreiding binnen gezinsverband drastisch gereduceerd.

Presymptomatische infectiegevallen (besmette personen die zich bevinden in de incubatietijd, de tijd tussen infectie en het optreden van symptomen/gezondheidsklachten) blijken 40% meer bij te dragen aan de verspreiding van het coronavirus dan symptomatische gevallen (besmette personen met gezondheidsklachten). De relatief hoge infectiviteit van kinderen binnen gezinsverband maakt dat heropening van scholen en kinderopvangcentra zorgvuldig moet worden overwogen. Verzorgers van zeer jonge kinderen moeten prioriteit krijgen ten aanzien van bescherming, omdat kinderen die nog niet eerder infecties hebben doorgemaakt, vatbaar zijn voor besmetting met het coronavirus (Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study, Lancet Infectious Diseases, 18 januari 2021).

4. Indexgevallen
Het Morbidity and Mortality Weekly Report van het CDC meldt clusters van coronabesmettingen die in verband worden gebracht met kinderdagverblijven. In de drie geanalyseerde kinderdagverblijven werd een volwassen persoon, een medewerker van het kinderdagverblijf, aangewezen als indexgeval. Die kinderen die door de indexpersoon op kinderdagverblijf zijn besmet, hebben het virus aan personen binnen het gezin overgebracht. In één geval heeft een kind van 8 maanden oud het coronavirus na besmetting op het kinderdagverblijf, aan de ouders doorgegeven. Het CDC beveelt aan kinderen vanaf 2 jaar oud en medewerkers van kinderdagverblijven een mondneusmasker te laten dragen (Transmission Dynamics of COVID-19 Outbreaks Associated with Child Care Facilities- Salt Lake City, Utah, April-July 2020, Morbidity and Mortality Weekly Report, 18 September 2020;69(37):1319-1323).

National Geographic maakt melding van een IJslandse studie, nog te publiceren, die is uitgevoerd in samenwerking met deCODE. Volgens National Geographic wijst de studie uit dat kinderen voor de helft zo vaak worden geïnfecteerd met SARS-CoV-2 en het coronavirus voor de helft zo vaak verspreiden als volwassenen. De boodschap van zowel de grote cohortstudie als die van de IJslandse studie is evenwel eenduidig: een school kan niet veilig open, als de graad van gemeenschapstransmissie ("community transmission") hoog is. Scholen blijven vatbaar voor uitbraken/clustervorming van corona-infecties. Als scholen heropend worden, wordt gedeeltelijke heropening overwogen; het gaat daarbij níet om volle klaslokalen (Exclusive: Kids catch and spread coronavirus half as much as adults, Iceland study confirms, National Geographic, 10 december 2020).

Resumerend
- Kinderen tussen de 0-1 jaar oud zijn vatbaar voor infectie met het coronavirus, omdat zij nog geen getraind immuunsysteem hebben;
- De American Academy of Pediatrics heeft in de afgelopen 2 weken een toename van 12% van het aantal besmettingsgevallen onder kinderen geconstateerd;
- De virale lading bij asymptomatische kinderen met een coronavirusinfectie is hoger dan de virale lading bij volwassenen die vanwege COVID-19 in het ziekenhuis zijn opgenomen en reeds 7 dagen symptomatisch zijn;
- Kinderen tussen de 0-20 jaar blijken 60% meer bij te dragen aan verspreiding van het virus binnen gezinsverband, dan volwassenen boven de 60 jaar;
- Presymptomatische infectiegevallen dragen 40% meer bij aan de verspreiding van het coronavirus dan symptomatische gevallen;
- Dat kinderen het coronavirus asymptomatisch verspreiden, moet dringend worden erkend en met adequate maatregelen (afstand + mondneusmaskers + adequate ventilatie en onderwijs op afstand) worden beantwoord om de SARS-CoV-2-pandemie te kunnen bestrijden;
- De relatief hoge infectiviteit van kinderen binnen gezinsverband maakt dat heropening van scholen en kinderopvangcentra zorgvuldig moet worden overwogen. Verzorgers van zeer jonge kinderen moeten prioriteit krijgen ten aanzien van bescherming, omdat kinderen die nog niet eerder infecties hebben doorgemaakt, vatbaar zijn voor besmetting met het coronavirus;
- Het CDC beveelt aan kinderen vanaf 2 jaar oud en medewerkers van kinderdagverblijven een mondneusmasker te laten dragen;
- Een school kan niet veilig open, als de graad van gemeenschapstransmissie ("community transmission") hoog is. Scholen blijven vatbaar voor uitbraken van corona-infecties en als scholen heropend worden, wordt gedeeltelijke heropening aangeraden.





dinsdag 20 oktober 2020

SARS-CoV-2/COVID-19 Hypercoagulation, thrombosis, embolism and urokinase pathways: an up-to-date research collection

Haemostasis and vasculature: COVID-19 characterized by thrombosis and hypercoagulability

 
Below is a classic collection of verified and updated thrombosis research. I have selected sources that are applicable to COVID-19 as well as to mechanisms of coagulopathy in general.

ADAMTS-13's failure to cut Von Willebrand Factor (VWF)
ADAMTS13 activity, Von Willebrand Factor, Factor VIII and D-dimers in COVID-19 inpatients, Thrombosis Research 2020 Aug; 192: 174-175;
Targeting VWF levels and macrophage activation in severe COVID-19: Consider low volume plasma exchange and low dose steroid, Thrombosis Research 2020 Aug; 192:2;

Aspirin (Acetylsalicylic acid) use and cardiovascular management of COVID-19
Apirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19, Anesthesia & Analgesia: October 21, 2020;
Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19?, Drugs 80, 1383-1396(2020);

Antiviral agents and interaction with anticoagulant drugs
Direct oral anticoagulants (DOAC) plasma levels' striking increase in severe COVID-19 patients treated with antiviral agents: The Cremona experience, Journal of Thrombosis and Haemostasis 2020 May 6;

Capillary hypertension

Effect of Coronavirus Disease 2019 in Pulmonary Circulation. The Particular Scenario of Precapillary Pulmonary Hypertension, Diagnostics (Basel) 2020 Aug; 10(8): 548;

Cardiovascular complications in COVID-19
Right Atrial Thrombus in Transient in a COVID-19 Patient: Clinical Echocardiographic Features--Case Report and Literature Review, SN Comprehensive Clinical Medicine 2020 Oct 8: 1-3;
Cardiovascular Implications of Patients with COVID-19, JAMA Cardiology 2020 Jul;5(7):1-8;
Coronavirus and Cardiovascular Disease, Myocardial Injury and Arrhytmia (all factors explained), JACC 2020 Oct 27; 76(17): 2011-2023;
COVID-19, myocardial edema and dexamethasone, Medical Hypotheses Vol. 145, December 2020;
Rescue venoarterial extracorporeal membrane oxygenation (ECMO) after cardiac arrest in COVID-19 myopericarditis, Cardiovascular Revascularization Medicine, 30 September 2020;

Acute myocardial injury is common in patients with COVID-19 and impairs their prognosis, BMJ Heart 2020 Aug; 106(15): 1154-1159;

COVID-19 Coagulopathy (CAC)
Coagulopathy in COVID-19: Focus on vascular thrombotic events, Journal of Molecular Cell Cardiology 2020 Sep; 146: 32-40;
SARS-CoV-2 and coagulation disorders in different organs, Life Science 2020 Nov 1; 260: 118431;
The coagulopathy, endotheliopathy and vasculitis of COVID-19, Inflammation Research 2020 Sep 12: 1-9;
Coagulopathy in COVID-19, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2103-2109;
Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, Circulation 2020 Aug 11; 142(6): 611-614 (Note: PAI-1 and procoagulants are significantly elevated in COVID-19 as compared to other viruses);
Comment: checking for hyperhomocysteinemia in COVID-19, Journal of Thrombosis and Haemostasis, 08 October 2020;
Pulmonary intravascular coagulopathy in COVID-19 pneumonia, Lancet Rheumatology Vol. 2, Issue 8, E458, August 01, 2020;
The unique characteristics of COVID-19 coagulopathy, Critical Care 2020; 24: 360;

Coagulation markers
Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant (thrombin-antithrombin complex levels, TAT and plasmin-antiplasmin (PAP)), Journal of Thrombosis and Haemostasis, Vol. 18, Issue 9, September 2020, p2428-2430;

COVID-19 thrombotic activity: pathogenesis of coronavirus SARS-CoV-2

Characterization of heparin and SARS-CoV-2 Spike glycoprotein binding interactions, Antiviral Research Vol. 181, September 2020, 104873;
Multifactorial pathogenesis of COVID-19-related coagulopathy. Can defibrotide have a role in the early phases of coagulation disorders?, Journal of Thrombosis and Haemostasis, 21 July 2020;
Thrombotic Complications in Patients with COVID-19: Pathophysiological Mechanisms, Diagnosis and Treatment, Cardiovascular Drugs and Therapy Journal 2020 Oct 19: 1-15;
Pulmonary Arterial Thrombosis in COVID-19: Results from a Prospective, Single-Center, Clinicopathologic Case Series, Annals of Internal Medicine 2020 May 14;

Deep Vein Thrombosis (DVT)
Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2358-2363;
Response to: Incidence of DVT among non-ICU patients hospitalized for COVID-19 despite thromboprophylaxis: hypoxia as a clinically relevant risk for DVT needs further investigation;

Embolism

Late Pulmonary Embolism after COVID-19 Pneumonia Despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001790;
Pulmonary embolism: A complication of COVID-19 infection, Thrombosis Research 2020 Sep; 193: 79-82;
A Review of Venous Thromboembolism Phenomena in COVID-19 Patients, Current Problems in Cardiology 2020 Aug 28; 100692;
Pulmonary embolism in acute medicine: a case-based review incorporating latest guidelines in the COVID-19 era, British Journal of Hospital Medicine Vol. 81, Issue 6, 2 June 2020;
Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence (thrombosis in coronavirus is similar to SARS-1 (2003), differs from influenza; low incidence of DVT suggests pulmonary thrombosis rather than embolism), Circulation, Vol. 142, Issue 2, July 14, 2020;
COVID-19 Complicated by Acute Pulmonary Embolism, Radiology: Cardiothroracic Imaging Vol. 2, nr. 2, 2020;
Diagnosis and Treatment of Pulmonary Embolism During the COVID-19 Pandemic, Chest Journal, August 26, 2020;

Fibrinolysis
Fibrinolysis and COVID-19: A plasmin paradox, Journal of Thrombosis and Haemostasis Vol. 18, Issue 9, September 2020, p2118-2122;
Study of alteplase for respiratory failure in SARS-CoV-2/COVID-19: Study design of the phase IIa STARS trial, Journal of Research and Practice in thrombosis and haemostasis Vol. 4, Issue 6, August 2020, p984-996;

Hypercoagulability
In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis Vol. 18, Issue 10, October 2020, p2646-2653;
COVID-19 versus HIT (heparin-induced thrombocytopenia) hypercoagulability, Thrombosis Research  2020 Dec; 196: 38-51;
Hypercoagulability of COVID-19 patients in Intensive Care Unit: A report of thromboelastography findings and other parameters of hemostasis, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1738-1742;
Immunothrombosis in the Pathogenesis of COVID-19 Coagulopathy (CD177 and NET upregulation in severe COVID-19), NEJM Journal Watch, August 17, 2020;

Immunothrombosis

Immunothrombotic Dysregulation in COVID-19 Pneumonia is Associated With Respiratory Failure and Coagulopathy (granulocytes, neutrophils and platelets), Circulation Vol. 142, Issue 12, September 22, 2020;

Interleukin-1 (IL-1) and Thromboxane induction
IL-I induces Thromboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL1-receptor antagonist (IL-1Ra), Journal of Biological Regulators and Homeostatic Agents 2020 Aug 3;34(5);
Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19, Journal of Biological Regulators and Homeostatic Agents 2020 Sep 18;34(5);

Long-term cardiovascular damage by COVID-19

Outcomes of Cardiovascular MRI'ing in Patients Recently Recovered from COVID-19, JAMA Cardiology, July 27, 2020;
Long-term Health Consequences of COVID-19, JAMA, October 5, 2020;

Microthrombosis in COVID-19
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications, Circulation Research 2020 Jul 31; 127(4): 571-587;

Platelet responses
COVID-19 patients exhibit reduced procoagulant platelet responses, Journal of Thrombosis and Haemostasis, 18 September 2020;

RAAS (Renin-Angiotensin-Aldosterone System) and cardiovascular circulatory disease
β-Arrestin-Biased Angiotensin II (Ang II) Receptor Agonists for COVID-19, Circulation Vol. 142, Issue 4, July 28, 2020;

Sepsis

The Role of Microvascular Thrombosis in Sepsis, Anaesthesia and Intensive Care Vol. 32, Issue 5, October 1, 2004;

Stroke
SARS-CoV-2 infection and its association with thrombosis and ischemic stroke: A review, The American Journal of Emergency Medicine, 30 September 2020;

Thrombocytopenia
Exploring possible mechanisms for COVID-19 induced thrombocytopenia: Unanswered questions, Journal of Thrombosis and Haemostasis Vol. 18, Issue 6, June 2020, p1514-1516;

Treatment options and management

Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory, Thrombosis Journal 2020; 18: 17;
Plasminogen improves lung lesions and hypoxemia in patients with COVID-19, QJM: An International Journal of Medicine Vol. 113, Issue 8, August 2020, p539-545;
Tissue plasminogen activator (tPA) treatment for COVID-19 associated ARDS: A case series, Journal of Thrombosis and Haemostasis Vol. 18, Issue 7, July 2020, p1752-1755;
The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection in Vitro in a Cell-Type-Dependent Manner, MDPI Viruses 2020 Jun; 12(6):629;
Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID-19, British Journal of Haematology Vol. 190, Issue 5, September 2020, p286-288;
IL-1 induces thromboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra), Journal of Biological Regulators and Homeostatic Agents 2020 Aug 3;34(5);
Rescue venoarterial extracorporeal membrane oxygenation (ECMO) after cardiac arrest in COVID-19 myopericarditis, Cardiovascular Revascularization Medicine, 30 September 2020;
Apirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In-Hospital Mortality in Hospitalized Patients with COVID-19, Anesthesia & Analgesia: October 21, 2020;
Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19?, Drugs 80, 1383-1396(2020);

Urokinase pathways towards thrombotic activity
Hypoxia Stimulates Urokinase Receptor Expression Through a Heme Protein-Dependent Pathway, ASH Blood Journal Vol. 91, Issue 9, May 1, 1998;

V and X Factors and therapeutic inhibition options

(Xa Factor) Response to "Studies on hemostasis in COVID-19 careful reporting of the laboratory methods, their significance and their limitation": don't throw the baby out with the bathwater (on testing with anti-Xa kit), Journal of Thrombosis and Haemostasis, 28 August 2020;
Dual inhibition of Factor XIIa and Factor XIa as a therapeutic approach for safe thromboprotection, Journal of Thrombosis and Haemostasis, 12 October 2020;
COVID-19 and Blood Clots (Factor V activity strongest among all clinical parameters), Harvard News & Research September 09, 2020;

maandag 19 oktober 2020

Extensive reading recommendations on SARS-CoV-2/COVID-19: all mechanisms involved (Part 6)


Factors involved in SARS-CoV-2/COVID-19

Activated endothelium as a source of Acute Lung Injury (ALI)/ARDS
Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients, BMJ Thorax Journal Vol 63, Issue 10, October 2008;
Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS
, Pulmonary Circulation 2018 Apr-Jun; 8(2);

Acute Lung Injury (ALI)
A Perspective on Erythropoietin as a Potential Adjuvant Therapy for Acute Lung Injury (ALI)/ARDS in Patients with COVID-19, Archives of Medical Research 2020, Aug 11;

Coagulation
Thromboinflammation and the hypercoagulability of COVID-19, Journal of Thrombosis and Haemostasis, 13 April 2020;

Embolism
Pulmonary embolism in COVID-19 patients: a French multicentre cohort study, European Heart Journal Vol. 41, Issue 32, 21 August 2020, p3058-3068;

Hypoxia and HIF as a link between sepsis and thrombosis
Hypoxia and HIF activation as a possible link between sepsis and thrombosis, Thrombosis Journal 2019; 17: 16;
The stimulation of thrombosis by hypoxia, Thrombosis Research Vol. 181, p77-83, September 01, 2019;
Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19, Clinical Kidney Journal 2020 Aug; 13(4): 494-499;
Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage, Clinical and Experimental Immunology, Journal of Translational Immunology, 26 September 2020;
COVID-19: hemoglobin, iron and hypoxia beyond inflammation: A narrative review, Clinics and Practice 2020 May 19; 10(2): 1271;
miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target, Angiogenesis 2018; 21(2): 183-202;

Hypoxia and Reactive Oxygen Species (ROS) (oxidative stress)
Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia, Journal of Molecular Medicine 2007 Dec;85(12):1309-15;
Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema (curcumin as a NFkB blocker attenuates hypoxia-induced edema), Experimental Biology and Medicine Vol. 233, Issue 9, 2008;

Pathogenesis and structure of SARS-CoV-2
Does the pathogenesis of SARS-CoV-2 decrease at high-altitude?, Respiratory Physiology & Neurobiology Vol. 277, June 2020;
Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein, MDPI Viruses 2012 Jun;4(6): 1011-1033;
Structure, Function and Evolution of Coronavirus Spike Proteins, Annual Reviews Virology 2016 Sep 29; 3(1): 237-261;
Cleavage of the SARS Coronavirus Spike Glycoprotein by Airway Proteases Enhances Virus Entry into Human Bronchial Epithelial Cells in Vitro, PLoS 2009; 4(11): e7870;

Pattern Recognition Receptors, Interferon pathways and cytokine cascades
Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage, Clinical and Experimental Immunology, Journal of Translational Immunology, 26 September 2020;

Pulmonary vascular (right ventricular) consequences of COVID-19

Novel insights on the pulmonary vascular consequences of COVID-19, Lung Cellular and Molecular Physiology 2020 Aug 1; 319(2): L277-288;

Sepsis
Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular thrombotic disease, Thrombosis Journal 2019; 17: 10;
Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS, Pulmonary Circulation 2018 Apr-Jun; 8(2);

Therapeutics and possible treatment options for COVID-19

Oxytocin as a Potential Adjuvant against COVID-19 Infection, Endocrine, Metabolic & Immune Disorders Drug Targets 2020, Sep 10;
Prophylactic efficacy of Quercetin in ameliorating the hypoxia induced vascular leakage in lungs of rats, PLoS One 2019; 14(6);
Nifedipine inhibits hypoxia induced transvascular leakage through downregulation of NFkB, Respiratory Physiology & Neurobiology Vol. 183, Issue 1, 31 July 2012, p26-34;

zaterdag 17 oktober 2020

Extensive reading recommendations on SARS-CoV-2/ COVID-19: all mechanisms involved (Part 5)

So many factors involved! A non-exhaustive overview of factors involved in COVID-19

ADAMTS-13

All complications of COVID-19

Overview of lethal human coronaviruses, Signal Transduction and Targeted Therapy 2020; 5: 89;

B cell profiles
Illuminating vitamin D effects on B cells- the Multiple Sclerosis perspective, Immunology 2016 Mar; 147(3): 275-284;

Cardiovascular complications of COVID-19
Anticipating the long-term cardiovascular effects of COVID-19, Journal of Thrombosis and Thrombolysis 2020 Sep 3: 1-13;
COVID-19 and Heart Failure With Preserved Ejaction Fraction, JAMA September 30, 2020;

Coagulation
Unique transcriptional changes in coagulation cascade genes in SARS-CoV-2 infected lung epithelial cells: A potential factor in COVID-19 coagulopathies, NIH MedRvix Preprint, 2020 Jul 7;
COVID-19 and Coagulopathy:  FAQ, ASH 24 September 2020;

Development of therapeutics for COVID-19

Challenging pathway towards the identification of SARS-CoV-2/COVID-19 therapeutics, Journal of Antimicrobial Chemotherapy Vol. 75, Issue 9, September 2020, p2381-2383;
COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks, International Journal of Molecular Sciences 2020 Jul; 21(14): 4953;
SARS-CoV-2/COVID-19 and advances in developing potential therapeutics and vaccines to counter this emerging pandemic, Annals of Clinical Microbiology and Antimicrobials 2020; 19: 40;
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing, Nature 586, 113-119(2020);

Embolism
COVID-19 and Pulmonary Embolism: FAQ, 22 September 2020;

Immunology
T-helper type I cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells, Nutrition Vol. 23, Issue 2, February 2007, p157-163;
Zinc signals and immune function (NK-, T- and B-cells), BioFactors Vol. 40, Issue 1, January/February 2014, p27-40;

Inflammatory response to SARS-CoV-2 in COVID-19

Understanding COVID-19: From Origin to Potential Therapeutics, International Journal of Environmental Research and Public Health 2020 Aug;17(16): 5904;

Inhibitors to explore
Coronaviruses and Nature's Pharmacy for the Relief of COVID-19 (inhibitory properties of natural compounds), Revista Brasileira de Farmacognosia 2020 Oct 6: 1-19;

Interferon
Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells is Associated with Viral Antagonism of STAT1 Phosphorylation, The Journal of Infectious Diseases Vol. 222, Issue 5, 1 September 2020;
Auto-antibodies against type I IFNs in patients with life-threatening COVID-19, AAAS Science, 24 Sep 2020 (treatment with injected or nebulized IFN-β may have beneficial effects);

Macrophages
Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells is Associated with Viral Antagonism of STAT1 Phosphorylation, The Journal of Infectious Diseases Vol. 222, Issue 5, 1 September 2020;

Nsp3 and STAT1 in cytokine storm syndrome
A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19, Viruses 2020 Jun; 12(6): 646;

Oxidative Stress
Zinc status is associated with inflammation, oxidative stress, lipid and glucose metabolism, The Journal of Physiological Sciences 2018; 68(1): 19-31;
Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease, Verhandelingen van de Koninklijke Academie voor Geneeskunde van België 2008;70(3):193-219;

Pathogenesis, evolution and structure of SARS-CoV-2
Rampant C > U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for their Short- and Long-Term Evolutionary Trajectories, mSphere 2020 May-Jun; 5(3);
Mutation Patterns of Human SARS-CoV-2 and Bat RATG13 Coronavirus Genomes are Strongly Biased Towards C > U Transitions, Indicating Rapid Evolution in Their Hosts, Genes (Basel.) 2020 Jul; 11(7):761;
Molecular epidemiology, evolution and phylogeny of SARS coronavirus, Infection, Genetics and Evolution 2019 Jul; 71: 21-30;
Overview of lethal human coronaviruses, Signal Transduction and Targeted Therapy 2020; 5: 89;
2017 Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus, PLoS Pathogens 2017 Nov;13(11);
Signal hotspot mutations in SARS-CoV-2 evolve as the virus spreads and actively replicates in different parts of the world, Virus Research 2020 Nov; 289: 198170;

Possible treatment options
Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19, MDPI Nutrients 2020, 12(8), 2358;
Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, MDPI Nutrients 2020, 12(9), 2738;
A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection, Frontiers in Immunology 2020; 11:1736;
Statin therapy and SARS-CoV-2: an available and potential therapy?, European Heart Journal of Cardiovascular Pharmacotherapy 2020, May 7 2020;
Nutraceuticals have potential for boosting the Type I Interferon (IFN) response to RNA viruses, including influenza and coronavirus, Progress in Cardiovascular Diseases 2020 May-June; 63(3): 383-385;
Azithromycin and Glucosamine May Amplify the Type I Interferon (IFN) Response to RNA viruses in a complementary fashion, Immunology Letters 2020 Sep 28;

Sepsis and septic shock
Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease, Thrombosis Journal 2019; 17: 10;

donderdag 8 oktober 2020

Thromboinflammation and hypercoagulation in COVID-19 patients: slides

COVID-19 is known for its highly (pro)thrombotic events following SARS-CoV-2 infection. Ultimately, disruption of the vasculature results in multiple organ failure and long-term COVID-19 related cardiorespiratory damage. While both host immunity and inflammatory and pathogenic features of this SARS-Coronavirus contribute to vascular injury, it is the virus that is the cause of the thromboinflammatory state that characterizes COVID-19. In the following slides, I will describe the mechanisms underlying thrombotic events in COVID-19 patients.

Markers to assess the thromboinflammatory state of COVID-19 patients
Thrombocyopenia in COVID-19: while values are normal at the time of hospital admission, thrombocytopenia appears as a progressive feature
Dysregulation of thrombin and fibrin in COVID-19
Urokinase pathway involvement in COVID-19 thrombosis

maandag 5 oktober 2020

A remaining challenge: hypercoagulability characterizing COVID-19, despite anticoagulation practices

Mechanisms of coagulation and thrombosis in COVID-19
 

Over the past eight months it has become increasingly clear that COVID-19 is characterized by hypercoagulation and thromboinflammation. The pathogen SARS-CoV-2 itself, the innate host immunity response, haemostatic factors, the Renin-Angiotensin-Aldosterone System (RAS/RAAS) and the complement system are wired up to evoke a procoagulant, thromboinflammatory state in COVID-19 affected patients. The mechanisms enhance thromboinflammation and reduce fibrinolysis (the breakdown of clots). 

A few reports indicate that the hypercoagulant state in COVID-19 remains, in spite of thromboprophylaxis. In an early report, Deep Venous Thrombosis (DVT) was observed among non-Intensive Care Unit patients receiving thromboprophylaxis with either enoxaparin or fondaparinux (Incidence of deep vein thrombosis among non-ICU patients for COVID-19 despite pharmacological thromboprophylaxis, Journal of Thrombosis and Haemostasis 2020;18:2358-2363). 

Another, more recent study reports ongoing activation of coagulation and fibrinolysis despite low therapeutic anticoagulation in COVID-19 patients. Hypofibrinolytic states (impairment of the breakdown of fibrin clots) occur, even in the presence of Low Molecular Weight Heparin (LMWH). It is hypothesized that low therapeutic anticoagulant therapies are insufficient to downregulate coagulation activation in COVID-19 (In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis 2020;18:2646-2653). 

Keeping it simple: is it just the case that prophylaxis at hospital admission is too late?
One key factor, a major factor, might be explanatory for ongoing thromboinflammation, the occurrence of Deep Venous Thrombosis (even after hospital discharge) and hypercoagulation in spite of prophylaxis: time. 

I hypothesize that the administration of thromboprophylaxis might be too late to curb already ongoing thrombotic activity in the vasculature, as thromboprophylaxis is received at the time of hospital admission, which is a main of 4 to 5 days after SARS-CoV-2 infection. If thromboinflammation occurs before or a few days from the onset of symptoms, thromboprophylaxis fails to break down fibrin accumulation and stabilized fibrin structures in the microvasculature. Markedly, a study involving 107 SARS-CoV-2 infected patients, chronic use of anticoagulation is associated with decreased thrombotic complications typical for COVID-19. Only 17 out of 107 chronically anticoagulated patients required Intensive Care (Chronic therapeutic anticoagulation is associated with decreased thrombotic complications in SARS-CoV-2 infection, Journal of Thrombosis and Haemostasis Vol. 18, Issue 10, October 2020, p2640-2645).

Nevertheless, questions on timing of thromboprophlaxis and therapeutic options for non-chronic anticoagulated COVID-19 remain to addressed. This is further complicated by a recent finding.

Pathogenesis of SARS-CoV-2: how this coronavirus impairs anticoagulation therapies
A recent finding is that the S-protein (spike) of SARS-CoV-2 binds heparin and heparan sulfate (Characterization of heparin and SARS-CoV-2 spike glycoprotein binding interactions, Antiviral Research Vol. 181, September 2020, 104873), which explains why heparin prophylaxis according to standard-dose LMWH or Unfractioned Heparin (UFH) is insufficient to reduce thrombotic activity in COVID-19 patients. The effect of nebulized heparin is under investigation.

A key role for hypoxia?
There are several topics to address. The timing and dose of anticoagulation therapies or thromboprophylaxis are essential, but mechanisms underlying thromboinflammation might offer insight into the presumed ongoing procoagulant state in COVID-19. Hypoxia and Hypoxia-inducible transcription factors (HIF) are a possible link between viral sepsis and thrombosis (Hypoxia and HIF activation as a possible link between sepsis and thrombosis, Thrombosis Journal 2019; 17: 16). The need for research of hypoxia as a trigger for thrombosis is expressed (Hypoxia- an overlooked trigger for thrombosis in COVID-19 and other critically ill patients, Journal of Thrombosis and Haemostasis, 29 July 2020; Incidence of Deep Vein Thrombosis among non-ICU Patients Hospitalized for COVID-19 Despite Pharmacological Prophylaxis: Response).

Making the shift towards more distinctive parameters to assess hypercoagulation: urokinase markers
Shifting towards distinctive parameters is recommended to provide more therapeutic targets. The urokinase pathway offers specific markers to assess the fibrinolytic state of a patient. PAP (plasmin-antiplasmin) and TAT (thrombin-antithrombin) as well as tPAI-C (tissue plasminogen activator-plasminogen activator inhibitor 1 complex) are the suggested specific markers to improve anticoagulation practice (Specific coagulation markers may provide more therapeutic targets in COVID-19 patients receiving prophylactic anticoagulant, Journal of Thrombosis and Haemostasis, 25 June 2020).

Noteworthy, an article published in ASH Blood from 1 May 1998 reviews the role of hypoxia in stimulating the urokinase-type plasminogen activator (uPAR) receptor, thereby enhancing cellular invasion (Hypoxia Stimulates Urokinase Receptor Expression Through a Heme Protein-Dependent Pathway, ASH Blood (1998) 91 (9):3300-3307).