Het "ongebruikelijke" karakter van Heparine-geïnduceerde trombocytopenie (HIT) deel I: Platelet Factor 4 (PF4)/Heparine-complexen en "pseudo-HIT"

Wat is HIT?
Heparine-geïnduceerde trombocytopenie wordt gedefinieerd als een daling in het aantal bloedplaatjes van 50% of meer. HIT treedt meestal binnen 5-10 dagen na toediening van heparine op. Type I HIT komt door niet-immuungerelateerde activering van bloedplaatjes. Type I verloopt meestal niet ernstig. Type II HIT komt door activering van bloedplaatjes door het immuunsysteem (Greinacher, in: Platelets Fourth Edition, 2019). De binding van HIT-antilichamen aan bloedplaatjes zorgt voor overactivering van bloedplaatjes, waarbij trombine wordt gegenereerd. Dit mechanisme kan trombose veroorzaken.

De inaccuratie van "HIT": soms treedt HIT al op vóórdat heparine is toegediend
Er wordt terughoudend omgegaan met het voorschrijven van heparinederivaten in het geval een bloedstollingsstoornis voldoet aan de belangrijkste kenmerken van HIT. Het probleem met de diagnose "HIT", is dat HIT niet altijd HIT is. Al meer dan twintig jaar wordt in de literatuur met regelmaat gesproken van gevallen van "pseudo-HIT". Bij een échte, klassieke HIT ontwikkelt de patiënt een tekort aan bloedplaatjes na toediening van heparine. Soms heeft de patiënt niet eerder heparine ontvangen, waardoor eigenlijk niet van een "klassieke HIT" kan worden gesproken. Toch is het onderscheid van belang voor het bepalen van het juiste antistollingsbeleid. De toediening van heparine zou de situatie namelijk erger maken: door meer bloedplaatjes te activeren, wordt meer trombine aangemaakt, met bloedstolsels en het risico op een embolie tot gevolg.

Heparine-geïnduceerde trombocytopenie (HIT) wordt veroorzaakt door de activering van bloedplaatjes in reactie op Immunoglobuline G-antilichamen (IgG-antilichamen). De IgG-antilichamen herkennen complexen van Platelet Factor 4 (PF4), die zich binden aan heparine of negatief geladen polymeren, "polyanions". De chemokine Platelet Factor 4 (ook wel CXCL4) komt vrij tijdens de activering van bloedplaatjes. HIT Immunoglobuline-antilichamen (IgG Ab) activeren bloedplaatjes. Alléén IgG-antilichamen kunnen binden aan FcgRII-receptoren op bloedplaatjes. Het Fab-gedeelte van HIT-IgG-antilichamen bindt aan FP4-heparine en het Fc-gedeelte van HIT-IgG verbindt zich met de FcRII-receptor op de bloedplaatjes. Dit mechanisme stimuleert bloedplaatjesaggregatie en vrijgekomen PF4 bindt nog meer heparine, om vervolgens meer antigenen te vormen op de bloedplaatjes (Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and resultant platelet activation, Blood: Hemostasis, Thrombosis and Vascular Biology Vol. 96, Number 1, 1 juli 2000).

Het stellen van de diagnose "HIT" gebeurt nadat het testen op heparine-afhankelijke, bloedplaatjesactiverende antilichamen die PF4/heparinecomplexen (PF4/H) herkennen, een positieve uitslag geeft. Dit is een functioneel assay. Het criterium is dat het assay (de test) zowel PF4 als activering van bloedplaatjes vaststelt. HIT-antilichamen hebben de eigenschap om bloedplaatjes te activeren en te binden aan PF4/heparinecomplexen. De complexiteit hierbij is dat een positieve test op PF4/H en HIT-antilichamen, gelijkenis vertoont met de detectie van het Antifosfolipide Antilichaamsyndroom (APS) en met de detectie van uitsluitend anti-PF4-antilichamen (Antiphospholipid and anti-PF4 antibodies: an association affecting anti-PF4/heparin assay analysis, Journal of Thrombosis and Haemostasis Vol. 7, Issue 7, Juli 2009). 

Sensitisatie: herkenning van antigenen na eerder doorgemaakte infecties
De anti-PF4/heparine-complex-immuunreactie komt veelvuldig voor in de chirurgische context: in 75% van de patiënten die een hartoperatie ondergaat, worden anti-PF4/H-antilichamen gemeten binnen 1 tot 2 weken na de operatie.

Het ongebruikelijke aan HIT is dat patiënten anti-PF4/H-IgG-antilichamen aanmaken binnen 4 dagen na een eerste toediening van heparine. Er moet dus sprake zijn van pre-immunisatie ten opzichte van PF4/heparine (Arepally, Nothing typical about HIT, Blood: Inside Blood Vol. 113, Issue 20, 14 mei 2009). Dat kan worden geïllustreerd aan de hand van mondbacteriën. Een zeer oud, misschien wel rudimentair mechanisme van de mens is om overdreven met anti-PF4-H-antilichamen te reageren op bacteriële infecties. PF4 bindt aan aërobe mondbacteriën, waardoor dezelfde antigenen worden ontwikkeld als bij PF4/Heparine-complexen. Eerder doorgemaakte tandvleesinfecties zorgen ervoor dat PF4 wordt herkend door HIT-antilichamen. Tandvleesontstekingen roepen anti-PF4/H-antilichamen op die bij een volgende infectie of operatie zorgen voor herkenning, "sensitisatie". Antigenen tegen PF4/Heparine-complexen die van nature in mensen voorkomen, zijn bovendien in staat om een breed spectrum aan bacteriën te herkennen.

Bij een verdenking van HIT wordt toediening van hoge doses heparine afgeraden om de volgende reden. Ongefractioneerde heparine (UFH) kan zich binden aan PF4/H-complexen. Het risico is dat een PF4/HIT-antigen ontstaat. Daarentegen hebben polysaccharide-anticoagulanten zoals Fondaparinux wél de neiging om anti-PF4/H-antilichamen op te roepen, maar niet om deze te binden aan PF4-complexen. Daarmee wordt HIT vermeden.

Greinacher & Warkentin, 2009
Een studie van Greinacher (de professor die het verband tussen de COVID-vaccins en trombotische trombocytopenie recentelijke aantoonde) uit 2009 toont aan dat de immuunreactie tegen PF4/heparinecomplexen verschilt van "klassieke" immuunreacties, in die zin dat het géén typische primaire immuunreactie is, waarbij in eerste instantie IgM antilichamen worden aangemaakt, gevolgd door een latere immuunrespons met IgG. Anders dan bij een typische primaire immuunrespons, wordt op dag 6 al een hoog niveau van IgG waargenomen. De reactie met antilichamen neemt snel af, zelfs bij toediening van heparine aan gevallen die kunnen worden getypeerd als "HIT". Dit maakt een typische secundaire immuunrespons onwaarschijnlijk.

Er worden meerdere verklaringen aangedragen. De ontwikkeling van antilichamen tegen PF4/heparine-complexen kan het resultaat zijn van een immuunreactie die niet afhankelijk is van T-cellen. In dat geval zouden B-cellen gestimuleerd worden door PF4/heparine-antigeen-complexen. Dit komt voor bij reacties op virussen die een repetitief patroon (van epitopen) hebben. Repetitieve patronen roepen een B-celreactie op zonder dat sprake is van activering van T-geheugencellen. De immuunrespons kan worden opgeroepen door eerdere blootstelling van PF aan glycosaminoglycanen, lange suikerketens die voorkomen in bindweefsel, kraakbeen en botten. Deze ketens worden normaal gesproken afgebroken om opstapeling van glycosaminoglycanen te voorkomen. Nog een factor die bijdraagt aan immunisering is hiervoor genoemd: dat zijn grote chirurgische ingrepen. Bij grote medische operaties worden bloedplaatjes geactiveerd, die voor ontwikkeling van lange complexen van PF4/heparine zorgen. In reactie op lange complexen van PF4/H, worden ook B-celreacties opgeroepen, onafhankelijk van T-geheugencellen.

Marginale B-cellen: B-cellen van het profiel "geen actieve herinnering"
Toch moet er een vorm van "geheugen" betrokken zijn de bij vorming van antilichamen tegen PF4/H. Pasgeborenen ontwikkelen na toediening van heparine, géén anti-PF4/H-complex-antilichamen. Dit betekent dat de immunisatie door heparine laag is bij pasgeborenen. In tegenstelling tot het "getrainde" immuunsysteem, is het immuunsysteem van pasgeborenen nog naïef. Een verklaring is dat "marginale" B-cellen, B-cellen zonder actieve herinneringen, gestimuleerd worden door de clustering van PF4 in reactie op bijvoorbeeld ontstekingen of zware operaties. De marginale B-cellen hebben géén actieve herinnering, maar worden geactiveerd door PF4/H-clusters en een ontstekingsreactie. Dit type B-cel, zonder actieve herinneringen, raakt binnen korte tijd betrokken bij de ontwikkeling van IgG-antilichamen, waarbij de marginale B-cellen ook binnen korte tijd weer inactief raken (Greinacher, Warkentin et al., The temporal profile of the anti-PF4/heparin immune response, Blood: Thrombosis and Haemostasis Vol. 113, Issue 20, 14 mei 2009). 

Anti-PF4/Heparine-antilichamen verdwijnen in de loop van 3 maanden, omdat géén geheugen-B-cellen met PF4/H-specifiteit worden aangemaakt. Omdat ze geen actieve herinnering hebben, hebben marginale B-cellen een tweede stimulus nodig om PF4/H-antilichamen van het type IgG te stimuleren. Referentie aan de studie over tandvleesontstekingen en het later optreden van PF4/Heparine-antilichamen door een tweede stimulus, bevestigt dit (Association with natural anti-platelet factor 4/heparin antibodies with periodontal disease, Blood: Platelets and Thrombopoiesis Vol. 118, Issue 5, 4 augustus 2011).

 

Extensive reading recommendations on SARS-CoV-2/COVID: all mechanisms involved (Part 1)

I this message, I will present you all the research papers on Coronavirus Disease 2019 (COVID) I have bookmarked since January 2020. These are extensive papers on SARS-CoV-1 (2003) and SARS-CoV-2 (2019) I have retrieved from the PubMeb database on NCBI and the Wiley Library.

 

All mechanisms involved in COVID-19

There is a ton of information on the mechanisms underlying SARS-CoV infection and the severity of COVID-19. This is the case because (a) SARS-CoV-2 is not entirely new, but shares great similarities with SARS-CoV-1 (2003) and (b) because not all mechanisms are exclusive to SARS' etiology, but are also seen in infections caused by other pathogens, ór, even common in systemic syndromes (say, for example, aHUS). Scientists do compare diseases and viruses, to reveal patterns in similarities and differences. Rarities can reveal a lot about mechanisms underlying other diseases. In short, thrombosis in pregnancy caused by a deficiency in ADAMTS-13, which leads to failure to cleave Von Willebrand Factor (VWF) and therefore contributes to extensive thrombus formation, is also seen in some severe (juvenile) cases of COVID.

Thus, systemic syndromes, common immunity and thromboinflammatory mechanisms need an in-depth view to find solutions to balance the key factors in COVID-19.

ACE2
ACE2 in the brain: properties and future directions, Journal of Neurochemistry 2008 Dec; 107(6): 1482-1494;
COVID-19 and relative ACE2 deficiency: a role in disease severity and therapeutic response, Open Heart 2020; 7(1): e001302;

ARDS
Pathophysiology of COVID-19 associated Acute Respiratory Distress Syndrome: a multicentre prospective observational study, Lancet Respiratory Medicine, August 27, 2020;
COVID-19 pneumonia: ARDS or not?, Critical Care 24, Art. No. 154 (2020);

Autophagy 
Autophagy during viral infection- a double-edged sword, Nature Reviews Microbiology 16, 341-354(2018);

Cardiovascular complications of SARS-CoV-2/COVID-19
Potential effects of coronaviruses on the cardiovascular system, JAMA Cardiology 2020;5(7):831-840;
SARS-CoV-2 and cardiovascular complications: From molecular mechanisms to pharmaceutical treatment, Biochemical Pharmacology 2020 Aug; 178: 114114;

Central Nervous System (CNS) complications caused by SARS-CoV-2
Cerebral Venous Thrombosis: A typical presentation of COVID-19 in the young, Journal of Stroke Cerebrovascular Disease 2020 August; 29(8): 104989;
Meningoencephalitis without respiratory failure in a young female patient with COVID-19 in Downtown Los Angeles, early April 2020, Brain Behavior and Immunology 2020 July;87: 33;
Pathophysiology of the COVID-19- entry to the CNS through the nose, Acta Oto-Laryngologica, 28 June 2020;
Cerebral Venous Sinus Thrombosis as a Presentation of COVID-19, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001691;
Extensive cerebral venous sinus thrombosis: a potential complication in a patient with COVID-19, BMJ Case Reports 2020; 13(8): e236820;

Coagulation
The role of type 1 Interferons (IFN) in coagulation induced by gram-negative bacteria, Immunobiology and Immunotherapy, Vol. 135, Issue 14, 2 April 2020;
Physiology, coagulation pathways;
Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with DAD, Journal of Clinical Investigation, 1989 July; 84(1);
Coagulation abnormalities and thrombosis in patients with COVID-19, Haematology, Vol. 7, Issue 6, E438-E440, June 01, 2020;
Coagulopathy in COVID-19, Journal of Thrombosis and Haemostasis, 2020;18:2103-2109;
In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation, Journal of Thrombosis and Haemostasis, 06 August 2020;
Changes in coagulation and fibrinolysis of post-SARS osteonecrosis in a Chinese population, International Orthopaedics 2006 June; 30(3): 143-146;
The Coagulation Factors Fibrinogen, Thrombin and Factor XII in Inflammatory Disorders- a Systemic Review, Frontiers Immunology, 26 July 2018;
Pulmonary intravascular coagulopathy in COVID-19 pneumonia, Lancet Rheumatology Vol. 2, Issue 8, E458-459, August 01, 2020;

Comparative tropism and transmission (profiling COVID)
Comparative tropism, replication kinetics and cell damage profiling of SARS-CoV-2 and SARS-CoV, Lancet Microbe, Vol. 1, Issue 1;

Cytokine cascade/cytokine release syndromes/cytokine storms
Analysis of cytokine profile and heme metabolism byproducts after hemorrhagic stroke, Critical Care 2013; 17(Suppl. 13), 19 June 2013;
The cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist Tocilizumab may be the key, International Journal of Antimicrobial Agents, Vol. 55, Issue 5, May 2020, 105954;
Cytokine release syndrome in severe COVID-19, Science, Vol. 368, Issue 6490, 01 May 2020;
Expansion of myeloid-derived suppressor cells in patients with severe COVID-19, Cell Death & Differentiation (2020), 08 June 2020;
The cytokine storm of severe influenza and development of immunomodulatory therapy, Cellular & Molecular Immunology 13, 3-10(2016);
SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of  cytokine "storm" and risk factor for damage of hematopoietic stem cells, Leukemia 2020; 34(7): 1726-1729;
Cytokine storm intervention in the early days of COVID-19 pneumonia, Cytokine & Growth Factor Reviews Vol. 53, June 2020, pp 38-42;
Up-regulation of IL-6 and TNF-a induced by SARS-coronavirus spike protein in murine macrophages via NF-kB pathway, Virus Research 2007 September; 128(1): 1-8;

Deficiencies
G6PD deficiency in the COVID-19 pandemic: ghost within a ghost, Hematology, Oncology and Stem Cell Therapy 2020, April 18;

Disseminated Intravascular Coagulation (DIC) and differentiations of DIC (noteworthy!)
DIC in COVID-19: Implications for prognosis and treatment?, Journal of Thrombosis and Haemostasis, Letter, 26 April 2020;
Local hemostasis, immunothrombosis and systemic DIC in trauma and traumatic shock, Critical Care 2015; 19(1):72;
Normal prothrombinase activity, increased systemic thrombin activity and lower antithrombin levels in patients with DIC at an early phase of trauma: comparison with acute coagulopathy of trauma-shock, Surgery Vol. 154, Issue 1, p48-57, July 01, 2013;
Differentiating DIC with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock, Journal of Thrombosis and Haemostasis, 22 March 2013, Vol. 11, Issue 5, May 2013;

Endotheliitis and endotheliopathy
Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study, Lancet Haematology Vol.7, Issue 8, E575-E582, August 01, 2020;
The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection, Critical Care 2020; 24: 353, June 16, 2020;

Enterocytes
SARS-CoV-2 productively infects human gut enterocytes, Science Vol. 369, Issue 6499, 03 July 2020;

Eosinophils
Eosinophil responses during COVID-19 infections and coronavirus vaccination, Journal of Allergy and Clinical Immunology, Vol. 146, Issue 1, July 2020, pp 1-7;
Clinical features of 85 fatal cases of COVID-19 from Wuhan. A retrospective observational study, American Journal of Respiratory and Critical Care Medicine, Vol. 201, Issue 11, 2020;

Fibrosis
Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy, Lancet Respiratory Medicine (viewpoint), Vol. 8 Issue 8, August 1, 2020;
SARS Coronavirus and Lung Fibrosis, Molecular Biology of the SARS-Coronavirus, 2009 July 22;
The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis, Antiviral Research 2017 July; 143;
Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in fibroblasts and macrophages, Current pharmaceutical design 2007;13(12):1247-56;
SARS Coronavirus and Lung Fibrosis, Zuo et al., Molecular Biology of the SARS-Coronavirus, Chapter 15, 24 October 2009, pp. 247-258;

Hemostasis and fibrinolysis
Serpins in thrombosis, hemostasis and fibrinolysis, Journal of Thrombosis and Haemostasis 2007 July: 5;
Association of Plasminogen Activator Inhibitor 1 (SERPINE1) polymorphisms and aneurysmal subarachnoid hemorrhage, World Neurosurgery, Vol. 105, September 2017;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis 2020;18;
High incidence of VTE (venous thromboembolic events) in anticoagulated severe COVID-19 patients, Journal of Thrombosis and Haemostasis 2020;18;
Hematological findings and complications of COVID-19 (high risk of venous thromboembolism), American Journal of Hematology Vol. 95, Issue 7, July 2020;
Fibrinolytic abnormalities in ARDS and versatility of thrombolytic drugs to treat COVID-19, Journal of Thrombosis and Haemostasis, Vol. 18, Issue 7, July 2020, pp 1548-1555;

HLA Haplotypes 
COVID-19 infection: the perspectives on immune responses (Edt.) (Hyaluronan markers), Cell Death & Differentiation 27, 1451-1454(2020);

Hormone secretion and sex differences
Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients, Andrology, 20 May 2020;
TLR7 is higher in women than in men and its expression leads to higher immune responses, Journal of Biological Regulators and Homeostatic Agents 2020 March-April; 34(2):339-343;

Hyperviscosity 
COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia?, Lancet Correspondence, Vol. 395, Issue 10239, June 06, 2020;

Immunity: T cell profile and prognostic markers
Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients, Cellular & Molecular Immunology 17, 541-543(2020);
T Cell Responses to Whole SARS-Coronaviruses in Humans, Journal of Immunology 2008, October 15, 181(8):5490-5500;
Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates, PLoS Pathogens 2010 February; 6(2): e1000756;
Abnormal immunity of non-survivors with COVID-19: predictors (Outcome: Neutrophilia, lymphocytopenia, low CD4+ cells and decreased Complement C3 are prognostic markers of a worse outcome), Infectious Diseases of Poverty 9, Art. No. 108(2020);

Depletion of CD4 and CD8 Positive T cells Impairs Venous Thrombus Resolution in Mice, International Journal of Molecular Sciences 2020 March; 21(5): 1650

Immunomodulation
Hypothesis for potential pathogenesis of SARS-CoV-2 infection- a review of immune changes in patients with viral pneumonia, Emerging Microbes & Infections 2020; 9(1);
Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: Potential of pentoxifylline and dipyridamole, Medical Hypotheses 2020 October; 143: 110051;

Immunoglobulin treatment
High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With COVID-19, Open Forum Infectious Diseases, Vol. 7 Issue 3, March 2020;

Inflammation, Toll-like Receptor (TLR) Signaling and stem cells
Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes, Scientific Reports 7, 2935 (2017);
Identification of Oxidative Stress and TLR-4 Signaling as a key pathway of Acute Lung Injury, Cell 2008, April 2008; 133(2);
Attenuation of Innate Immunity by Andrographolide Derivates Through NF-kB Signaling Pathway, Scientific Reports 7, Art. No.: 4738(2017);

Inflammation, regulation
Thy-1 (CD90) regulates the extravasation of leukocytes during inflammation, European Journal of Immunology 2011, 41:645-656;

Inflammatory phenotypes
Prevalence of phenotypes of ARDS in critically ill patients with COVID-19: a prosprective observational study, Lancet Respiratoy Medicine, August 27, 2020;

Inhibition
Potential protective and therapeutic role of immune checkpoint inhibitors against viral infections and COVID-19, Immunotherapy, 29 June 2020
Immunotherapeutic implications of IL-6 blockade for cytokine storm, Immunotherapy, 6 July 2016;

Interferons (IFN-x)
Dysregulation of type I interferon responses in COVID-19, Comment, Nature Reviews Immunology 20, 397-398(2020);
Inhibition of Interferon-γ Signaling in Oligodendroglia Delays Coronavirus Clearance Without Altering Demyelination, American Journal of Pathology 2006 March; 168(3): 796-804;
Gamma Interferon Signaling in Oligodendrocytes is Critical for Protection from Neurotropic Coronavirus Infection, Journal of Virology 2010 March;84(6);
Type I and Type III Interferons- Induction, Signaling, Evasion and Application to Combat COVID-19

Long-term complications of SARS-Coronaviruses
Long-term bone and lung consequences associated with hospital-aquired SARS: a 15-year follow-up from a prospective cohort study, Bone Research 8, Art. No. 8 (2020);
Late occurence of pulmonary embolism in SARS-CoV-2 pneumonia: a case series, Giornale Italiano di Cardiologia 2020;21(7):523-525;

Macrophages
SARS Coronavirus-Induced Lung Epithelial Cytokines Exacerbate SARS Pathogenesis by Modulating Intrinsic Funcions of Monocyte-Derived Macrophages and Dendritic Cells, Journal of Virology April 2009, Vol. 83, No. 7;
M2 polarized macrophages induced by CSE promote proliferation, migration and invasion of alveolar basal epithelial cells, International Immunopharmacology, Vol. 28, Issue 1, September 2015;
Macrophages: a Trojan horse in COVID-19?, Nature Reviews Immunology 20, 351(2020);
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nature Reviews Immunology 20, 355-362(2020);

MMPs

Matrix Metalloproteases in Aberrant Fibrotic Tissue Remodeling, Proceedings of The American Thoracic Society, 2006 June, Vol. 3(4):383-8;

Matrix Metalloproteinase-9 (MMP-9) Regulates Vein Wall Biomechanics in Murine Thrombus Resolution, PLoS One, September 25, 2015;

Matrix Metalloproteinase-9 Inhibition Reduces Inflammation and Improves Motility in Murine Models of Post-Operative Illeus, Gastroenterology, 2011 October; 141(4):1283-1292;

Matrix Metalloproteinase activity in the lung is increased in Hermansky-Pudlak Syndrome, Orphanet Journal of Rare Diseases 14, Art. No. 162 (2019);

Neurotransmitters
Action of Neurotransmitters: Acetylcholine, adrenaline and serotonin on Arterial Thrombosis induced by a laser beam, Thrombosis Research Vol. 84, Issue 3, p189-198, November 01, 1996;

Neutrophils and NETs
Biomarkers in Lung Diseases: Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 Bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration, American Journal of Physiology, Lung Cellular and Molecular Physiology, 2018 January 1;314(1);
In sickness and in health- how neutrophil extracellular traps (NET) works in infections, selected diseases and pregnancy, Journal of Inflammation 16, Art. No. 15 (2019);
NET: Villains and Targets in Arterial, Venous and Cancer-Associated Thrombosis, Journal of Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Vol. 39, Issue 9, September 2019;
Thrombosis: tangled up in NETs, Blood 2014 May 1, 123(18): 2768-2776;
Excessive Neutrophils and NETs in COVID-19, Frontiers Immunology, 18 August 2020;
Neutrophils and NETs drive Necroinflammation in COVID-19, MDPI Cells, 2 June 2020;

Open Reading Frame (ORF) driving cell death
SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death, Cell Death & Disease 9, Art. No. 904(2018);
The ORF3a protein of SARS-CoV-2 induces apoptosis (programmed cell death) in cells, Cellular & Molecular Immunology 17, 881-883(2020);
SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes, Cell Death Discovery 5, Art. No.: 101(2019);

Pathogenesis of SARS & SARS-CoV-2/COVID
Pathophysiology characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of COVID-19, Cardiovascular Pathology, 2020 July-August; 47:107228;
COVID-19: immunopathology and its implications for therapy, Nature Reviews Immunology 20, 269-270(2020);
Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS, Journal of Pathology, Vol. 210, Issue 3, November 2006;
SARS: The first pandemic of the 21st century, Pediatric Research Vol. 56, No. 1, 2004;

Platelets (and their relation to ADAMTS, thrombi and Von Willebrand Factor (VWF))
Platelet-to-lymphocyte ratio is associated with prognosis in patients with COVID-19, Journal of Medical Virology, 17 March 2020;
Human Platelets Contain and Release an Active ADAMTS-13 Like Metalloprotease, Blood, Vol. 104, Issue 11, November 16, 2004;
What a drag: necrotic platelets induce remote neutrophil thrombi following ischemic gut injury, Journal of Thrombosis and Haemostasis, Vol. 16, Issue 5, May 2018, pp 819-821;
Platelet Interaction with Innate Immune Cells, Transfusion Medicine and Hemotherapy, 2016 March; 43(2): 78-88;
Regulation of Innate Immune Responses by Platelets, Frontiers in Immunology 2019; 10: 1320;

Pyroptosis
Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools, Virologica Sinica 35, 266-271(2020);

Renin-Angiotensin Aldosterone System (RAAS) & Kinin-Kallikrein System (KKS)
A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of ACE Inhibitors: Focus on Perindopril, Cardiology and Therapy 8, 179-191(2019);
What have we learned about the Kallikrein-Kinin and Renin-Angiotensin Systems in neurological disorders?, World Journal of Biological Chemistry, 2014 May 26; 5(2): 130-140;
Role of Kallikrein in Blood Pressure Regulation, Hypertensive Cardiovascular Disease: Pathophysiology and Treatment, pp. 68-103;
New agents modulating the RAAS: Will there be a new therapeutic option?, Experimental Biology and Medicine, 2016 Nov;241(17):1888-1899;
ACE2 activity and human atrial fibrillation: increased plasma ACE2 activity is associated with aFib and more advanced left atrial structural remodelling, EP Europace, Vol. 19,  Issue 8, August 2017;
Ang II-induced upregulation of AT1 receptor expression: sequential activation of NF-kB and Ekl-1 in neurons (activation of the RAS in the brain promotes sympathic excitation in heart failure), American Journal of Cell Physiology 2010 September; 299(3): C561-C569;
Ang II revisited: new roles in inflammation, immunology and aging, EMBO Molecular Medicine 2010 July; 2(7): 247-257;
NF-kB and CREB Are Required for Ang II Type 1 Receptor Upregulation in Neurons, PLoS One, November 11, 2013;

Systemic diseases: SIRS,  Kawasaki and MIS-C
Multisystem Inflammatory Syndrome in Children: A systematic review, EClinicalMedicine, September 04, 2020;

Thrombocytopenia
Thrombocytopenia and its association with mortality in COVID-19, Journal of Thrombosis and Haemostasis 2020;18;
Thrombocytopenia is associated with severe COVID-19 infections: a meta-analysis, Clinical Chimica Acta, Vol. 506, July 2020;
Cardiac dysfunction and thrombocytopenia-associated Multiple Organ Failure inflammation phenotype in a severe paediatric case, Lancet Child & Adolescent Health, Vol. 4, Issue 7, July 01, 2020;
Sudden severe thrombocytopenia in a patient in the recovery stage of COVID-19, Haematology Vol. 7, Issue 8, E624, August 01, 2020;

Thrombosis and thromboembolism
Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19, Vol. 395, Issue 10236, May 16, 2020;
Acute pulmonary embolism in COVID-19 related hypercoagulability, Journal of Thrombosis and Haemostasis 2020 May 30: 1-4;
COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy and Follow-Up, JACC, Vol. 75, Issue 23, June 2020;
Describing the point prevalence and characteristics of Venous Thromboembolism in patients with Thrombotic Thrombocytopenic Purpura (TTP), Journal of Thrombosis and Haemostasis, 23 July 2020;
Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action, British Journal of Haematology 2020;
Arterial Mesentric Thrombosis as a complication of SARS-CoV-2 infection, European Journal of Case Reports in Internal Medicine 2020; 7(5): 001690;
Late Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001790;
Multisystemic Infarctions in COVID-19: Focus on the Spleen, European Journal of Case Reports in Internal Medicine 2020; 7(7): 001747;
Deep Venous Thrombosis (DVT) in a non-critically ill patient with COVID-19 infection, Thrombosis Research 2020 August; 192: 27-28;

Treatment options/therapeutics/prophylaxis
Could Ergothioneine Aid in the Treatment of Coronavirus Patients?, Antioxidants, MDPI, 2020 July; 9(7): 595;
CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement, Stem Cell Reviews and Reports 2020 April 20:1-7;
Temporal Relationship of Viral Load, Ribavirin, Interleukin (IL)-6 and IL-8 and Clinical Progression in Patients With SARS, Clinical Infectious Diseases 2004, October 1; 39(7): 1071-1075;
Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits, Scientific Reports 5, Art. No.:8856(2016);
Effective treatment of severe COVID-19 patients with tocilizumab, PNAS May 19, 2020 117(20) 10970-10975;
17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection, Clinics 2020; 75: e1980; 
Curative anticoagulaton prevents endothelial lesion in COVID-19 patients, Journal of Thrombosis and Haemostasis 2020;18:2391-2399;
Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system, Toxicology Reports 2020;7: 658-663;
Glucocorticoid Therapy for COVID-19 Critically ill Patients with Severe Acute Respiratory Failure, ClinicalTrials.gov;
Interferon-α2b Treatment for COVID-19, Frontiers in Immunology, 15 May 2020;
Lessons learned to date on COVID-19 Hyperinflammatory Syndrome: Considerations for Interventions to Mitigate SARS-CoV-2 Viral Infection and Detrimental Inflammation, Frontiers Immunology, 29 May 2020;
COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks (Remdesivir, teicoplanin and/or dalbavancin), International Journal of Molecular Sciences 2020 July; 21(14):4953;
Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients, EBioMedicine Vol. 59, 102969, September 01, 2020;
Glycyrrhizin (Liquorice), an active component of liquorice roots, and replication of SARS-associated coronavirus, Lancet 2003 June 14; 361(9374): 2045-2046;
Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities, Lancet Respiratory Medicine Vol. 8, Issue 8, P822-830, August 01, 2020;

Urokinase
Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in COVID-19 pneumonia, Critical Care 24, Art. No.: 187 (2020);
COVID-19 and pneumonia: a role for the uPA/uPAR System, Drug Discovery Today, Vol. 25 Issue 8, August 2020;
Elevated plasminogen as a common risk factor for COVID-19 susceptibility, Physiological Reviews Vol. 100, Issue 3, July 2020;
Multifaceted role of the Urokinase-Type Plasminogen Activator (uPA) and its receptor (uPAR): Diagnostic, Prognostic and Therapeutic Applications, Frontiers Oncology, 12 February 2018;

Von Willebrand Factor
Von Willebrand Factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain inhjury, Thrombosis and Haemostasis, Vol. 132, Issue 10, September 6, 2018;
ADAMTS-13 activity, Von Willebrand Factor, Factor VII and D-dimers in COVID-19 inpatients, Thrombosis Research 2020 August; 192: 174-175;
Involvement of ADAMTS13 and VWF in thromboembolic events in patients infected with SARS-CoV-2, International Journal of Laboratory Hematology 2020 May 22: 10.1111/ijlh.13244;