</head> <body>Authors: <br/> Goar Frishman, Helmholtz Zentrum München /Institute of Experimental Genetics, Munich, Germany <br/> <br/> Gisela Fobo, Helmholtz Zentrum München / Institute of Experimental Genetics, Munich, Germany <br/> <br/> Corinna Montrone, Helmholtz Zentrum München / Institute of Experimental Genetics, Munich, Germany <br/> <br/> Marek Ostaszewski, Luxembourg Centre for Systems Biomedicine (LCSB), Luxembourg <br/> <br/> Description: Thrombosis model of COVID-19 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:modelVersion>4.0</celldesigner:modelVersion> <celldesigner:modelDisplay sizeX="7000" sizeY="20000"/> <celldesigner:listOfIncludedSpecies> <celldesigner:species id="s253" name="F8a"> <celldesigner:notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body/> </html> </celldesigner:notes> <celldesigner:annotation> <celldesigner:complexSpecies>s435</celldesigner:complexSpecies> <celldesigner:speciesIdentity> <celldesigner:class>PROTEIN</celldesigner:class> <celldesigner:proteinReference>pr31</celldesigner:proteinReference> <celldesigner:state> <celldesigner:listOfStructuralStates> <celldesigner:structuralState structuralState="active"/> </celldesigner:listOfStructuralStates> </celldesigner:state> </celldesigner:speciesIdentity> </celldesigner:annotation> </celldesigner:species> <celldesigner:species id="s252" name="F9a"> <celldesigner:notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body> Ang I can be cleaved by NEP to Ang (1–7). 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<bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:mesh:D013923"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:mesh:D055806"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:9606"/> </rdf:Bag> </bqbiol:isDescribedBy> </rdf:Description> </rdf:RDF> </annotation> </species> <species metaid="s636" id="s636" name="s86" compartment="c15" initialAmount="0"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>ACE2 functions as a carboxypeptidase, cleaving a single residue from angiotensin I (AngI), generating Ang1-9, and a single residue from angiotensin II (AngII) to generate Ang1-7. The ACE2 homologue ACE, by contrast, cleaves the decapeptide AngI into the octapeptide AngII. Thus, ACE2 counterbalances the function of ACE and negatively regulates AngII production. To test whether Spike-Fc injections indeed affect the function of the renin-angiotensin system, AngII levels in the lungs of acid- and Spike-Fc–treated mice were analyzed. Acid aspiration increased AngII levels in the lungs of wild-type mice. Notably, the authors observed a further, significant increase in AngII levels in the lung tissue of mice treated with Spike-Fc. 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PMID:11551226 AT-III inhibits thrombin,factors IXa, Xa and XIa. 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PMID: 7391081 The effective contact activation of Hageman factor in plasma requires prekallikrein and HMWK, and that plasmas deficient in either of these proteins do not develop normal clotting, kinin, and fibrinolytic activities upon exposure to glass. 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PMID: 17395591 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:name>PMID:427127, PMID:17395591</celldesigner:name> <celldesigner:reactionType>TRUNCATION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s376" alias="sa252"/> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s366" alias="sa308"/> <celldesigner:baseProduct species="s459" alias="sa310"/> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection arm="0" index="0" value="unknown"/> <celldesigner:lineDirection arm="1" index="0" value="unknown"/> <celldesigner:lineDirection arm="2" index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:editPoints num0="0" num1="0" num2="0" tShapeIndex="0">0.16435404807084453,0.30876423149905285</celldesigner:editPoints> <celldesigner:line width="1.0" color="ff000000"/> <celldesigner:listOfModification> <celldesigner:modification type="CATALYSIS" modifiers="s434" aliases="csa26" targetLineIndex="0,2"> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:linkTarget species="s434" alias="csa26"> <celldesigner:linkAnchor position="WSW"/> </celldesigner:linkTarget> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:modification> <celldesigner:modification type="CATALYSIS" modifiers="s455" aliases="csa35" targetLineIndex="0,3" editPoints="0.5934792845346295,0.07768584392195699"> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> <celldesigner:lineDirection index="1" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:linkTarget species="s455" alias="csa35"> <celldesigner:linkAnchor position="E"/> </celldesigner:linkTarget> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:modification> </celldesigner:listOfModification> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#re261"> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:427127"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:9606"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:17395591"/> </rdf:Bag> </bqbiol:isDescribedBy> </rdf:Description> </rdf:RDF> </annotation> <listOfReactants> <speciesReference metaid="CDMT00112" species="s376"> <annotation> <celldesigner:extension> <celldesigner:alias>sa252</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfReactants> <listOfProducts> <speciesReference metaid="CDMT00113" species="s366"> <annotation> <celldesigner:extension> <celldesigner:alias>sa308</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> <speciesReference metaid="CDMT00125" species="s459"> <annotation> <celldesigner:extension> <celldesigner:alias>sa310</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfProducts> <listOfModifiers> <modifierSpeciesReference metaid="CDMT00126" species="s434"> <annotation> <celldesigner:extension> <celldesigner:alias>csa26</celldesigner:alias> </celldesigner:extension> </annotation> </modifierSpeciesReference> <modifierSpeciesReference metaid="CDMT00193" species="s455"> <annotation> <celldesigner:extension> <celldesigner:alias>csa35</celldesigner:alias> </celldesigner:extension> </annotation> </modifierSpeciesReference> </listOfModifiers> </reaction> <reaction metaid="re262" id="re262" name="PMID:30083158, PMID: 12878586" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. PMID: 30083158 Kinetic parameters revealed that the soluble form of the enzyme (C4b,C2a) cleaved C5 at a catalytic rate similar to that of the surface-bound form (EAC1,C4b,C2a). PMID: 12878586 When the density of C3b molecules on the cell surface becomes sufficiently high, the existing C3 convertases (C4b2a and C3bBb) gain the ability to cleave C5, leading to formation of C5a and C5b. PMID: 30083158 The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. C6 binds the labile C5b intermediate, resulting in a stable C5b6 complex. C7 binds C5b6, anchoring the newly formed C5b7 complex to the membrane surface. C8, a heterotrimeric protein composed of C8α, C8β and C8γ, is incorporated into the assembly precursor forming C5b8 and marking the first membrane penetrating event. Finally, multiple copies of C9 join the assembly and span membrane, resulting in the final membrane attack complex (MAC). PMID: 28630159 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:name>PMID:30083158, PMID: 12878586</celldesigner:name> <celldesigner:reactionType>TRUNCATION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s380" alias="sa314"/> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s381" alias="sa315"/> <celldesigner:baseProduct species="s365" alias="sa253"/> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection arm="0" index="0" value="unknown"/> <celldesigner:lineDirection arm="1" index="0" value="unknown"/> <celldesigner:lineDirection arm="2" index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:editPoints num0="0" num1="0" num2="0" tShapeIndex="0">0.22013651877132467,0.22252559726961962</celldesigner:editPoints> <celldesigner:line width="1.0" color="ff000000"/> <celldesigner:listOfModification> <celldesigner:modification type="CATALYSIS" modifiers="s455" aliases="csa35" targetLineIndex="0,4" editPoints="0.5665254397291086,-0.38599761467092364"> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> <celldesigner:lineDirection index="1" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:linkTarget species="s455" alias="csa35"> <celldesigner:linkAnchor position="E"/> </celldesigner:linkTarget> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:modification> <celldesigner:modification type="CATALYSIS" modifiers="s382" aliases="csa27" targetLineIndex="0,2" editPoints="0.3001455350774931,-0.03726909696082448 0.5609919512937518,0.1794646911880493"> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection index="0" value="unknown"/> <celldesigner:lineDirection index="1" value="unknown"/> <celldesigner:lineDirection index="2" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:linkTarget species="s382" alias="csa27"> <celldesigner:linkAnchor position="SW"/> </celldesigner:linkTarget> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:modification> </celldesigner:listOfModification> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#re262"> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:30083158"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:9606"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:12878586"/> </rdf:Bag> </bqbiol:isDescribedBy> </rdf:Description> </rdf:RDF> </annotation> <listOfReactants> <speciesReference metaid="CDMT00127" species="s380"> <annotation> <celldesigner:extension> <celldesigner:alias>sa314</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfReactants> <listOfProducts> <speciesReference metaid="CDMT00128" species="s381"> <annotation> <celldesigner:extension> <celldesigner:alias>sa315</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> <speciesReference metaid="CDMT00139" species="s365"> <annotation> <celldesigner:extension> <celldesigner:alias>sa253</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfProducts> <listOfModifiers> <modifierSpeciesReference metaid="CDMT00197" species="s455"> <annotation> <celldesigner:extension> <celldesigner:alias>csa35</celldesigner:alias> </celldesigner:extension> </annotation> </modifierSpeciesReference> <modifierSpeciesReference metaid="CDMT00207" species="s382"> <annotation> <celldesigner:extension> <celldesigner:alias>csa27</celldesigner:alias> </celldesigner:extension> </annotation> </modifierSpeciesReference> </listOfModifiers> </reaction> <reaction metaid="re263" id="re263" name="PMID:5058233" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>Nascent C5b combines with C6 and C7,resulting in the formation of a C5b67 trimolecular complex. PMID: 5058233 The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. C6 binds the labile C5b intermediate, resulting in a stable C5b6 complex. C7 binds C5b6, anchoring the newly formed C5b7 complex to the membrane surface. C8, a heterotrimeric protein composed of C8α, C8β and C8γ, is incorporated into the assembly precursor forming C5b8 and marking the first membrane penetrating event. Finally, multiple copies of C9 join the assembly and span membrane, resulting in the final membrane attack complex (MAC). PMID: 28630159 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:name>PMID:5058233</celldesigner:name> <celldesigner:reactionType>HETERODIMER_ASSOCIATION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s381" alias="sa315"/> <celldesigner:baseReactant species="s385" alias="sa318"/> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s397" alias="csa28"> <celldesigner:linkAnchor position="W"/> </celldesigner:baseProduct> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection arm="0" index="0" value="unknown"/> <celldesigner:lineDirection arm="1" index="0" value="unknown"/> <celldesigner:lineDirection arm="2" index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:editPoints num0="0" num1="0" num2="0" tShapeIndex="0">0.3811092353934278,0.3889323506402551</celldesigner:editPoints> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#re263"> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:5058233"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:9606"/> </rdf:Bag> </bqbiol:isDescribedBy> </rdf:Description> </rdf:RDF> </annotation> <listOfReactants> <speciesReference metaid="CDMT00141" species="s381"> <annotation> <celldesigner:extension> <celldesigner:alias>sa315</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> <speciesReference metaid="CDMT00148" species="s385"> <annotation> <celldesigner:extension> <celldesigner:alias>sa318</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfReactants> <listOfProducts> <speciesReference metaid="CDMT00149" species="s397"> <annotation> <celldesigner:extension> <celldesigner:alias>csa28</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfProducts> </reaction> <reaction metaid="re264" id="re264" name="PMID:5058233" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>Nascent C5b combines with C6 and C7,resulting in the formation of a C5b67 trimolecular complex. PMID: 5058233 The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. C6 binds the labile C5b intermediate, resulting in a stable C5b6 complex. C7 binds C5b6, anchoring the newly formed C5b7 complex to the membrane surface. C8, a heterotrimeric protein composed of C8α, C8β and C8γ, is incorporated into the assembly precursor forming C5b8 and marking the first membrane penetrating event. Finally, multiple copies of C9 join the assembly and span membrane, resulting in the final membrane attack complex (MAC). PMID: 28630159 </body> </html> </notes> <annotation> <celldesigner:extension> <celldesigner:name>PMID:5058233</celldesigner:name> <celldesigner:reactionType>HETERODIMER_ASSOCIATION</celldesigner:reactionType> <celldesigner:baseReactants> <celldesigner:baseReactant species="s397" alias="csa28"> <celldesigner:linkAnchor position="NE"/> </celldesigner:baseReactant> <celldesigner:baseReactant species="s389" alias="sa321"/> </celldesigner:baseReactants> <celldesigner:baseProducts> <celldesigner:baseProduct species="s396" alias="csa29"> <celldesigner:linkAnchor position="S"/> </celldesigner:baseProduct> </celldesigner:baseProducts> <celldesigner:connectScheme connectPolicy="direct"> <celldesigner:listOfLineDirection> <celldesigner:lineDirection arm="0" index="0" value="unknown"/> <celldesigner:lineDirection arm="1" index="0" value="unknown"/> <celldesigner:lineDirection arm="2" index="0" value="unknown"/> </celldesigner:listOfLineDirection> </celldesigner:connectScheme> <celldesigner:editPoints num0="0" num1="0" num2="0" tShapeIndex="0">0.39335338987413593,0.24012681226048205</celldesigner:editPoints> <celldesigner:line width="1.0" color="ff000000"/> </celldesigner:extension> <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/"> <rdf:Description rdf:about="#re264"> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:pubmed:5058233"/> </rdf:Bag> </bqbiol:isDescribedBy> <bqbiol:isDescribedBy> <rdf:Bag> <rdf:li rdf:resource="urn:miriam:taxonomy:9606"/> </rdf:Bag> </bqbiol:isDescribedBy> </rdf:Description> </rdf:RDF> </annotation> <listOfReactants> <speciesReference metaid="CDMT00150" species="s397"> <annotation> <celldesigner:extension> <celldesigner:alias>csa28</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> <speciesReference metaid="CDMT00151" species="s389"> <annotation> <celldesigner:extension> <celldesigner:alias>sa321</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfReactants> <listOfProducts> <speciesReference metaid="CDMT00152" species="s396"> <annotation> <celldesigner:extension> <celldesigner:alias>csa29</celldesigner:alias> </celldesigner:extension> </annotation> </speciesReference> </listOfProducts> </reaction> <reaction metaid="re266" id="re266" name="PMID:284414" reversible="false"> <notes> <html xmlns="http://www.w3.org/1999/xhtml"> <head> <title/> </head> <body>Stable complexes of phospholipid and protein were formed by C5b--7, C5b--8, C5b--9, and the MAC (C5b--9 dimer) and they exhibited densities of 1.2164, 1.184, 1.2055, and 1.2275 g/ml, respectively. PMID: 284414 The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. C6 binds the labile C5b intermediate, resulting in a stable C5b6 complex. C7 binds C5b6, anchoring the newly formed C5b7 complex to the membrane surface. C8, a heterotrimeric protein composed of C8α, C8β and C8γ, is incorporated into the assembly precursor forming C5b8 and marking the first membrane penetrating event. Finally, multiple copies of C9 join the assembly and span membrane, resulting in the final membrane attack complex (MAC). 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PMID: 6796960 The first step requires cleavage of C5 into the small anaphylatoxin C5a and the large fragment C5b by the C5 convertase. C6 binds the labile C5b intermediate, resulting in a stable C5b6 complex. C7 binds C5b6, anchoring the newly formed C5b7 complex to the membrane surface. C8, a heterotrimeric protein composed of C8α, C8β and C8γ, is incorporated into the assembly precursor forming C5b8 and marking the first membrane penetrating event. Finally, multiple copies of C9 join the assembly and span membrane, resulting in the final membrane attack complex (MAC). 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PMID:11290788 These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the alternative and lectin-based complement pathways. 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Skin and lung tissues from 5 patients with severe COVID-19 characterized by respiratory failure (n= 5) and purpuric skin rash (n = 3) were examined. The pattern of COVID-19 pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the interalveolar septa by neutrophils. No viral cytopathic changes were observed and the diffuse alveolar damage (DAD) with hyaline membranes, inflammation, and type II pneumocyte hyperplasia, hallmarks of classic acute respiratory distress syndrome, were not prominent. These pulmonary findings were accompanied by significant deposits of terminal complement components C5b-9 (membrane attack complex), C4d, and mannose binding lectin (MBL)-associated serine protease (MASP)2, in the microvasculature, consistent with sustained, systemic activation of the alternative and lectin-based complement pathways. 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PMID: 2437112 The level of SERPINF2-Plasmin Complex (PIC) was higher in COVID-19 patients were higher than health controls, and also higher in the patients with thrombotic disease than without thrombotic disease in whole blood. 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PMID:12091055 Although IL-6 alone had only a modest effect on PAI-1 expression, in combination with IL-1, it caused a synergistic induction of PAI-1 mRNA accumulation. PMID:8034668 Aldosterone increases expression of PAI-1 in H9c2 cells expressed NR3C2. PMID:20591974 Ang II activates PAI-1 gene expression through the AT1 receptor and involves the calcium-dependent activation of calcineurin and the nuclear translocation of NFAT. 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These effects were observed within 10 min and were partially suppressed by eplerenone. Moreover, acute administration of aldosterone in mice enhanced platelet accumulation at the site of endothelial injury induced by laser and increased the area of irreversibly activated platelets in FeCl3-induced thrombus. These results demonstrate that aldosterone acutely affects platelets, coagulation, and fibrinolysis, leading to an enhanced thrombosis. The aldosterone effects were mediated partially via a mineralocorticoid receptor. The mechanism seems to involve non-genomic signaling since the effects were observed within a few minutes of aldosterone administration. 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Valsartan reduced the ALDO-induced changes in bleeding time and platelet adhesion, as well as in coagulation, fibrinolysis, and NO metabolite levels. The effect of AT 1 blockade in ALDO-induced thrombosis was similar to the effect of MR blockade. However, dual blockade of AT 1 and MR showed no additional benefit. ALDO prothrombotic action is partially mediated via AT 1 receptor in the mechanism involving enhanced platelet activation, induced coagulation, impaired fibrinolysis and reduced NO bioavailability. 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Severe acute respiratory syndrome coronavirus 2 binds angiotensin-converting enzyme 2 of the rennin-angiotensin system, resulting in hypokalemia. 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