COVID-19, thrombosis and anticoagulation (Homo sapiens)

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2, 95666Degradation of surplus chainsby proteasomes and lysosomesLysosomesHepG2MG132LactacystinLeupeptinNH4ClChloroquineFGB (Bβ)6666666664413, 51Mainly hepatocytes,HepG2 cells6ETransfer to blood"The two end nodules (D regions/domains) consist out of Bβ and γ chains, In the center a slightly smaller nodule (E region/domain) consists out of two intertwined Aα alpha chains"Transfer to Golgi Start in ER, completed in Golgi:- N-linked Glycosylation of Bβ and γ chainsHydroxylationPost ER stage:- Tyrosine sulfation of the γ′ variant- Phosphorylation of AαERCoordinated transcription andtranslation on ERD-domain:Relevant other pathways:Fibrin meshFactor XIII:FGAFibrinogenPlasminFGG (γ)FGB (Bβ)FibrinogenDEDFGA (Aα)Formation of fibrin clot (clotting cascade)Blood clotting cascadeFGA (AαE)1-3%Blood clotting and drug effectsFactor XIII A chain3Complement and coagulation cascadesPlatelet-mediated interactions with vascular and circulating cellsFibrinDDEFibrin degradation products (FDPs)FibrinEDDThrombinFibrinEDDFibrinDEDFibrinDEDFibrinDEDFibrinDEDFibrinEDDFactor XIII B chain3, 57Crosslinkedfibrin mesh11D-DimerD2, 8DEDDFGG (γ')8–10%D-domain (alternative splicing):FGG (γ)FGB (Bβ)FGA (Aα)FGBFGG6FGG (γ)6FGB (Bβ)FGA (Aα)66Translocation into ERFGA (Aα)FGG (γ)FGB (Bβ)FGG (γ)66Within ER lumen: Aαγ and Bβγ dimer formation6FGA (Aα)FGG (γ)FGB (Bβ)FGA (Aα)FGG (γ)FGB (Bβ)6Within ER lumen: AαBβγtrimer formationFGA (Aα)6FGG (γ)FGB (Bβ)FGA (Aα)FGG (γ)FGB (Bβ)Within ER lumen: (AαBβγ)2heximer formationFGA (Aα)FGG (γ)FGB (Bβ)FGA (Aα)FGG (γ)FGB (Bβ)GolgiDetails on D+E regionsFGA (Aα)FGG (γ)FGG (γ)FGGFGA (Aα)FGG (γ)66ProteasomesHepG2FGALysosomes andproteasomes COS6ProteasomesCOS66FGB (Bβ)6FGB6ProteasomesCOSLeupeptinMG1326MG1326


Description

Several hospitals and researchers have reported links between thrombosis and anticoagulation quite regularly for COVID-19 patients.

This pathways combines this information, including biological mechanisms involved, in one graphical overview. The D-dimer is one of the protein fragments produced when a blood clot dissolves within the (human) body; when not properly degraded could lead to thrombosis.

The graphical visualisation of (crosslinked) fibrin mesh leading to D-dimers is inspired by Wikipedia.

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Ontology Terms

 

Bibliography

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  1. Kirschbaum NE, Budzynski AZ; ''A unique proteolytic fragment of human fibrinogen containing the A alpha COOH-terminal domain of the native molecule.''; J Biol Chem, 1990 PubMed Europe PMC Scholia
  2. Velavan TP, Meyer CG; ''Mild versus severe COVID-19: Laboratory markers.''; Int J Infect Dis, 2020 PubMed Europe PMC Scholia
  3. Thomas A, Biswas A, Dodt J, Philippou H, Hethershaw E, Ensikat HJ, Ivaskevicius V, Oldenburg J; ''Coagulation Factor XIIIA Subunit Missense Mutations Affect Structure and Function at the Various Steps of Factor XIII Action.''; Hum Mutat, 2016 PubMed Europe PMC Scholia
  4. Glenn KC, Frost GH, Bergmann JS, Carney DH; ''Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis.''; Pept Res, 1988 PubMed Europe PMC Scholia
  5. Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É; ''Factor XIII: a coagulation factor with multiple plasmatic and cellular functions.''; Physiol Rev, 2011 PubMed Europe PMC Scholia
  6. Redman CM, Xia H; ''Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion.''; Ann N Y Acad Sci, 2001 PubMed Europe PMC Scholia
  7. Ichinose A, McMullen BA, Fujikawa K, Davie EW; ''Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments.''; Biochemistry, 1986 PubMed Europe PMC Scholia
  8. Adam SS, Key NS, Greenberg CS; ''D-dimer antigen: current concepts and future prospects.''; Blood, 2009 PubMed Europe PMC Scholia
  9. Connors JM, Levy JH; ''COVID-19 and its implications for thrombosis and anticoagulation.''; Blood, 2020 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
121715view13:49, 26 February 2022EweitzModified description
120608view23:33, 17 December 2021EweitzRefine case, copy
118848view09:24, 2 June 2021EweitzOntology Term : 'hepatocyte' added !
118847view09:24, 2 June 2021EweitzOntology Term : 'COVID-19' added !
118846view09:23, 2 June 2021EweitzOntology Term : 'DOID:2945' removed !
115849view15:25, 18 March 2021DeSlAdded refs for XIII (A and B)
115848view15:22, 18 March 2021DeSlAdded ref for plasmin conversion
115847view15:20, 18 March 2021DeSlAdded ref for thrombin conversion
115845view15:18, 18 March 2021DeSlAdded additional inhibitors for degradation, including ref.
115844view15:11, 18 March 2021DeSlAdded first proteolytic inhibitors
115842view15:05, 18 March 2021DeSlAdded refs for degradation steps
115841view15:04, 18 March 2021DeSlAdded degradation steps
115838view14:48, 18 March 2021DeSlAdded details on fibrinogen in comments
115834view14:20, 18 March 2021DeSlAdded PMID:11460506 for interactions within hepatocyte (middle of model)
111155view08:37, 21 July 2020EgonwFixed typo in ShapeType :/
111154view08:35, 21 July 2020EgonwMade the pathways clickable
110542view09:44, 18 May 2020FehrhartOntology Term : 'severe acute respiratory syndrome' added !
110541view09:44, 18 May 2020FehrhartOntology Term : 'disease pathway' added !
110537view15:37, 17 May 2020DeSlAdded details of Golgi step
110536view15:33, 17 May 2020DeSlAdded missing IDs D-dimer, new fibrinogen node
110535view14:48, 17 May 2020DeSlAdded lit. ref and more details on heximer formation
110534view14:37, 17 May 2020DeSlAdded hepatocyte
110533view13:20, 17 May 2020DeSlLast details on fibrinogen formation.
110532view13:10, 17 May 2020DeSlMore details on heximerisation
110529view12:13, 17 May 2020DeSlAdded additional details on fibrin formation
110525view11:47, 17 May 2020DeSlModified description
110524view11:42, 17 May 2020DeSlModified description
110523view07:22, 17 May 2020EgonwAdded an identifier for FDP
110516view10:57, 16 May 2020DeSlModified description
110515view10:54, 16 May 2020DeSlAdded D+E domain explanation
110514view10:46, 16 May 2020DeSlAdded IDs for alternative splicing D-domain
110513view10:43, 16 May 2020DeSlAdded D-domain alternative splicing
110512view10:36, 16 May 2020DeSlChanged double graphical lines to two singles for visualisation purpose.
110511view10:31, 16 May 2020DeSlAdded D-domain + IDs
110510view10:25, 16 May 2020DeSlStarting to add details on D-E-D glycotprotein
110492view11:59, 14 May 2020DeSlConnected unconnected line
110474view13:43, 13 May 2020DeSlModified description
110472view13:34, 13 May 2020DeSlModified description
110471view13:30, 13 May 2020DeSlOntology Term : 'blood coagulation disease' added !
110470view13:30, 13 May 2020DeSlOntology Term : 'thrombosis' added !
110468view12:29, 13 May 2020DeSlAdded ref covid + thrombosis
110467view12:28, 13 May 2020DeSlAdded refs
110466view12:23, 13 May 2020DeSlAdded D-Dimer step
110465view12:19, 13 May 2020DeSlNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Blood clotting and drug effectsPathwayWP4580 (WikiPathways)
Blood clotting cascadePathwayWP272 (WikiPathways)
ChloroquineMetaboliteCHEBI:3638 (ChEBI)
Complement and coagulation cascadesPathwayWP558 (WikiPathways)
D-DimerMetaboliteQ198526 (Wikidata)
FGA (Aα)ProteinP02671 (Uniprot-TrEMBL) "fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene"
FGA (AαE)ProteinNP_000499.1 (NCBI Protein) "Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen"
FGAGeneProduct2243 (Entrez Gene)
FGB (Bβ)ProteinP02675 (Uniprot-TrEMBL) "the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene"
FGBGeneProduct2244 (Entrez Gene)
FGG (γ')ProteinNP_068656.2 (NCBI Protein) "alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen"
FGG (γ)ProteinP02679 (Uniprot-TrEMBL) "fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene"
FGGGeneProduct2266 (Entrez Gene)
Factor XIII A chainProteinP00488 (Uniprot-TrEMBL) Catalytically active
Factor XIII B chainProteinP05160 (Uniprot-TrEMBL) Not catalytically active, believed to stabilise A chain
Fibrin degradation products (FDPs)MetaboliteQ2162109 (Wikidata)
FibrinMetaboliteQ27205 (Wikidata)
FibrinogenMetaboliteQ381899 (Wikidata)
Formation of fibrin clot (clotting cascade)PathwayWP1818 (WikiPathways)
LactacystinMetaboliteCHEBI:52722 (ChEBI)
LeupeptinMetaboliteCHEBI:6426 (ChEBI)
MG132Metabolite462382 (PubChem-compound)
NH4ClMetaboliteCHEBI:31206 (ChEBI)
PlasminProteinP00747 (Uniprot-TrEMBL)
Platelet-mediated interactions with vascular and circulating cellsPathwayWP4462 (WikiPathways)
ThrombinProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions

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