Investigating systemic inflammation and hypercoagulability in psoriasis: implications for cardiovascular disease

Simple item page
dc.contributor.advisorPretorius, Etheresiaen_ZA
dc.contributor.authorVisser, Maria Johanna Elizabethen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Physiological Sciences.en_ZA
dc.date.accessioned2022-11-22T08:39:17Z
dc.date.accessioned2023-01-16T12:48:12Z
dc.date.available2022-11-22T08:39:17Z
dc.date.available2023-01-16T12:48:12Z
dc.date.issued2022-12
dc.descriptionThesis (PhD)--Stellenbosch University, 2022.en_ZA
dc.description.abstractENGLISH ABSTRACT: Psoriasis (PsO) is a common immune-mediated inflammatory disease of the skin, typically presenting as erythematous plaques covered with silvery scales. The condition is of multifactorial aetiology, encompassing interactions between environmental factors, genetic susceptibility, and dysregulated immune responses. The pathogenesis of PsO is predominantly driven by interleukin (IL)-17. In addition, inflammatory mediators associated with T helper (TH) 1, TH17, and TH22 subsets are also overexpressed in psoriatic skin. Moreover, these inflammatory molecules may also be detected in the systemic circulation of patients with PsO. The disease is not solely limited to cutaneous sites, as multiple comorbidities have been linked to the condition. Notably, patients with PsO have been reported to have a significantly increased risk of cardiovascular disease (CVD). A potential mechanism that might contribute to this association is the presence of a hypercoagulable state – driven by persistent systemic inflammation – in these individuals. A pro-inflammatory milieu may favour coagulation, while suppressing natural anticoagulant mechanisms. In addition, inflammation may also alter – albeit indirectly – the fibrin clot structure and, by extension, the properties of the fibrin network. Therefore, the aim of this study was to assess the haemostatic profile and investigate potential alterations in fibrin clot structure in patients with PsO, compared to healthy individuals. Whole blood samples were collected from patients with PsO (n=20) and healthy control subjects (n=20). The concentrations of blood-based markers of inflammation and endothelial and platelet activation were determined using enzyme-linked immunosorbent assays. Coagulation status was assessed by thromboelastography. The fibrin network architecture was analysed by scanning electron microscopy. Fibrin secondary structure was assessed through the examination of formalin-fixed, paraffin-embedded plasma clot sections using fluorescence microscopy and Fourier transform infrared (FTIR) spectroscopy. In order to detect areas rich in β-sheet structures, Congo red staining was performed, and sections were examined with brightfield and fluorescence microscopy. To determine if there were quantitative differences in the distribution of specific secondary structural elements in fibrin clots, FTIR analysis was conducted. Elevated levels of inflammatory molecules (C-reactive protein, serum amyloid A, soluble intercellular adhesion molecule-1, and soluble P-selectin) were associated with PsO, thereby confirming the presence of systemic inflammation in patients with PsO. Thromboelastographic analysis revealed an increased tendency towards clot formation, that was also associated with disease presence. Moreover, the ultrastructure of fibrin clots from patients with PsO was altered – these clots were denser and consisted of thicker fibrin fibres, as compared to control subjects. Regarding the secondary structure of fibrin, the presence of β-sheet-rich areas, as identified by Congo red fluorescence, was detected in fibrin clots from both groups. Accordingly, FTIR analysis also did not show any significant differences between the secondary structure composition of fibrin clots from patients with PsO and those of healthy control subjects. Taken together, the results of this study indicate that a hypercoagulable state is present in patients with PsO. This hypercoagulability seems to be a result of persistent systemic inflammation, rather than alterations to the molecular structure of fibrin. The hypercoagulable state in PsO might have implications for the management of CVD risk for individuals living with the condition.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Psoriase (PsO) is ’n algemene immuun-bemiddelde inflammatoriese velsiekte wat tipies voorkom as rooierige verhewe vlekke bedek met silwerkleurige skubbe. Die toestand is van multifaktoriale etiologie, wat interaksies tussen omgewingsfaktore, genetiese vatbaarheid en wangereguleerde immuunresponse insluit. Die patogenese van PsO word hoofsaaklik deur interleukin (IL)-17 aangedryf. Daarbenewens word inflammatoriese mediators wat met T-helper (TH) 1, TH17 en TH22 subversamelings geassosieer word, ook ooruitgedruk in psoriatiese vel. Boonop kan hierdie inflammatoriese molekules ook in die sistemiese sirkulasie van pasiënte met PsO opgespoor word. Die siekte is nie net beperk tot kutane areas nie, aangesien veelvuldige komorbiditeite aan die toestand gekoppel is. Daar is veral gerapporteer dat pasiënte met PsO ’n aansienlik verhoogde risiko vir kardiovaskulêre siekte (KVS) het. ’n Moontlike meganisme wat tot hierdie assosiasie kan bydra, is die teenwoordigheid van ’n hiperstolbare toestand – aangedryf deur kroniese sistemiese inflammasie – in hierdie individue. ’n Pro-inflammatoriese milieu kan stolling bevoordeel, terwyl natuurlike antistollingsmeganismes onderdruk word. Daarbenewens kan inflammasie ook die fibrienklontstruktuur – alhoewel indirek – en, by uitbreiding, die eienskappe van die fibriennetwerk verander. Daarom was die doel van hierdie studie om die hemostatiese profiel te assesseer en potensiële veranderinge in fibrienklontstruktuur in pasiënte met PsO, in vergelyking met gesonde individue, te ondersoek. Heelbloed monsters is versamel vanaf pasiënte met PsO (n=20) en gesonde individue (n=20). Die konsentrasies van bloedgebaseerde inflammasiemerkers en merkers van endoteel- en bloedplaatjieaktivering is bepaal deur gebruik te maak van ensiemgekoppelde immunosorbenttoetse. Stollingstatus is deur trombo-elastografie geanaliseer. Fibriennetwerkargitektuur is deur skandeerelektronmikroskopie geanaliseer. Die sekondêre struktuur van fibrien is ondersoek deur die analise van formalien-gefikseerde paraffien- ingebedde plasma klontsnitte deur gebruik te maak van fluoressensiemikroskopie en Fourier transform infrarooi (FTIR) spektroskopie. Om areas ryk aan β-plaat strukture op te spoor, is Kongorooi kleuring uitgevoer, en snitte is ondersoek met helderveld- en fluoressensiemikroskopie. Om te bepaal of daar kwantitatiewe verskille in die verspreiding van spesifieke sekondêre strukturele elemente in fibrienklonte was, is FTIR-analise uitgevoer. Verhoogde vlakke van inflammatoriese molekules (C-reaktiewe proteïen, serumamiloïed A, oplosbare intersellulêre adhesiemolekule-1 en oplosbare P-selektien) is met PsO geassosieer en die teenwoordigheid van sistemiese inflammasie in pasiënte met PsO word sodoende bevestig. Trombo-elastografiese analise het ’n verhoogde neiging tot klontvorming aan die lig gebring, wat ook geassosieer is met siekte teenwoordigheid. Boonop was die ultrastruktuur van fibrienklonte van pasiënte met PsO veranderd – hierdie klonte was digter en het bestaan uit dikker fibrienvesels, in vergelyking met kontrolegroeppasiënte. Met betrekking tot die sekondêre struktuur van fibrien is die teenwoordigheid van β-plaatryke areas, soos geïdentifiseer deur Kongorooi fluoressensie, opgespoor in fibrienklonte van beide groepe. Gevolglik het FTIR-analise ook geen betekenisvolle verskille tussen die sekondêre struktuursamestelling van fibrienklonte van pasiënte met PsO en dié van gesonde kontrolepasiënte getoon nie. In samevatting dui die resultate van hierdie studie aan dat ’n hiperstolbare toestand teenwoordig is in pasiënte met PsO. Hierdie hiperstolbaarheid wil voorkom om 'n resultaat te wees van konstante sistemiese inflammasie, eerder as gevolg van veranderinge aan die molekulêre struktuur van fibrien. Die hiperstolbare toestand in PsO kan implikasies hê vir die besturing van KVS risiko in individue wat lewe met die kondisie.af_ZA
dc.description.versionDoctoralen_ZA
dc.format.extentxiii, 125 pages : illustrations (some color)en_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/126064
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subjectPsoriasis -- Pathogenesisen_ZA
dc.subjectInflammation -- Mediatorsen_ZA
dc.subjectCardiovascular diseasesen_ZA
dc.subjectHypercoagulable stateen_ZA
dc.subjectFibrinen_ZA
dc.subjectUCTDen_ZA
dc.titleInvestigating systemic inflammation and hypercoagulability in psoriasis: implications for cardiovascular diseaseen_ZA
dc.typeThesisen_ZA
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
visser_investigating_2022.pdf
Size:
16.12 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Doctoral Degrees (Physiological Sciences)