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Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus
Thesis (MSc)--Stellenbosch University, 2023.
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| Language: | English |
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Stellenbosch : Stellenbosch University
2023
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| _version_ | 1867613853053878272 |
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| access_status_str | Open Access |
| author | Maphumulo, Siphosethu Cassandra |
| author2 | Pretorius, Etheresia |
| author_browse | Maphumulo, Siphosethu Cassandra Pretorius, Etheresia |
| author_facet | Pretorius, Etheresia Maphumulo, Siphosethu Cassandra |
| author_sort | Maphumulo, Siphosethu Cassandra |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (MSc)--Stellenbosch University, 2023. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/128456 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:42:44.343Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/128456 Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus Maphumulo, Siphosethu Cassandra Pretorius, Etheresia Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences. Type 2 diabetes -- Patients Type 2 diabetes mellitus -- Complications -- Pathophysiology Proteins -- Denaturation Blood -- Coagulation Insulin resistance UCTD Thesis (MSc)--Stellenbosch University, 2023. ENGLISH ABSTRACT: Introduction: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition associated with hypercoagulability and a heightened risk of cardiovascular disease. Mechanisms driving the alterations in the blood coagulation system are multifactorial. These alterations play a crucial role in the development of circulatory complications and vascular damage resulting in cardiovascular pathology in patients with T2DM. In this study, we postulate that thrombotic endotheliitis represents an important pathological process, alongside the abnormal metabolic environment, driving hypercoagulability and increased thrombotic propensity in these patients. It is described by systemic inflammation, endothelial dysfunction, insoluble amyloid plasma protein aggregates in circulation, abnormal fibrin clot structure, and a dysregulated circulating pro-coagulant plasma protein profile. Objectives: This study had various objectives. First, to evaluate the coagulation profiles of patients with T2DM and healthy individuals. Second, to assess the plasma levels of serum amyloid A (SAA) and soluble P-selectin, key markers of inflammation and platelet activation, in patients with T2DM compared to healthy individuals. Third, to investigate the presence of well-known markers of endothelial dysfunction, tissue factor (TF) and platelet endothelial cell adhesion molecule-1 (PECAM-1) inside insoluble plasma protein aggregates detected in the plasma of patients with T2DM compared to healthy individuals. Furthermore, this study aimed to determine if there were any changes to the ultrastructure of fibrin clots formed in plasma of patients with T2DM in comparison to clots formed in healthy individuals. Lastly, we set out to analyse the plasma levels of various proteins implicated in coagulation. Methods: Platelet-poor plasma (PPP) of 50 participants (n=20 healthy individuals and n=30 patients with T2DM) was used for analysis in this study. Thromboelastography was used to assess coagulation profiles and enzyme-linked immunosorbent assays were used to quantify plasma levels of SAA and soluble P-selectin. Fluorescence microscopy was utilized to analyse the presence of TF and PECAM-1 entrapped inside insoluble plasma protein aggregates and atomic force microscopy was used to assess the fibrin network architecture for structural changes. Finally, mass spectrometry-based proteomics was utilized to assess the levels of circulating pro-coagulant proteins in plasma. Results: Patients in our T2DM cohort were associated with a hypercoagulable state and significantly elevated plasma levels of SAA, in part, reflecting a proinflammatory state. The increased soluble P-selectin levels seen in patients with T2DM were not statistically significant. Moreover, patients with T2DM were associated with significantly larger insoluble plasma protein aggregates, suggestive of higher levels of TF and PECAM-1 released into circulation. Furthermore, aberrant fibrin clot structure and formation were observed in fibrin clots from patients with T2DM. Lastly significantly elevated levels of numerous pro-coagulant proteins were found in the plasma of patients with T2DM. Conclusion: The results of this study indicate that a hypercoagulable state is present in patients with T2DM, characterized by the pathological process described as thrombotic endotheliitis which plays a central role in abnormal blood clotting with an increased propensity to cardiovascular damage as seen in T2DM. AFRIKAANSE OPSOMMING: Inleiding: Tipe 2 Diabetes Mellitus (T2DM) is ‘n chroniese metaboliese toestand wat geassosieer word met hiperstolbaarheid en ‘n verhoogte risiko vir kardiovaskulêre siekte. Die meganismes wat die veranderinge in bloedstollingsstelsel aandryf is multifaktorieël. Hierdie veranderinge speel ‘n deurslaggewende rol in die ontwikkeling van sirkulatoriese komplikasies en vaskulêre skade, wat lei tot kardiovaskuêre patologie in pasiënte met T2DM. In hierdie studie postuleer ons dat thrombotiese endotheliitis – gekenmerk deur sistemiese inflammasie, endoteel wanfunksie, onoplosbare amiloïed plasma proteïen aggregate in sirkulasie, abnormale fibrienklontstruktuur, asook ‘n wanreguleerde sirkulerende pro-koagulante plasmaproteïenprofiel – 'n belangrike patologiese proses voorstel saam met die abnormale metaboliese omgewing, hiperstolbaarheid en verhoogde trombotiese geneigdheid by hierdie pasiënte. Doelwitte: Hierdie studie het verskeie doelwitte gehad. Eerstens, om die stollingsprofiele van pasiënte met T2DM en gesonde individue te evalueer. Tweedens, om die plasma vlakke van serumamiloïed A (SAA) en oplosbare P-selektien, hoof merkers van inflammasie en plaatjieaktiveering, te ondersoek in pasiënte met T2DM in vergelyking met gesonde individue. Derdens, om te ondersoek of bekende merkers van endoteel wanfunksie, weefsel faktor (TF) en plaatjie endoteelsel adhesie molekule-1 (PECAM-1); teenwoordig is binne die onoplosbare plasma proteïen aggregate, gevind in die plasma van pasiënte met T2DM in vergelyking met gesonde individue. Die studie het ook beoog om te bepaal of daar enige veranderinge was aan die ultrastruktuur van fibrienklonte gevorm in die plasma van pasiënte met T2DM in vergelyking met die klonte van gesonde individue. Laastens het ons die plasma vlakke van ‘n verskeidenheid proteїene wat by stolling betrokke is, geanaliseer. Metodes: Plaatjie-arme plasma (PPP) van 50 deelnemers (n=20 gesonde individue en n=30 pasiënte met T2DM) is gebruik vir analise in die studie. Trombo-elastografie is gebruik om die stollingstatus te assesseer en ensiemgekoppelde immunosorbenttoetse is gebruik om die plasma vlakke van SAA en oplosbare P-selektien te kwantifiseer. Fluoressensiemikroskopie is benut om die teenwoordigheid van TF en PECAM-1 vasgevang in onoplosbare plasma proteïen aggregate te analiseer en atoomkragmikroskopie is gebruik om die fibrien netwerk argitektuur te assesseer vir strukturele veranderinge. Laastens, is massaspektrometrie-gebaseerde proteomika gebruik om die vlakke van sirkulerende pro-koagulante proteïene in plasma te bepaal. Resultate: Pasiënte met T2DM was betekenisvol geassosieer met ‘n hiperstolbare tostand en betekenisvolle verhoogde plasma vlakke van SAA, wat deels 'n pro-inflammatoriese toestand weerspieël. Die verhoogde plasma vlakke van oplosbare P-selektien in pasiënte met T2DM het geen betekenisvolle veranderinge getoon nie. Verder is daar gevind dat pasiënte met T2DM betekenisvol geassosieer is met groter onoplosbare plasma proteïen aggregate geassosieer is, wat suggereer dat hoër vlakke TF en PECAM-1 vrygestel word in die sirkulasie. Boonop is afwykende fibrienklontstruktuur en -vorming waargeneem in fibrienklonte van pasiënte met T2DM. Ten slotte is betekenisvolle toenames in die vlakke van talle pro-koagulante proteïene in die plasma van pasiënte met T2DM gevind. Afsluiting: Die resultate van hierdie studie dui aan dat 'n hiperstolbare toestand teenwoordig is in T2DM, gekenmerk deur die patologiese proses wat beskryf word as trombotiese endotelitis wat 'n sentrale rol speel in die abnormale bloedstolling met ‘n verhoogde geneigdheid tot kardiovaskulêre skade, soos gesien in T2DM pasiente. Masters 2023-03-04T15:29:23Z 2023-08-30T13:11:18Z 2023-03-30 2023-03-04T15:29:23Z 2023-08-31T09:18:46Z 2023-03-04T15:29:23Z 2023-08-31T09:18:46Z 2023-03 Thesis https://scholar.sun.ac.za/handle/10019.1/128456 en Stellenbosch University application/pdf xvii, 152 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Type 2 diabetes -- Patients Type 2 diabetes mellitus -- Complications -- Pathophysiology Proteins -- Denaturation Blood -- Coagulation Insulin resistance UCTD Maphumulo, Siphosethu Cassandra Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title | Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title_full | Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title_fullStr | Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title_full_unstemmed | Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title_short | Blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| title_sort | blood coagulopathy and dysregulated circulating proteins associated with type 2 diabetes mellitus |
| topic | Type 2 diabetes -- Patients Type 2 diabetes mellitus -- Complications -- Pathophysiology Proteins -- Denaturation Blood -- Coagulation Insulin resistance UCTD |
| url | https://scholar.sun.ac.za/handle/10019.1/128456 |
| work_keys_str_mv | AT maphumulosiphosethucassandra bloodcoagulopathyanddysregulatedcirculatingproteinsassociatedwithtype2diabetesmellitus |