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Inflammation and fibrin structure in patients with end-stage renal disease

Jonas Angel Sjøland  


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Accepted by: Faculty of Health Sciences University of Southern Denmark
Defended on: August 31, 2007
Official opponents: Jørgen Ingerslev, professor, MD, DMSc , Søren Risom Kristensen, MD, DMSc , Uffe Holmskov, professor, MD, DMSc
Tutors: Jørgen Gram, MD, DMSc , Johannes Sidelmann, assistant professor, PhD , Robert Smith Pedersen, MD

Published in the PhD Database: September 4, 2007


English abstract
The present Ph.D. thesis is based on four papers and one manuscript carried out at Dept. of Clinical Biochemistry and Dept. of Nephrology, Ribe County Hospital, Esbjerg, as well at Dept. for Thrombosis Research, Institute of Public Health, University of Southern Denmark. The thesis addresses fibrin structure characteristics in terms of non-traditional risk factors for developing cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). These patients suffer from an unexplained high risk of developing CVD. Patients with manifest CVD are known to produce fibrin clot structures having tight and rigid network configurations and reduced susceptibility to fibrinolysis. It is believed that such fibrin clot structures may increase the risk of CVD by facilitating atherosclerosis formation. For the present Ph.D. thesis various analytical assays for studying fibrin structure characteristics were modified and optimized (incl. assays for turbidity, permeability, compaction, scanning electron microscopy and immunoaffinity chromatography). It was shown that in ESRD patients the fibrin clots were made of tight and rigid fibrin network structures having reduced fibrinolysis susceptibility. The observed fibrin structure characteristics correlated significantly with several markers of systemic inflammation, whereas markers of azothemia showed no such correlations. In a clinical cross-over trial with intraperitoneal heparin to ESRD patients on peritoneal dialysis it was shown that intraperitoneal heparin treatment reduced the intraperitoneal inflammation, causing a secondary reduction of the systemic inflammation. Moreover so, the fibrinolysis susceptibility of fibrin networks made from plasma samples became significantly improved following the reduced systemic inflammation. In all, the Ph.D. thesis shows that fibrin clot structures developed from plasma samples from ESRD patients are considerably different from those of healthy individuals, and that the fibrin structure characteristics in ESRD patients are associated mainly with the magnitude of systemic inflammation. Large-scale follow-up studies are, however, needed to assess the impact of fibrin structure characteristics on CVD morbidity and mortality in ESRD patients, but also to investigate the impact of reduced inflammation on fibrinolytic susceptibility and CVD outcome in these patients.


Danish abstract
Ph.d.-afhandlingen bygger på fem arbejder udgået fra Klinisk biokemisk afdeling og Nefrologisk afdeling, Sydvestjysk Sygehus, Esbjerg, samt Afdeling for Tromboseforskning, Institut for Sundhedstjenesteforskning, Syddansk Universitet. Afhandlingen beskæftiger sig med ikke-traditionelle risikofaktorer til forklaring af hvorfor patienter med terminal nyreinsufficiens (ESRD) har en betragtelig øget risiko for udvikling af hjertekarsygdom (CVD). Fokus for undersøgelserne har været patienternes evne til at danne og opløse fibrin, og i særdeleshed rollen af fibrinets struktur. I forbindelse hermed blev en række analytiske metoder optimeret og videreudviklet (bl.a. turbidimetri, permeabilitet, compaction, skanning elektron mikroskopi og immunoaffinitetskromatografi). Fibrinstrukturen hos patienter med kendt CVD er karakteriseret ved tætte og rigide netværk, som har øget modstandskraft overfor fibrinolyse. Dette formodes at øge risikoen for CVD gennem bl.a. øget forekomst af åreforkalkning. I indeværende ph.d.-afhandling er det vist, at patienter med ESRD, i lighed med CVD patienter, danner tætte og rigide fibrinstrukturer, som er mere modstandsdygtige overfor fibrinolyse end fibrinstrukturer fra raske kontroller. Årsagen til ESRD patienternes anderledes fibrinstrukturer fandtes primært at være associeret til forekomsten af kronisk systemisk inflammation, herunder i særlig høj grad øget plasma fibrinogenkoncentration. Derimod var graden af azotæmi af mindre betydning. I et klinisk overkrydsningsforsøg med intraperitoneal lav-molekylært heparin til ESRD patienter i posedialyse blev det vist, at nedsat intraperitoneal inflammation kunne reducere den systemiske inflammation, hvilket afstedkom en forbedring af fibrinolyseegenskaberne. Samlet viser ph.d.-afhandlingen at fibrinstrukturerne hos ESRD patienter er væsensforskellige fra raske individer, og at fibrinstrukturegenskaberne hos disse patienter hovedsageligt synes afhængige af den kroniske systemiske inflammation. Større og længerevarende kliniske studier savnes dog for at kunne fastlægge betydningen af forskellige fibrinstrukturegenskaber på risikoen for CVD hos ESRD patienter. Desuden bør undersøges om hvorvidt en reduktion af den kroniske systemiske inflammation hos disse patienter tillige vil kunne minimere patienternes risiko for CVD gennem forbedrede fibrinstrukturegenskaber.