Von Willebrandov faktor i faktor VIII u kroničnoj bolesti presatka protiv primatelja

doctoral thesis

• Title (english): Von Willebrand factor and Factor VIII in chronic Graft-versus-Host Disease
• Author: Antonela Lelas
• Mentor: Dražen Pulanić (mentor)
• Committee member: Radovan Vrhovac (predsjednik povjerenstva)
• Committee member: Vlatko Pejša (član povjerenstva)
• Committee member: Silva Zupančić-Šalek (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2025-03-19, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine
• Universal decimal classification (UDC): 616 - Pathology. Clinical medicine

Abstract

Kronična bolest presatka protiv primatelja (cGvHD) kasna je komplikacija alogenične transplantacije krvotvornih matičnih stanica (alo-PKMS) koju karakterizira imuna disregulacija. U svakodnevnoj kliničkoj praksi istaknuta je potreba za neinvazivnim i lako dostupnim biomarkerom koji bi pouzdano pokazivao aktivnost bolesti i pomogao u modulaciji terapijske strategije. Von Willebrandov faktor (VWF) i faktor VIII (FVIII) su koagulacijski faktori koji djeluju kao upalni markeri koji mogu odražavati i endotelnu aktivaciju, inače poznati etiopatogenetski čimbenik nastanka cGvHD-a. Njihov biomarkerski potencijal u procjeni aktivnosti bolesti opisivan je ranije u autoimunim bolestima koje klinički nalikuju cGvHD-u. Rezultati naše studije pokazali su kako su razine VWF i FVIII značajno više kod bolesnika oboljelih od cGvHD-a u odnosu na kontrole koji nisu razvili cGvHD (VWF:Ag 268,2% vs 191,9%, p=0,003; VWF:RCo 261,8% vs 178,2%, p= 0,003; FVIII 2,17 vs 1,82, p=0,006). Daljnom analizom pokazano je kako su razine VWF:Ag iznad 246,3% i VWF:RCo iznad 271,4% u inicijalnoj fazi bolesti dijagnostički pokazatelj pojave cGvHD-a visoke specifičnosti (92,3%) i dobre osjetljivosti (67,5%). Pokazano je i da su razine faktora povezane s postojanjem manifestacija cGvHD u jetri, ustima i gastrointestinalnom traktu. Ovim longitudinalnim istraživanjem po prvi put je pokazano kako su razine VWF i FVIII povišene dugo nakon postavljanja dijagnoze cGvHD-a i da su povezane s aktivnošću bolesti. Navedeni rezultati ukazuju na moguću dugotrajnu ulogu endotela u aloimunom odgovoru povezanim s cGvHD-om čime se dodatno ističe potreba za bazičnim istraživanjima koji bi dodatno objasnili biologiju bolesti. Potrebno je provesti dodatna istraživanja biomarkerskog potencijala VWF kao dijagnostičkog sredstva u predmanifestnoj fazi bolesti te u procjeni odgovora na terapiju čime bi se mogla omogućiti ranija terapijska intervencija i smanjenje nastanka ireverzibilih i teških sekvela bolesti.

Abstract (english)

Chronic Graft-versus-Host Disease (cGvHD) is a late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by immune dysregulation. In clinical practice, there is a critical need for a non-invasive and easily accessible biomarker that can reliably indicate disease activity and assist in tailoring therapeutic strategies. Von Willebrand factor (VWF) and factor VIII (FVIII) are coagulation factors that function as inflammatory markers and can reflect endothelial activation, a known etiopathogenetic factor in the development of cGvHD. Their biomarker potential in assessing disease activity has been previously described in autoimmune diseases that clinically resemble cGvHD. Our study results showed that VWF and FVIII levels were significantly higher in patients with cGvHD compared to controls who did not develop cGvHD (VWF 268.2% vs 191.9%, p=0.003; VWF 261.8% vs 178.2%, p=0.003; FVIII 2.17 vs 1.82, p=0.006). Further analysis revealed that VWF levels above 246.3% and VWF levels above 271.4% in the initial phase of the disease are diagnostic indicators of cGvHD with high specificity (92.3%) and good sensitivity (67.5%). It was also shown that these factor levels are associated with the presence of cGvHD manifestations in the liver, mouth, and gastrointestinal tract. This longitudinal study demonstrated for the first time that VWF and FVIII levels remain elevated long after the diagnosis of cGvHD and correlate with ongoing disease activity. These findings suggest a possible long-term role of the endothelium in the alloimmune response related to cGvHD, highlighting the need for basic research to further explain the biology of the disease. Additional studies are needed to investigate the biomarker potential of VWF as a diagnostic tool in the pre-manifestation phase of the disease and in assessing response to therapy, which could enable earlier therapeutic intervention and reduce the occurrence of irreversible and severe disease sequelae.

• Keywords: Von Willebrandov faktor; faktor VIII; kronična bolest presatka protiv darivatelja; biomarker; endotelna aktivacija; endotelna disfunkcija
• Keywords (english): Von Willebrand factor; factor VIII; chronic Graft-versus-Host Disease; biomarker; endothelial activation; endothelial dysfunction
• Language: croatian
• URN:NBN: urn:nbn:hr:105:917405
• Project: Number: IP-2016-06-8046; Title: Novi biomarkeri kronične bolesti presatka protiv primatelja; Title: New biomarkers in chronic Graft-versus-Host disease; Acronym: Bio-cGVHD; Leader: Dražen Pulanić; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Research Projects
• Study programme: Title: Biomedicine and Health Sciences; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
• Type of resource: Text
• Extent: 98 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2025-03-27 09:06:43