Thesis Iris Kreft

On 20 November 2024 Sanquin researcher Iris Kreft defended her thesis 'Profiles in Spectra: Mass spectrometry-based proteomics of plasma and platelets in hematological disorders' at Utrecht University.

Promotor: Prof AB Meijer PhD
Co-promotor: M van den Biggelaar PhD
Venue: Academy Building, Utrecht University 

Abstract

Proteins are key regulators of biological processes and variations in their quantity and quality are related to disease. In this thesis, we use state-of-the-art mass spectrometry (MS) to demonstrate how protein profiling can provide insights into hematological disorders.  

First, we studied variation in plasma protein levels in healthy blood donors, before, during and after whole blood donation. This showed the ability of MS to identify and quantify plasma proteins and plasma protein complexes that reflect the functionality of platelets, red blood cells and immune cells.  

Next, we investigated plasma profiles of patients with hematological disorders, including acute myeloid leukemia, graft-versus-host disease, and thrombosis. Here, we discovered specific protein changes related to inflammatory responses and found that protein levels in patients at risk of thrombosis could be linked to the underlying disease or treatment. 

In children with inherited platelet disorders, we mapped the platelet proteome to unravel the effects of genetic mutations on protein profiles. We discovered that mutations in cytoskeleton-related genes have a significant impact on platelet proteomes and constructed a disease map which enabled identification of both known as well as novel proteins associated with alpha-granules. This study enhances the understanding of genotype-phenotype relationships and provides opportunities to investigate bleeding disorders of unknown cause. 

Finally, we developed a MS method for the identification and quantification of benign polymorphisms and pathogenic variants of the adhesive glycoprotein Von Willebrand Factor. We showed that MS can be used as a diagnostic assay in patients with Von Willebrand disease to support disease classification. 

Chapters

Chapter 1
General introduction and topics addressed in this thesis

Chapter 2
Mass spectrometry-based analysis on the global plasma proteome after a whole blood donation abstract

Chapter 3
Plasma profiling of acute myeloid leukemia with fever- and infection-related complications during chemotherapy-induced neutropenia abstract

Chapter 4
Longitudinal plasma profiling of allogeneic hematopoietic stem cell transplantation recipients reveals heterogeneous development and associations with GvHD

Chapter 5
Absence of COVID-19 associated changes in coagulation and thrombosis in the ferret Model abstract

Chapter 6
Unbiased plasma proteomic profiling in patients at risk of thromboembolic events

Chapter 7
Proteomic landscapes of inherited platelet disorders with different etiologies abstract

Chapter 8
Variant mapping using mass spectrometry-based proteotyping as a diagnostic tool in Von Willebrand Disease abstract

Chapter 9
Summarizing discussion

Download

Download PhD thesis (university repository)

Thesis Iris Kreft