Thesis Marein Schimmel
On 20 June 2017 (12:00 hrs) Marein Schimmel defended her thesis 'Sickle cell disease: pathogenesis and biomarkers' at the University of Amsterdam.
Promotores: Prof DPM Brandjes MD PhD and prof MHJ van Oers MD PhD
Copromotores: BJ Biemond PhD and prof SS Zeerleder MD PhD
Venue: Agnietenkapel, Oudezijds Voorburgwal 231, Amsterdam
Summary
Sickle cell disease (SCD) is a monogenetic disease wherein the haemoglobin complex of erythrocytes is affected, resulting in sickle haemoglobin. Sickle cell patients suffer from haemolytic anaemia, recurrent painful (micro)-vascular occlusions, secondary organ damage and early death. The pathophysiology of vaso-occlusive crises (VOC) includes neutrophil and endothelial activation, increased cellular adhesion and coagulation activation.
The aim of the research presented in this thesis was to study clinical biomarkers that may help identification of patients at risk of development of SCD related complications as these are lacking, but required to improve their clinical management.
In two of the clinical observational cohort studies that we executed, plasma levels of nucleosomes were found to have high potential to identify patients in VOC at risk of development of a serious VOC related complication, acute chest syndrome. The observed relation between levels of nucleosomes and neutrophil activation markers in plasma of patients with VOC in these studies might be an indication for the presence of Neutrophil Extracellular Traps(NET). In a subsequent experimental study we found sera of sickle cell patients able to induce NET formation in neutrophils from healthy donors. Iron chelation was effective to prevent NET formation in a subset of sickle cell sera.
In addition, this thesis includes two prospective longitudinal cohort studies in which we aimed to identify biomarkers related to the development of SCD related long-term organ complications and mortality.
Ultimately, the studies described in these thesis may help the identification of new potential targets of therapy for sickle cell patients.
Chapters
Chapter 1
General introduction and scope of the thesis
Chapter 2
Nucleosomes and neutrophil activation in sickle cell disease painful crisis
Haematologica. 2013 Nov;98(11):1797-803
Chapter 3
Inflammatory and endothelial markers during vaso-occlusive crisis in sickle cell disease
Chapter 4
Dynamics of von Willebrand factor reactivity in sickle cell disease during vaso-occlusive crisis and steady state
J Thromb Haemost. 2017 Apr 29
Chapter 5
Free iron in sera of patients with sickle cell disease mediates the release of neutrophil extracellular traps
Chapter 6
Urinary zinc loss in sickle cell disease primarily due to increased bone degradation
Am J Hematol. 2016 Jun;91(6):E311-2
Chapter 7
N-terminal pro-B-type natriuretic peptide, tricuspid jet flow velocity and death in adults with sickle cell disease
Am J Hematol. 2015 Apr;90(4):E75-6
Chapter 8
Prospective evaluation of chronic organ damage in adult sickle cell patients. A seven-year follow-up study
Chapter 9
Summary of results and future perspectives
Download
Download PhD thesis (university repository)