The condition in which in the oxygen-carrying capacity of RBCs or their number is insufficient to meet physiological needs is characterized as anemia. Anemia is an underestimated burden of disease and despite that the vast majority of anemia is caused by iron deficiency, a substantial number of anemias are hemolytic and inherited.
Hereditary hemolytic anemia is a very heterogeneous disorder and can originate from a wide range of genetic defects. The heterogeneity, in combination with a low prevalence and poor disease understanding, makes hereditary hemolytic anemia very challenging to diagnose. In addition, the poor understanding of disease results in an unsatisfactory limited number of treatment options.
The results described in this thesis were therefore aimed 1) to improve the understanding of hereditary hemolytic anemia, both on the cellular level as on the clinical level, 2) to find common pathophysiological features that are disturbed in hereditary hemolytic anemia, 3) to develop and validate new diagnostics to improve the diagnostic workflow for hereditary hemolytic anemia.
This thesis therefore describes the use of new diagnostics and aims to increase our understanding of hereditary hemolytic anemia. Hereditary hemolytic anemia is characterized by unstable RBCs that lead to premature uptake of the RBC from the circulation (hemolysis). Hereditary hemolytic anemia constitutes of many RBC disorders, such as sickle cell anemia, thalassemia, hereditary spherocytosis, hereditary elliptocytosis, hereditary xerocytosis, pyruvate kinase deficiency and hexokinase deficiency. The primary and molecular causes of these diseases are often well understood, as these disorders usually originate from mutations in genes coding for hemoglobin, RBC membrane proteins or metabolic enzymes of the RBC. Less is however known for the secondary events, such as red blood cell vesiculation, that lead to the actual hemolysis and premature uptake of pathological RBCs in these rare diseases. Also, relatively less is known about the heterogeneity in cellular properties and its relation with the disease-severity in these disorders.
To improve our understanding of hereditary hemolytic anemia and to improve diagnostics for these diseases, multiple studies were carried out to either improve or facilitate the use of new diagnostics and to improve the understanding of hereditary hemolytic anemia.