Hereditary anemias: more complex than ever

Part 1: New crossroads. The first part describes two new concepts in an attempt to unravel novel pathophysiological features of hereditary anemias. Chapter 2 reviews the pathophysiological aspects of pyruvate kinase (PK) deficiency, focusing on the interplay between PK-activity and reticulocyte maturation, stretching the importance of adequate oxidative control for normal mitophagy, which forms the fulfilling step of reticulocyte maturation. We propose late-stage ineffective erythropoiesis as a key pathophysiological concept in pyruvate kinase deficiency. Chapter 3 and 4 focusses on the erythropoietin (EPO)-fibroblast growth factor 23 (FGF23) signaling pathway in hereditary anemias. This, only briefly, previously described link between EPO and FGF23 may add to the understanding of (insufficient) EPO upregulation or responsiveness in hereditary anemias, as well as the bone mineralization disorders complicating these diseases. We speculate on a potential role for this pathway, not directly linked to erythroferrone (ERFE), as a target for treatment with the opportunity to ameliorate ineffective erythropoiesis and development of disease complications. Part 2: The challenge called heterogeneity. This part includes three articles that discuss unique disease characteristics and unique phenotypic appearances. Sickle cell disease earned a unique place among the hemolytic anemias as an important part of hemolysis does not occur extravascular (e.g. in the spleen or liver), but in the (micro)circulation itself. The relative balance between intra- and extravascular hemolysis seems to determine one’s risk of vasculopathic disease complications. In chapter 5 we introduce a ratio of two laboratory markers that represents the contribution of intravascular hemolysis to total hemolysis in an individual sickle cell disease patient, and this simple ratio was clearly associated with pulmonary hypertension and early death. Chapter 6 describes the unique monocyte transcriptome of sickle cell disease patients, sketching the balance of both pro- and anti-inflammatory pathways. In this chapter, we highlight the leading role of heme-oxygenase 1, an enzyme that breaks down heme, in determining this balance. Chapter 7 describes our attempt to untangle the relation between genotypes and phenotypes in hereditary spherocytosis. Which turned out to be an unproductive attempt. This led us speculating on the importance of other (genetic and non-genetic) modifying factors in determining phenotypic profiles. Part 3: About iron. This part focusses on the interplay between iron and erythropoiesis. Chapter 8 functions as a bridge between part 2 and part 3, as it reports on disease- specific patterns of the EPO-ERFE-hepcidin signaling pathway regulating iron. However, with the notion that broad inter-individual variety exists in each disease. Chapter 9 reflects on old, previously unpublished iron absorption and ferrokinetic data. This data provides an answer on the question what happens with intestinally absorbed iron in an already saturated portal circulation. And finally, chapter 10 describes the results of the PPI shine again study, a phase III randomized, placebo-controlled trial in a cross-over design investigating the efficacy of proton pump inhibitors in the prevention and treatment of iron-loading in patients with non-transfusion-dependent hereditary anemias.