Hemoglobin loss from erythrocytes in vivo results from spleen-facilitated vesiculation

Utrecht University, Utrecht, Utrecht, Netherlands
Blood (Impact Factor: 10.45). 02/2003; 101(2):747-51. DOI: 10.1182/blood-2002-02-0500
Source: PubMed


Previous studies have shown that approximately 20% of hemoglobin is lost from circulating red blood cells (RBCs), mainly during the second half of the cells' life span. Because hemoglobin-containing vesicles are known to circulate in plasma, these vesicles were isolated. Flow cytometry studies showed that most RBC-derived vesicles contain hemoglobin with all hemoglobin components present. The hemoglobin composition of the vesicles resembled that of old RBCs. RBC cohort studies using isotope-labeled glycine have been described, which showed a continuous presence of this label in hemoglobin degradation products. The label concentration of these products increased during the second half of the RBC life span, accompanied by a decrease within the RBC. It is concluded that the hemoglobin loss from circulating RBCs of all ages can be explained by shedding hemoglobin-containing vesicles. This loss occurs predominantly in older RBCs. Apparently the spleen facilitates this process since asplenia vesicle retention within RBCs of all ages has been described, accompanied by an increase in the percentage of total HbA(1). The present study shows that in old RBCs of asplenic individuals, the decrease of hemoglobin content per cell such as seen in old RBCs of control individuals is absent due to an increase in the absolute amount of HbA(1c) and HbA(1e2). It is concluded that hemoglobin-containing vesicles within old RBCs are "pitted" by the spleen.

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Available from: Giel J C G M Bosman, Oct 04, 2015
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    • "In the mean-time all inclusion bodies are also being removed. In splenectomized patients or in patients with a non-functional spleen, phagocytosis of the inclusion bodies fails and results in a retention of a variety of intracellular inclusions within the RBC, such as Howell-jolly bodies (inclusions of nuclear chromatin remnants) (Wilkins and Wright, 2000), Heinz bodies (inclusions of denatured hemoglobin caused by oxidative damage) (Wilkins and Wright, 2000) siderocytes (RBC containing granules of iron that are not part of the cell's hemoglobin) (Wilkins and Wright, 2000) and Pappenheimer bodies inclusion bodies formed by phagosomes that have been engulfing excessive amounts of iron (Wilkins and Wright, 2000). Back in 1957 Crosby already showed that when siderocytes, tagged with radioactive chromium, were injected into a healthy patient with a functional spleen, there was a decline in siderocyte count without the loss of chromium labeled RBC. "
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    ABSTRACT: Macrophages tightly control the production and clearance of red blood cells (RBC). During steady state hematopoiesis, approximately 10(10) RBC are produced per hour within erythroblastic islands in humans. In these erythroblastic islands, resident bone marrow macrophages provide erythroblasts with interactions that are essential for erythroid development. New evidence suggests that not only under homeostasis but also under stress conditions, macrophages play an important role in promoting erythropoiesis. Once RBC have matured, these cells remain in circulation for about 120 days. At the end of their life span, RBC are cleared by macrophages residing in the spleen and the liver. Current theories about the removal of senescent RBC and the essential role of macrophages will be discussed as well as the role of macrophages in facilitating the removal of damaged cellular content from the RBC. In this review we will provide an overview on the role of macrophages in the regulation of RBC production, maintenance and clearance. In addition, we will discuss the interactions between these two cell types during transfer of immune complexes and pathogens from RBC to macrophages.
    Frontiers in Physiology 01/2014; 5:9. DOI:10.3389/fphys.2014.00009 · 3.53 Impact Factor
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    • "The striking resemblance between the hemoglobin composition of blood-borne vesicles and that of old erythrocytes, supports the conclusion that there is a continuous loss of hemoglobin in vesicles, which accelerates during the second half of the erythrocyte lifespan (Willekens et al., 2003). In the oldest erythrocytes of asplenic individuals , the decrease in hemoglobin is absent, concomitant with an increase in the absolute amounts of glycated and otherwise modified hemoglobin species (Willekens et al., 2003). Together with the previous observations that erythrocytes of patients without a functional spleen have an increased number of hemoglobincontaining vacuoles (Reinhart and Chien, 1988), and that there is a positive relation between the vacuole-containing erythrocytes and the percentage HbA1c (De Haan et al., 1988), these data suggest that hemoglobin-containing vesicles within old erythrocytes are removed from the erythrocytes in the spleen. "
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    ABSTRACT: THE CURRENTLY AVAILABLE DATA SUGGEST THAT EFFORTS TOWARD IMPROVING THE QUALITY OF RED BLOOD CELL (RBC) BLOOD BANK PRODUCTS SHOULD CONCENTRATE ON: (1) preventing the removal of a considerable fraction of the transfused RBCs that takes place within the first hours after transfusion; (2) minimizing the interaction of the transfused RBCs with the patient's immune system. These issues are important in reducing the number and extent of the damaging side effects of transfusions, such as generation of alloantibodies and autoantibodies and iron accumulation, especially in transfusion-dependent patients. Thus, it becomes important for blood bank research not only to assess the classical RBC parameters for quality control during storage, but even more so to identify the parameters that predict RBC survival, function and behavior in the patient after transfusion. These parameters are likely to result from elucidation of the mechanisms that underly physiological RBC aging in vivo, and that lead to the generation of senescent cell antigens and the accumulation of damaged molecules in vesicles. Also, study of RBC pathology-related mechanisms, such as encountered in various hemoglobinopathies and membranopathies, may help to elucidate the mechanisms underlying a storage-associated increase in susceptibility to physiological stress conditions. Recent data indicate that a combination of new approaches in vitro to mimick RBC behavior in vivo, the growing knowledge of the signaling networks that regulate RBC structure and function, and the rapidly expanding set of proteomic and metabolomic data, will be instrumental to identify the storage-associated processes that control RBC survival after transfusion.
    Frontiers in Physiology 12/2013; 4:376. DOI:10.3389/fphys.2013.00376 · 3.53 Impact Factor
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    • "In patients with thalassaemia intermedia, splenectomy was shown to increase the levels of PS-exposing microvesicles, potentially due to the diminished clearance of abnormal RBCs, which produce these PS-exposing microvesicles. Although vesiculation may be facilitated by the spleen in healthy subjects, this would not explain the post-splenectomy increase in RBC-derived microvesicles in thalassaemia intermedia patients (Willekens et al., 2003; Westerman et al., 2008). "
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    ABSTRACT: Hereditary hemolytic anemia encompasses a heterogeneous group of anemias characterized by decreased red blood cell survival because of inherited membrane, enzyme, or hemoglobin disorders. Affected red blood cells are more fragile, less deformable, and more susceptible to shear stress and oxidative damage, and show increased vesiculation. Red blood cells, as essentially all cells, constitutively release phospholipid extracellular vesicles in vivo and in vitro in a process known as vesiculation. These extracellular vesicles comprise a heterogeneous group of vesicles of different sizes and intracellular origins. They are described in literature as exosomes if they originate from multi-vesicular bodies, or as microvesicles when formed by a one-step budding process directly from the plasma membrane. Extracellular vesicles contain a multitude of bioactive molecules that are implicated in intercellular communication and in different biological and pathophysiological processes. Mature red blood cells release in principle only microvesicles. In hereditary hemolytic anemias, the underlying molecular defect affects and determines red blood cell vesiculation, resulting in shedding microvesicles of different compositions and concentrations. Despite extensive research into red blood cell biochemistry and physiology, little is known about red cell deformability and vesiculation in hereditary hemolytic anemias, and the associated pathophysiological role is incompletely assessed. In this review, we discuss recent progress in understanding extracellular vesicles biology, with focus on red blood cell vesiculation. Also, we review recent scientific findings on the molecular defects of hereditary hemolytic anemias, and their correlation with red blood cell deformability and vesiculation. Integrating bio-analytical findings on abnormalities of red blood cells and their microvesicles will be critical for a better understanding of the pathophysiology of hereditary hemolytic anemias.
    Frontiers in Physiology 12/2013; 4:365. DOI:10.3389/fphys.2013.00365 · 3.53 Impact Factor
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