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472 Part V Red Blood Cells

circumvents translational repression through the iron-responsive is finally extruded through the erythroblast membrane with the loss
element, iron regulatory protein system, thereby permitting export of about 5% to 10% of the hemoglobin that had been synthesized
of iron from erythroid precursor cells during the critical period when previously. The resultant reticulocyte continues to synthesize hemo-
cells commit to proliferation and differentiation, express high levels of globin for another 2 to 3 days until the cellular supply of mRNA is
transferrin receptor 1, and rapidly accumulate iron. As a consequence, exhausted, producing as much as 30% of the total hemoglobin
erythropoiesis may be partially suppressed when nonerythropoietic complement of the RBC. Eventually, the reticulocyte is released from
tissues risk developing iron deficiency. Iron export from erythroblasts the marrow, remodeled, and pitted of siderotic granules and debris
via FPN1B may account for the development of iron deficiency within the spleen to emerge as a mature RBC dedicated to oxygen
anemia as an initial, early manifestation of systemic iron deficiency. delivery over its lifespan of 3 to 4 months.
Nonetheless, when the cells begin to produce hemoglobin, FPN1B
expression diminishes and FPN1A predominates, allowing erythroid
cells to limit iron export through the iron-responsive element iron RECYCLING OF ERYTHROCYTE IRON BY MACROPHAGES
2
regulatory protein system and to efficiently manufacture heme. Fifth,
as noted earlier, cytosolic ferritin can be synthesized to sequester The major pathway of iron movement from erythroid cells is to a
6
surplus iron accumulations in a safe and soluble form. Sixth, a dedicated population of macrophages in the bone marrow, liver
mitochondrial ferritin, consisting of homopolymers of a nuclear (Kupffer cells), and spleen as RBCs reach the end of their lifespan
gene-encoded H-type ferritin (see later), can be expressed to protect (Fig. 35.5). Macrophages in the bone marrow also have the respon-
against mitochondrial iron accumulation in sideroblastic anemia and sibilities of culling defective immature erythroid cells to prevent their
6
some other disorders. Seventh, erythroblasts have the capacity to release into the circulation and of removing some deposits of eryth-
export excess heme through the feline leukemia virus subgroup C cel- rocyte ferritin from developing RBCs. During their time in the
16
lular receptor and avoid heme toxicity. Eighth, the heme importer bloodstream, RBCs undergo a multitude of modifications (oxidant
HRG1 is expressed in the membrane of early erythroid precursors damage, metabolic depletion, increasing intracellular calcium con-
and has been proposed as a possible pathway for acquisition of heme centrations, dehydration, decrease in cell volume, phosphatidylserine
in pathologic conditions. 16 exposure, formation of “senescent” antigens, and others) that lead to
Orthochromatic erythroblasts, with nuclei that are unable to their recognition and selective removal by specialized macrophages in
synthesize DNA, gradually lose most mitochondria and halt RNA the bone marrow, liver, and spleen. 16,17 On average, each of these
synthesis but continue to produce hemoglobin. The pyknotic nucleus macrophages can phagocytize one erythrocyte per day. After ingesting

Intravascular Hb Heme
RBC
hemolysis

Haptoglobin Hemopexin
Fe 2 Tf
Aging CD163
CD91

Extravascular
TFR1
hemolysis Tf
Senescent STEAP3
RBC
Fe 3+
Hb Fe 2+
HRG1
DMT1
HO-1
Heme Fe 2+ Ferritin Hemosiderin
Ferroportin
FLVCR Ceruloplasmin
Fe 2+ Fe 3+
Fe 2 Tf
Tf

Fig. 35.5 RECYCLING OF ERYTHROCYTE IRON BY MACROPHAGES. Most erythrocyte iron is
acquired by erythrophagocytosis of senescent red blood cells (RBCs), but smaller amounts are derived from
hemoglobin–haptoglobin and heme–hemopexin complexes. Iron derived from plasma transferrin (Tf) is a
minor portion of the total iron flux. Heme is catabolized, and the iron exported through ferroportin and
oxidized by ceruloplasmin. In the absence of iron deficiency, a portion of the iron is retained as ferritin
and hemosiderin. See text for details. DMT1, Divalent metal transporter 1; Fe 2 Tf, diferric transferrin;
FLVCR, feline leukemia virus subgroup C cellular receptor; Hb, hemoglobin; HO-1, heme oxygenase-1;
TFR1, transferrin receptor 1; HRG1: heme importer; STEAP3, six-transmembrane epithelial antigen of the
prostate 3. (Reproduced with permission from Beaumont C, Delaby C: Recycling iron in normal and pathological states.
Semin Hematol 46:328, 2009.)