Blood Cell Identification: 2011-C Mailing: Iron Deficiency ... · The differential diagnosis of iron deficiency anemia includes thalassemia and sideroblastic anemia, also microcytic
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Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
Peripheral blood smear in a patient with iron deficiency. Note the hypochromic, microcytes shown by the arrows. The central pallor in these red cells is significantly more than one third the cell diameter (hypochromic), while the red cell size is smaller than the small lymphocyte in this image. In addition, a thin elliptocyte is present (arrowhead).
In developed countries, however, this presentation is not common. Many patients in the United States with
iron deficiency anemia will have early iron deficiency with normal red cell indices and a relatively normal
peripheral blood smear. Only later will microcytosis, hypochromasia, anisocytosis, and poikilocytosis,
including thin elliptocytes, be seen on the blood smear. Iron-deficient red cells have abnormally stiff plasma
membranes, which contribute to the formation of elongated and elliptical hypochromic red cells.
The white blood cell count in iron deficiency anemia is normal or slightly decreased. Granulocytes may be
decreased and a few hypersegmented neutrophils may be observed. Greater numbers of the latter, though,
should raise the suspicion for concurrent folate or vitamin B12 deficiency. Platelets may be increased; in
severe anemia, they may be decreased.
Although bone marrow iron stores determined with Prussian blue stain of a bone marrow sample is the
“gold standard,” this invasive procedure is usually not needed in a straight forward case of iron deficiency
anemia. Expected response to a trial of oral iron therapy, as noted above, can be used. In addition,
decreased serum ferritin level can often supplant bone marrow sampling.
Serum ferritin is in equilibrium with the tissue and is a good, sensitive indicator of iron stores in most
patients. It is an acute phase reactant and may be elevated in inflammatory conditions, autoimmune
diseases, malignancy, and liver disease. In these conditions, a ferritin level within the normal range may
inaccurately mask underlying iron depletion (a false positive result for iron stores). Theoretically, raising the
lower end of the reference range in these patients may overcome this limitation; although standards by
which to do this are not well established. A low serum ferritin is generally not seen in conditions other than
iron deficiency.
Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
Hypochromic microcytes (inherited) or normocytic/macrocytic (acquired); variable anisopoikilocytosis; some cases show dimorphic red cell population or siderocytes
Serum Fe Decreased Decreased Normal or increased Increased
Ferritin Decreased Normal or increased Normal or increased Increased
Transferrin (TIBC) Increased Decreased Decreased or normal Decreased or normal
Bone marrow iron Absent Increased Increased Increased
Other useful information
Dietary, surgical, blood loss history
Identification of underlying disorder
Family history; hemoglobin analysis (such as HPLC, capillary or gel electrophoresis)
Family, medication, and nutritional history; if considering myelodysplastic syndrome, bone marrow evaluation with cytogenetics
Distinguishing between iron deficiency and anemia of chronic disease is the most common clinical problem.
Anemia of chronic disease is seen with a variety of chronic medical illnesses, including infections, chronic
immune activation (eg, systemic lupus erythematosus, rheumatoid arthritis), malignancies, and a number of
other disorders. The underlying medical illness causes release of cytokines and acute phase reactant
proteins that contribute to the anemia of chronic disease. Hepcidin, an acute phase reactant protein,
inhibits iron release from macrophages via its effect on the iron export protein ferroportin and decreases
iron absorption in the small intestine. These alterations result in inadequate iron availability for developing
erythroid precursors. Similar to iron deficiency, serum iron is low, but in contrast to iron deficiency, iron
transport proteins, as measured by TIBC, are decreased and bone marrow iron stores are increased.
Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
Sideroblastic anemias are a group of hereditary and acquired disorders that exhibit abnormal iron
metabolism and heme synthesis within the red blood cell. Inherited sideroblastic anemias are most often
hypochromic and microcytic, while acquired sideroblastic anemia may be normocytic or macrocytic. Causes
of acquired sideroblastic anemia include: myelodysplastic syndromes (clonal myeloid neoplasms), as well as
alcoholism, medications (eg, isoniazid, chloramphenicol), copper deficiency, and lead poisoning. In
sideroblastic anemias, iron becomes sequestered in the red blood cell mitochondria and is not available for
heme syntheses. In some cases, red cells with iron granules, a finding referred to as Pappenheimer bodies,
can be seen on the peripheral blood smear (Figure 2 below). Characteristic ring sideroblasts in the red cell
precursors show a ring-like accumulation of siderotic granules in mitochondria surrounding the nucleus
(Figure 3 on the following page). Serum iron, serum ferritin and bone marrow iron stores are all increased.
Figure 2. Sideroblastic Anemia
This image shows a peripheral blood smear from a patient with inherited sideroblastic anemia. This blood smear shows numerous hypochromic microcytes, many of which contain blue-purple staining iron granules referred to as Pappenheimer bodies. Red cells with iron granules can also be referred to as siderocytes.
Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
This image shows a Prussion blue iron stain performed on bone marrow aspirate material in a patient with the myelodysplastic syndrome refractory anemia with ring sideroblasts. The iron sequestered in mitochondria stains blue within the late erythroid precursors, and in some cells forms a ring around the nucleus (arrows).
Thalassemias are hereditary disorders of globin synthesis resulting in decreased numbers of hemoglobin
tetramers within red blood cells. Normal hemoglobin A tetramers are comprised of two α and two β globin
chains. Thalassemias result from decreased production of the normal α-globin (α-thalassemia) or β-globin (β-
thalassemia) subunit of the hemoglobin tetramer and result in variable clinical features depending on the
specific abnormality, number of affected genes, and degree of anemia. The peripheral blood smear will
show hypochromic, microcytes, and target cells (Figure 4 on the following page). In contrast to iron
deficiency anemia, increased polychromasia is seen on the blood smear, an indication of bone marrow
response to anemia. In addition, β-thalassemia may show basophilic stippling and/or circulating nucleated
red cells. Thalassemias occur predominantly in persons of Mediterranean, African, and Asian ancestry.
Family history and hemoglobin studies, such as high pressure liquid chromatography (HPLC) and gel or
capillary electrophoresis, may be useful. Homozygous hemoglobin E, a hemoglobinopathy characterized by
a mutation in the β-globin subunit of hemoglobin, shows similar clinical and blood smear findings to α-
thalassemia.
Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
This blood smear is from a patient with α-thalassemia. The red cell population is hypochromic, microcytic, and occasional target cells are seen (arrows). In contrast to iron deficiency, the RBC numbers may be normal or increased in thalassemia.
Blood Cell Identification: 2011-C Mailing: Iron Deficiency Anemia (IDA)
Schematic model of red cell membrane exhibiting the lipid bilayer with transmembrane proteins (including band 3 and glycophorin C) and skeletal membrane proteins (including α-spectrin, ß-spectrin, and protein 4.1).
Hereditary elliptocytosis and hereditary pyropoikilocytosis, on the other hand, are caused by defective
“horizontal” interactions. Horizontal interactions involve the proteins found at the inner surface of the RBC
membrane, including spectrin, actin, ankyrin, protein 4.1, and protein 4.2. The spectrin proteins form long,
linear arrays that create a meshwork that are anchored to the red cell lipid membrane by interactions with
ankyrin and protein 4.1. These skeletal proteins are essential in preserving membrane stability and
counteracting membrane fragmentation as the RBCs enter capillary beds and transit through the circulation.
The abnormalities in red cell shapes seen in the red cell membrane disorders are due to either a quantitative
decrease (or absence) in the amounts of proteins or in production of proteins that do not interact and self-
associate normally. The defect that underlies most cases of HE and HPP is a failure of spectrin
heterodimers to self-associate into spectrin heterotetramers that form the meshwork of proteins that create
the cytoskeletal structure. This is thought to arise from several different mutations that affect the structural
integrity of the “horizontal” red cell membrane cytoskeleton proteins. Thus, abnormal interactions between
the different proteins can arise due to mutations in α-spectrin, β-spectrin, band 3, and protein 4.1 genes
(Figure 3 above). When the interactions between these proteins are impaired, the horizontal stability of the
cytoskeleton is weakened as these proteins are essential for formation of a functional red cell cytoskeleton.
In addition, other mutations may impact the structural integrity of the red cell cytoskeleton. For example,
the necessary spectrin tetramer association is impaired by mutations in the alpha or beta-spectrin dimer-
dimer association regions. Finally, formation of the spectrin-actin-4.1 complex and its interaction with the
glycophorin protein to stabilize the membrane in a vertical fashion can be compromised by a defect in
Classic morphologic features of HPP. Numerous Classic morphologic features of HPP. Red cell fragments, fragmented cells and extensive polychromatophilic helmet cells, and elliptocytes are present. cells. Rare spherocytes are also seen.
Dependent on the degree and type of mutation present, cases of HPP may have more prominent
fragmented red cells or may have more prominent spherocyte formation. As a result of the increase in red
cell destruction, the bone marrow tries to offset the hemolysis by producing elevated numbers of red cell
precursors. These manifest as nucleated red blood cells and increased polychromatophilic cells in the
peripheral smear. As mentioned above, this severe red cell fragmentation manifests at temperatures of 45–46°C (as opposed to normal red blood cells fragmenting at 49°C). HPP is generally distinguished from
hemolytic forms of common HE by the abundance of spherocytes and fragmented cells and variable
numbers of intact elliptocytes in the blood smear.
Hematologic evaluation of parents and siblings can also be helpful in understanding the inheritance pattern
and nature of the defect. Useful additional laboratory data to aid in detecting hemolysis include elevated
lactate dehydrogenase (LDH), elevated indirect bilirubin, and low levels of haptoglobin. Reticulocyte counts
will be high as a compensatory mechanism for increased red cell destruction.
Interestingly, the blood smear and some laboratory abnormalities may also bear a close resemblance to
those seen in microangiopathic hemolytic anemia (MAHA), although its pathophysiology is quite separate
and distinct. While red cells in HPP fragment because of a congenital deficiency in red cell cytoskeletal
membrane proteins, the red cells in MAHA fragment as they undergo rips and tears by passing through
fibrin strands that have formed in the microcirculation. The blood smear findings of MAHA and HPP are so
similar that knowledge of the clinical history may be the only way to reliably distinguish the two entities.
Table 2 on the following page shows a comparison table of the two hemolytic disorders.