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How To Approach Chronic Anemia
How To Approach Chronic Anemia
1Division
of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville,
TN; 2VeteransAffairs Tennessee Valley Healthcare System, Nashville, TN; 3Department of Pediatrics,
The Ohio State University College of Medicine, Columbus, OH; and 4Department of Hematology/Oncology,
Nationwide Children’s Hospital, Columbus, OH
We present herein an approach to diagnosing the cause of chronic anemia based on a patient’s history and complete
blood cell count (CBC). Four patterns that are encountered frequently in CBCs associated with chronic anemias are
considered: (1) anemia with abnormal platelet and/or leukocyte counts, (2) anemia with increased reticulocyte counts,
(3) life-long history of chronic anemia, and (4) anemia with inappropriately low reticulocytes. The pathophysiologic
bases for some chronic anemias with low reticulocyte production are reviewed in terms of the bone marrow (BM)
events that reduce normal rates of erythropoiesis. These events include: apoptosis of erythroid progenitor and
precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is
impaired, and development of microcytosis due to heme-regulated eIF2␣ kinase inhibition of protein synthesis in
iron-deficient or thalassemic erythroblasts.
Chronic anemia associated with abnormal platelets causes of liver disease is important for diagnosing and treating
and or leukocytes chronic anemia. Some examples are: chronic alcohol consumption
Any disorder that disrupts the BM space may affect all blood cell can have direct BM toxicity and can be associated with poor intake
lineages. Furthermore, because HSCs and multilineage progenitors of folate; antiviral treatments for hepatitis C can suppress erythropoi-
between the HSC and BFU-E stages give rise to all blood cell types, esis; and hepatitis B, hepatitis C, or autoimmune hepatitis can be
a disease affecting these early-stage hematopoietic progenitors will complicated by aplastic anemia.
likely affect the platelets and leukocytes as well as erythrocytes.
Figure 2 includes the presentation of chronic anemia with decreased The absence of splenomegaly with multilineage cytopenias usually
platelets and leukocytes. Splenomegaly is a site of trapping of indicates a primary BM disease, including aplastic anemia, myelo-
multiple cell lineages, as seen in chronic liver disease with dysplasia (MDS), and acute leukemia or BM invasion by a
hypersplenism, spleen- and BM-based lymphoid proliferations such malignancy such as metastatic solid tumors. In addition to physical
as indolent B-cell lymphoma and hairy cell leukemia, and auto- disruption of the BM, the malignant population can induce chronic
immune cytopenias of systemic lupus erythematosus and Evans anemia by increasing apoptosis or restricting the differentiation of
syndrome. In chronic liver disease, portal hypertension from erythroid progenitors. One example is multiple myeloma, a BM-
cirrhosis enlarges the spleen and traps erythrocytes, platelets, and infiltrating disease in which most patients develop chronic anemia.
neutrophils, but the chronic anemia is often multifactorial, with Two members of the TNF-␣ family, Fas ligand (FasL) and
upper gastrointestinal hemorrhage due to varices combined with TNF-related apoptosis-inducing ligand (TRAIL), are specific media-
thrombocytopenia and/or coagulopathy.5 Discerning the underlying tors of apoptosis expressed by myeloma cells.6 Surface FasL and
TRAIL receptors are expressed by proerythroblasts and early ered as a potential factor in stimulating platelet production. Al-
basophilic erythroblasts, erythropoietic stages that depend upon though EPO and thrombopoietin (TPO) have been shown to have
EPO to prevent apoptosis (Figure 1). EPO inhibits Fas-mediated synergist effects on megakaryocytopoiesis, the partial homology of
erythroblast apoptosis,7 and down-modulation of Fas and FasL in the receptors for EPO and TPO does not appear to play a role,
these early-stage erythroblasts has been shown to be a mechanism of because no cross-competition between EPO and TPO could be
EPO’s antiapoptotic effects.8 Coculture of erythroblasts with my- detected for receptor binding in cells engineered to express both
eloma cells expressing FasL and TRAIL triggers the respective receptors.17 In severe iron deficiency anemia, patients may have
receptors in the erythroblasts, thereby activating apoptotic path- thrombocytopenia, which also resolves with iron therapy.18
ways.6 Multiple myeloma also induces apoptosis indirectly in early Chronic anemia can be accompanied by increased leukocytes in
erythroblasts when it suppresses renal EPO production. Several patients with chronic inflammation/infection, and the leukocyto-
types of malignancies reduce EPO levels due to cytokine-mediated sis may help to distinguish iron deficiency from the anemia of
suppression of EPO production.9 In many patients with multiple chronic inflammation. Conversely, chronic anemia is a negative
myeloma, paraprotein-mediated renal insufficiency decreases EPO prognostic sign when it is associated with increased platelets due
production further, and the degree of EPO deficiency is correlated to essential thrombocythemia19 or with increased leukocytes due
with the amount of BM infiltration and the proliferation rate of the to myelofibrosis.20
myeloma cells.10,11 Thalidomide chemotherapy12 and EPO adminis-
tration13 in myeloma patients can reverse the inhibited erythropoi- Chronic anemia with increased reticulocytes
esis and improve the anemia. Lastly, hepcidin, the hepatic hormone Chronic anemia unaccompanied by significant abnormalities of
that restricts iron flux from macrophages to erythropoietic cells by platelets or leukocytes can be separated into anemia with appropri-
down-regulating ferroportin-1 on macrophages, is induced by bone ately increased reticulocytes for the degree of anemia and anemia
morphogenetic protein 2 (BMP2), thereby contributing to chronic without an appropriate reticulocytosis (Figure 3). Absolute reticulo-
anemia in multiple myeloma.14 cyte counts and the reticulocyte index indicate whether BM
erythrocyte production is appropriately increased, as would be
Chronic anemia in MDS and aplastic anemia is often associated expected in patients with fully responsive erythropoietic
with low platelets and/or leukocytes. Excessive apoptosis destroys capacities, or not appropriately increased, as would be ex-
early-stage erythroid progenitors and multilineage hematopoietic pected in patients with impaired erythropoiesis. In chronic
cells, and the expressions of receptors for TNF-␣, FasL, and TRAIL anemia, an increased absolute number of reticulocytes or an
are increased in these 2 progenitor populations.15,16 Therefore, increased reticulocyte index indicates low-grade hemolysis or
intrinsic overexpression of these membrane TNF-␣ family receptors blood loss. Except in patients with liver disease, increased
that mediate apoptosis appears to play a significant role in the indirect serum bilirubin, increased lactate dehydrogenase,
development of the anemia in MDS and aplastic anemia. and decreased haptoglobin are characteristic of hemolysis. The
blood smear is the most helpful in these cases. After exclud-
Frequently, chronic anemia due to iron deficiency is accompanied ing acute disorders such as hemolytic-uremic syndrome,
by increased platelets, and this thrombocytosis resolves with iron thrombotic thrombocytopenia purpura, and peripartum-related
repletion. The cause of increased platelet counts is unknown, but syndromes, chronic intravascular hemolysis with erythrocyte
increased EPO levels in iron deficiency anemia have been consid- fragmentation is often associated with malignant tumors, large
hemangiomas, prosthetic heart valve defects, or direct external depend upon the severity of the globin deficiency. Chronic anemia
trauma (eg, march hemoglobinuria). Spherocytes on the smear due to ␣-thalassemia is caused by deletions or abnormalities
suggest hereditary spherocytosis or immune hemolysis; the involving 2 or 3 of the 4 ␣-globin genes on chromosome 16 and
latter can be diagnosed by surface Abs and/or complement result in ineffective erythropoiesis from early fetal life. Missing 1 of
components on erythrocytes in the direct antiglobulin test. 4 ␣-globins is asymptomatic, and missing all 4 ␣-globins usually
Normal erythrocyte morphology and negative direct Ab testing leads to fetal death. Missing 2 of 4 ␣-globin genes leads to the
indicate possible enzyme dysfunction. Glucose-6-phosphate de- ␣-thalassemia trait, which is characterized by mild microcytic
hydrogenase (G6PD), the most common RBC enzyme defi- anemia and is often diagnosed on newborn screening by the
ciency, is an exception in that eccentrocytes or blister cells with presence of ␥-globin tetramers known as Hgb Barts. If not
Hgb “puddled” away from the cell membrane are seen on diagnosed by newborn screening, patients who later have a CBC
peripheral smears. Without evidence of hemolysis, chronic performed will have a mild microcytic anemia that can be differenti-
anemia with increased reticulocytes can result from bleeding ated from iron deficiency anemia by a normal or elevated RBC
in patients who have not lost sufficient amounts of blood to number and a normal RBC distribution width.22 If only 2 of the
develop microcytosis from iron deficiency. Patients with intermit- 4 ␣-globin genes is missing, the Hgb electrophoresis will become
tent blood losses include many with menorrhagia or upper normal shortly after birth. Serum ferritin, which reflects total body
gastrointestinal lesions such as varices, arteriovenous malforma- iron stores, will be normal or elevated, further distinguishing the
tions, and ulcers. thalassemia trait from iron deficiency. When a definitive diagnosis
of 1 or 2 ␣-globin gene deletions is desired for treatment or genetic
Life-long history of abnormal CBC (no previously counseling, ␣-globin gene sequencing can be performed in specialty
normal CBC) laboratories. Missing 3 of 4 ␣-globin genes causes Hgb H disease,
Worldwide, the most common cause of congenital anemia is which may be symptomatic at birth with anemia and jaundice. The
thalassemia,21 which is the most frequent cause of a life-long history newborn screening in these cases will show greater than 10% Hgb
of undiagnosed chronic anemia (Figure 3). Thalassemia is character- Barts. Because fetal erythropoiesis changes over to adult erythropoi-
ized by deficient globin production with preservation of the RBC esis during the first several months of life, -globin tetramers will
number, leading to microcytic cells with decreased Hgb content per form and become evident on Hgb electrophoresis as Hgb H.
cell. The number of cells produced and the degree of microcytosis Children with Hgb H disease may be transfusion dependent or have