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Anemia can be defined as a reduction in hemoglobin concentration, hematocrit, or number of red blood cells per
cubic millimeter. The lower limit of the normal range is set at two standard deviations below the mean for age and
sex for the normal population. When a patient presents with anemia, it is important to establish whether the
abnormality is isolated to a single cell line (red blood cells only) or whether it is part of a multiple cell line
abnormality (red cells, white cells, and platelets). Abnormalities of two or three cell lines usually indicate one of the
following: Bone marrow involvement (e.g., aplastic anemia, leukemia)
The blood smear is very helpful in the diagnosis of anemia. It establishes whether the anemia is hypochromic,
microcytic, normocytic, or macrocytic and it also shows specific morphologic abnormalities suggestive of red cell
membrane disorders (e.g. spherocytes, stomatocytosis, or elliptocytosis) or hemoglobinopathies (e.g., sickle cell
disease, thalassemia).
Example: mean corpuscular volume (MCV) confirms the findings on the smear with reference to the red cell size,
microcytic (<80 fL), macrocytic (>98 fL), or normocytic (8298 fL).
A high value of MCHC (>35 g/dL) is characteristic of spherocytosis and a low value is commonly associated with
iron deficiency.
An elevated reticulocyte count suggests chronic blood loss or hemolysis; a normal or depressed count suggests
impaired red cell formation.
(normocytic, microcytic, or macrocytic), reflected in the color of red cells (normochromic or hypochromic);
and other special features, such as shape. These red cell indices are often judged qualitatively by physicians,
but precise quantitation is done in clinical laboratories using special instrumentation.
Mean cell volume: the average volume of a red blood cell, expressed in femtoliters (cubic micrometers)
Mean cell hemoglobin: the average content (mass) of hemoglobin per red blood cell, expressed in picograms
Mean cell hemoglobin concentration: the average concentration of hemoglobin in a given volume of packed
red blood cells, expressed in grams per deciliter
Megaloblastic Anemia
Causes of Megaloblastic Anemia
Vitamin B12 Deficiency
Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency
Pernicious anemia
Gastrectomy
Malabsorption states
Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis
Ileal resection, ileitis
Competitive parasitic uptake
Fish tapeworm infestation
Bacterial overgrowth in blind loops and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer
Folic Acid Deficiency
Decreased intake
Inadequate dietalcoholism, infancy
Impaired absorption
Malabsorption states
Intrinsic intestinal disease
Anticonvulsants, oral contraceptives
Increased loss
Hemodialysis
Increased requirement
Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis
Impaired use
Folic acid antagonists
Unresponsive to Vitamin B12 or Folic Acid Therapy
Metabolic inhibitors of DNA synthesis and/or folate metabolism, e.g., methotrexate
Modified from Beck WS: Megaloblastic anemias. In Wyngaarden JB, Smith LH (eds): Cecil Textbook of
Medicine, 18th ed. Philadelphia, WB Saunders, 1988, p. 900.
Aplastic Anemia
Major Causes of Aplastic Anemia
Acquired
Idiopathic
Primary stem cell defect
Immune mediated
Chemical agents
Dose related
Alkylating agents
Antimetabolites
Benzene
Chloramphenicol
Inorganic arsenicals
Idiosyncratic
Chloramphenicol
Phenylbutazone
Organic arsenicals
Methylphenylethylhydantoin
Streptomycin
Chlorpromazine
Insecticides (e.g., DDT, parathion)
Physical agents (e.g., whole-body irradiation)
Viral infections
Hepatitis (unknown virus)
Cytomegalovirus infections
Epstein-Barr virus infections
Herpes varicella-zoster
Miscellaneous
Infrequently, many other drugs and chemicals
Inherited
Fanconi anemia
Pathogenesis.
The pathogenesis of aplastic anemia is not fully understood. Indeed, it is unlikely that a single mechanism
underlies all cases. Two major etiologies have been invoked: an immunologically
mediated suppression and an intrinsic abnormality of stem cells ( Fig. 13-26 ).
Recent studies suggest that aplastic anemia results most commonly from suppression of stem cell function by
activated T cells.[46] It is postulated that stem cells are first antigenically
altered by exposure to drugs, infectious agents, or other unidentified environmental insults. This evokes a
cellular immune response, during which activated T cells produce cytokines such
as interferon-and TNF that prevent normal stem cell growth and development. This scenario is supported by
several observations. Immunosuppressive therapy with antithymocyte
globulin combined with drugs such as cyclosporine produces responses in 60% to 70% of patients, and
successful bone marrow transplantation requires "conditioning" with high doses of
myelotoxic drugs or radiation. In both instances, it is hypothesized these therapies work by suppressing or
killing autoreactive T-cell clones. The target antigens for T-cell attack are not
well defined. In some instances GPI-linked proteins may be the targets of sensitized T cells,
Transfusion
Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients
with a severe and symptomatic anemia.[13] Transfusion is palliative and should not be used as a substitute
for specific therapy. In chronic diseases associated with anemia of chronic disorders, erythropoietin may
be helpful in averting or reducing transfusions of packed RBCs.
Hemolytic transfusion reactions and transmission of infectious disease are risks of blood product
transfusions. Patients with autoimmune antibodies against RBCs are at greater risk of a hemolytic
transfusion reaction because of difficulty in cross-matching the blood. Occasionally, the blood of patients
with autoimmune hemolytic anemia cannot be cross-matched in vitro. In these cases, the patients require
in vivo cross-matching, in which incompatible blood is transfused slowly and periodic determinations are
made to ensure that the patient is not developing hemoglobinemia. This method should be used only in
patients with either significant hypoxia from the anemia or evidence of coronary insufficiency.
Although the traditional dosage of ferrous sulfate is 325 mg (65 mg of elemental iron) orally three times a
day, lower doses (eg, 15-20 mg of elemental iron daily) may be as effective and cause fewer side effects.
To promote absorption, patients should avoid tea and coffee and may take vitamin C (500 units) with the
iron pill once daily. If ferrous sulfate has unacceptable side effects, ferrous gluconate, 325 mg daily (35
mg of elemental iron) is a possible alternative for patients who cannot tolerate ferrous sulfate. [14]
A study in Iran demonstrated that once-weekly, low-dose iron supplementation can be effective in
improving iron status and in treating iron deficiency anemia. [15]Mozaffari-Khosravi et al randomly selected
and assigned 193 adolescent girls aged 14-16 years to receive either 150 mg ferrous sulfate once weekly
for 16 weeks or no iron supplementation. Before and after intervention, the percentage of anemia, iron
deficiency anemia, and iron deficiency were measured in both groups of girls.
Although the parameters measured before the intervention were not significantly different, at the end of
16 weeks, the group that received the ferrous sulfate had significant improvement in the same
parameters.[15] In addition, all cases of iron deficiency anemia were resolved in the group receiving the
low-dose iron supplementation.
Adults with iron deficiency anemia who cannot tolerate oral iron or who have an unsatisfactory response
to it can be treated with ferric carboxymaltose injection (Injectafer). The agent is given in two intravenous
infusions one week apart.
Iron deficiency anemia is prevalent in geographic locations where little meat is in the diet. Many of these
locations have sufficient dietary inorganic iron to equal the iron content in persons residing in countries in
which meat is eaten. However, heme iron is more efficiently absorbed than inorganic food iron. Folic acid
deficiency occurs among people who consume few leafy vegetables. Coexistence of iron and folic acid
deficiency is common in developing nations.
Certain patients seem to develop a salutary response with immunosuppressive therapy (ie, antithymocyte
globulin, cyclosporine). In a prospective study in 102 patients with severe aplastic anemia, 66%
responded to 6 months of treatment with antithymocyte globulin plus cyclosporine. The cyclosporine dose
was tapered over the subsequent 18 months. At 5 years, the relapse rate was 33%, which was
comparable to the rate in previous protocols in which cyclosporine was discontinued at 6 months without
taper, but the time to relapse was prolonged by about a year.
Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic,
marrow so that transfusion is not necessary and platelet and granulocyte counts increase to less
dangerous levels. (See Splenectomy.)
splenectomy
Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary
hemolytic disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvic
kinase deficiency). Improvement in survival rates has been reported in patients with aplastic anemia, but
splenectomy is not the preferential therapy. Leg ulcers have shown improvement in some patients with
thalassemia. Prior to splenectomy, patients should be immunized with polyvalent pneumococcal vaccine.
Preferably, this should be administered more than 1 week prior to surgery.
activity Restriction
The activity of patients with severe anemia should be curtailed until the anemia is partially corrected.
Transfusion can often be avoided by ordering bed rest, while therapy is initiated for a patient with
correctable anemia (eg, pernicious anemia).
March hemoglobinuria is a rare hemolytic disorder usually observed in young males. Individuals develop
hemoglobinuria after marching or running on hard surfaces. Curtailing the precipitating exercise (ie,
running on grass rather than concrete) and using shoes with reinforced soles are helpful in preventing
hemoglobinuria.
transfer Considerations
Patients with a benign etiology for anemia usually do not require transfer to another institution.
Occasionally, transfer is necessary to establish the etiology of the anemia or to provide a treatment that is
not locally available.
If patients are being transferred for diagnostic reasons, transferring them before transfusion is helpful. If
the transfusion is necessary before transfer to achieve hematopoietic stability, consult with the receiving
physician to determine laboratory tests that should be performed before transfusion. Patients who are
hemodynamically unstable should not be transported.
Medication
Therapeutic approaches to treat anemia include blood and blood products, immunotherapies,
hormonal/nutritional therapies, and adjunctive therapies. The goal of therapy in acute anemia is to restore
the hemodynamics of the vascular systems and to replace lost RBCs. To achieve this, the practitioner
may use mineral and vitamin supplements, blood transfusions, vasopressors, histamine (H2) antagonists,
and glucocorticosteroids.
Documentation of the etiology of anemia is essential in the selection of therapy. Not all microcytic
anemias are caused by iron deficiency; some are iron-overloading disorders. Similarly, not all
megaloblastic anemias are associated with either vitamin B-12 deficiency or folic acid deficiency.
Hereditary hemolytic disorders do not improve with corticosteroid therapy.
Packed red blood cells (PRBCs) are used preferentially to whole blood, since they limit volume, immune,
and storage complications. PRBCs have 80% less plasma, are less immunogenic, and can be stored
about 40 days (versus 35 d for whole blood). PRBCs are obtained after centrifugation of whole blood.
Leukocyte-poor PRBCs are used in patients who are transplant candidates/recipients and in those with
prior febrile transfusion reactions. Washed or frozen PRBCs are used in individuals with hypersensitivity
transfusion reactions.
Cryoprecipitate
This agent is used for the treatment of Von Willebrand disease. It contains fibrinogen, factor VIII, and von
Willebrand factor and can be used in lieu of factor VIII concentrate if the latter is unavailable.
Platelets
Patients who are thrombocytopenic and have clinical evidence of bleeding should receive a platelet
transfusion. Patients with platelet counts of less than 10,000/mcL are at risk for spontaneous cerebral
hemorrhage and require a prophylactic transfusion.
The preferred treatment for TTP and hemolytic-uremic syndrome is large-volume plasmapheresis with
FFP replacement. ITP is rarely treated with transfusion, as the transfused platelets are destroyed rapidly.
In stable patients, initial treatment is with prednisone. High-dose immunoglobulin and splenectomy are
very effective treatments.
Iron Products
Class Summary
Iron salts are used to provide adequate iron for hemoglobin synthesis and to replenish body stores of
iron. Iron is administered prophylactically during pregnancy because of the anticipated requirements of
the fetus and the losses that occur during delivery.
The required dose can be calculated (3.5 mg iron/g of hemoglobin) or obtained from tables in the
prescribing information. For IV use, this agent may be diluted in sterile 0.9% NaCl. Do not add to
solutions containing medications or parenteral nutrition solutions.
Vitamins
Class Summary
Vitamins are used to meet necessary dietary requirements and are used in metabolic pathways, as well
as DNA and protein synthesis.
Cyanocobalamin (vitamin B12) and folic acid are used to treat megaloblastic and macrocytic anemias
secondary to deficiency. Both vitamin B12 and folic acid are required for synthesis of purine nucleotides
and metabolism of some amino acids. Each is essential for normal growth and replication. Deficiency of
either cyanocobalamin or folic acid results in defective DNA synthesis and cellular maturation
abnormalities. Consequences of deficiency are most evident in tissues with high cell turnover rates (eg,
hematopoietic system).
Vitamin K deficiency causes elevation of prothrombin time and is commonly seen in patients with liver
disease.
Vitamin K
A decrease in levels of vitamin Kdependent factors (II, VII, IX, X, protein C, protein S) can lead to
bleeding. Vitamin K is also used to treat hemorrhagic disease of the newborn, Coumadin-induced
bleeding, and hypothrombinemia from other causes (eg, antibiotic, aspirin).
Electrolyte Supplements
Class Summary
Serum potassium levels can fall during therapy for severe cobalamin or folate deficiency and can lead to
sudden death. Therefore, potassium supplements may be indicated.
Depletion usually results from diuretic therapy, primary or secondary hyperaldosteronism, diabetic
ketoacidosis, severe diarrhea, if associated with vomiting, or inadequate replacement during prolonged
parenteral nutrition.
Potassium depletion sufficient to cause 1 mEq/L drop in serum potassium requires a loss of about 100 to
200 mEq of potassium from the total body store.
Vasopressors
Class Summary
These drugs decrease portal circulation pressure by diminishing blood flow due to vasoconstriction. The
major indication is variceal bleeding.
Vasopressin (Pitressin)
Vasopressin causes vasoconstriction of vascular smooth muscles and increases water permeability and
reabsorption in the collecting tubules. It decreases portal pressure in patients with portal hypertension.
Somatostatin (Zecnil)
Somatostatin diminishes blood flow to the portal system due to vasoconstriction, thus decreasing variceal
bleeding. It has similar effects to vasopressin but does not cause coronary vasoconstriction.
Cimetidine (Tagamet)
The primary indication is to reduce symptoms and accelerate healing of gastric ulcers. In the acutely
bleeding patient, it has limited benefit.
Ranitidine (Zantac)
Ranitidine inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces
gastric acid secretion, gastric volume, and hydrogen ion concentrations.
Famotidine (Pepcid)
Famotidine competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced
gastric acid secretion, gastric volume, and hydrogen ion concentrations.
Nizatidine (Axid)
Nizatidine competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in
reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
Glucocorticoids
Class Summary
These agents are used to treat idiopathic and acquired autoimmune hemolytic anemias.
Prednisone
Glucocorticoids inhibit phagocytosis of antibody-covered platelets. Treatment of ITP during pregnancy is
conservative unless the condition is severe. For severe cases, use the lowest dose of glucocorticoids. In
neonates, if the platelet count drops below 50,000-75,000 platelets/L, consider prednisone and
exchange transfusions and immunoglobulin.
TREATMENT
Nutritional Counseling
1. Maintain breast-feeding for at least 6 months, if possible.
2. Use an iron-fortified (612 mg/L) infant formula until 1 year of age (formula is
preferred to whole cows milk). Restrict milk to 1 pint/day.
3. Use iron-fortified cereal from 6 months to 1 year.
4. Use evaporated milk or soy-based formula when iron deficiency is due to
hypersensitivity to cows milk.
5. Provide supplemental iron for low-birth-weight infants:
a. Infants 1.52.0 kg: 2 mg/kg/day supplemental iron
b. Infants 1.01.5 kg: 3 mg/kg/day supplemental iron
c. Infants <1 kg: 4 mg/kg/day supplemental iron.
6. Facilitators of iron absorption such as vitamin C-rich foods (citrus, tomatoes,
and potatoes), meat, fish, and poultry should be included in the diet; inhibitors
of iron absorption such as tea, phosphate, and phytates common in vegetarian
diets should be eliminated.
Oral Iron Medication
1. Product: Ferrous iron (e.g., ferrous gluconate, ferrous ascorbate, ferrous lactate,
ferrous succinate, ferrous fumarate, or ferrous glycine sulfate) is effective. Ferric
irons and heavily chelated iron should not be used because they are poorly and
inefficiently absorbed.
2. Dose: 1.52.0 mg/kg elemental iron three times daily. Older children: ferrous
sulfate (0.2 g) or ferrous gluconate (0.3 g) given three times daily, to provide
100200 mg elemental iron. In children with GI side effects, iron once every
other day may be better tolerated with good effect.
3. Duration: 68 weeks after hemoglobin level and the red cell indices return to
normal.
4. Response:
a. Peak reticulocyte count experienced on days 510 following initiation of iron
therapy.
b. Following peak reticulocyte level, hemoglobin rises on average by 0.250.4
g/dL/day or hematocrit rises 1%/day during first 710 days.
c. Thereafter, hemoglobin rises more slowly: 0.10.15 g/dL/day.
5. Failure to respond to oral iron: If patient fails to respond to oral iron, the following
reasons should be considered:
a. Poor compliance (failure or irregular administration of oral iron); administration
can be verified by change in stool color to gray-black or by testing
stool for iron
b. Inadequate iron dose
c. Ineffective iron preparation
d. Persistent or unrecognized blood loss, with the patient losing iron as fast as
it is replaced
e. Incorrect diagnosis
f. Coexistent disease that interferes with absorption or utilization of iron (e.g.,
infection, inflammatory bowel disease, malignant disease, hepatic or renal
disease, or concomitant deficiencies of, for instance, vitamin B 12, folic acid,
thyroid, associated lead poisoning)
g. Impaired GI absorption (e.g., concurrent administration of large amounts of
antacids, which bind iron and histamine-2 blockers).
Blood Transfusion
A packed red cell transfusion should be given in severe anemia requiring correction
more rapidly than is possible with oral iron or parenteral iron or because of the
presence of certain complicating factors. This should be reserved for debilitated children
with infection, especially when signs of cardiac dysfunction are present and the
hemoglobin level is 4 g/dL or less.
Partial Exchange Transfusion
A partial exchange transfusion has been recommended in the management of a
severely anemic child under two circumstances:
Iron-Deficiency Anemia 45
1. In a surgical emergency, when a final hemoglobin of 910 g/dL should be
attained to permit safe anesthesia
2. When anemia is associated with congestive heart failure, in which case it is sufficient
to raise the hemoglobin to 45 g/dL to correct the immediate anoxia.