Anemia

• Anemia is a group of diseases characterized by a decrease in either

hemoglobin (Hb) or the volume Of red blood cells (RBCs),
resulting in decreased oxygen-carrying capacity of blood.

• TheWorld Health Organization defines anemia as Hb less than 13

g/dL (<130 g/L; <8.07 mmol/L) in men or Less than 12 g/dL
(<120 g/L; <7.45 mmol/L) in women.
 Erythropoiesis
• Erythropoiesis begins with a pluripotent stem cell in the
bone marrow undergoing differentiation and ends with
the appearance of RBCs in peripheral blood.
• The production of RBCs is stimulated by EPO, a
hormone secreted by the kidney in response to
detection of decreased oxygen-carrying capacity of
blood.
• EPO stimulates RBC production by stimulating dif-
ferentiation of RBC precursors in the bone marrow to
become reticulocytes.
• Reticulocytes become erythrocytes after 1 to 2 days in
the bloodstream.
• Pathophysiologic classification of anemia

• 1-Blood Loss
• Acute: trauma, ulcer, hemorrhoids
• Chronic: ulcer, vaginal bleeding, aspirin ingestion
• 2-Inadequate Red Blood Cell Production
• A-Nutritional deficiency: vitamin B12, folic acid, iron
• B-Erythroblast deficiency: bone marrow failure (aplastic anemia,
• irradiation, chemotherapy, folic acid antagonists) or bone marrow infiltration
(leukemia, lymphoma, myeloma, metastatic solid tumors, myelofibrosis)
• C-Endocrine deficiency: pituitary, adrenal, thyroid, testicular
• D-Chronic disease: renal, liver, infection, granulomatous, collagen vascular
• 3-Excessive Red Blood Cell Destruction
• A-Intrinsic factors: hereditary (G6PD), abnormal hemoglobin synthesis
• B-Extrinsic factors: autoimmune reactions, drug reactions, infection (endotoxin)
• Morphlogical classification of anemia
• 1-Macrocytic
• Defective maturation with decreased production
• Megaloblastic: pernicious (vitamin B12 deficiency), folic acid
deficiency
• 2-Normochromic, Normocytic
• Recent blood loss
• Hemolysis
• Chronic disease
• Renal failure
• Autoimmune
• Endocrine
• 3-Microcytic, Hyperchromic
• Iron deficiency
• Genetic abnormalities: sickle cell, thalassemia
• Anemia of inflammation (AI) is a newer term used
to describe both anemia of chronic disease and
anemia of critical illness.
• AI is an anemia that traditionally has been
associated with infectious or inflammatory
processes, tissue injury, and conditions associated
with release of proinflammatory cytokines
 Diseases Causing Anemia of Inflammation
• Chronic infections
• Tuberculosis
• Osteomyelitis
• Chronic urinary tract infections
• Chronic inflammation
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Inflammatory bowel disease Inflammatory
• osteoarthritis
• Gout
• Malignancies
• Carcinoma
• Lymphoma Leukemia
• Multiple myeloma
 • Effect of age
• Age-related reductions in bone marrow reserve can
render elderly patients more susceptible to anemia
caused by multiple minor and often unrecognized
diseases (eg, nutritional deficiencies) that negatively
affect erythropoiesis.

• Pediatric anemias are often due to a primary

hematologic abnormality.
• The risk of IDA is increased by rapid growth spurts
and dietary deficiency.
CLINICAL PRESENTATION
 Diagnosis
• 1. A CBC is a necessary first step in evaluating a patient
with anemia.
• If the Hgb and Hct are less than the normal range, the
patient is anemic.
• Subsequent evaluations of RBC indices and the
peripheral smear often are necessary to determine the
etiology (and ultimately, the treatment) of the anemia.
• 2. Evaluating the mean corpuscular volume (MCV) is
the next step in an anemia workup. It is classified as
microcytic, normocytic, or macrocytic if the MCV is
below, within, or above the normal range of 80 to 96
fL/cell, respectively.
 DIAGNOSIS
• Microcytic Anemia and Iron Evaluation
• Iron studies should be evaluated in the setting of a
low MCV. These include:
• Serum iron
• Serum ferritin—the best indirect determinant of body
iron
• stores. It is commonly decreased in patients with IDA
• Total iron-binding capacity (TIBC)—quantifies the iron-
binding capacity of transferrin and is increased in IDA
• Transferrin saturation (serum iron/TIBC)—indicates the
amount of transferrin that is bound with iron; it is
lower in IDA
 Diagnosis
• Macrocytic Anemia
• Evaluate folic acid and vitamin B12 levels in the
setting of an elevated MCV
• Normocytic Anemia
• Evaluate reticulocytes and CBC
• High reticulocyte counts may indicate RBCs loss via
acute blood loss, hemolysis, or splenic
sequestration
• Low serum iron with normal to increased ferritin
consistent with ACD(anemia of chronic disease )
 Treatment
Desired Outcomes

• The goal of anemia therapy is to increase Hgb to

levels that improve red cell oxygen-carrying
capacity, alleviate symptoms, and prevent
complications from anemia.
• Normal Hgb val- ues are 14.0 to 17.5 g/dL for
males and 12.3 to 15.3 g/dL for females.
• It is important to note that continuation of
therapy should be assessed primarily by
resolution of clinical symptoms
 Nonpharmacologic Therapy
• Transfusion of RBC
• The safety concern ,cost, availability of this
therapy. So indicated only as below
• Typically, only patients with acute symptoms (ie,
dyspnea, chest pain) and Hgb concentrations in
the range of 7.0 to 9.0 g/dL (70–90 g/L ) require
blood transfusions.
• Diet
• ingesting a diet that is rich in iron, folic acid, or
vitamin B12 should be encouraged
 Pharmacological
• Iron-Deficiency Anemia

• Oral treatment
• The initial treatment of IDA is oral iron therapy that
provides 150 to 200 mg of elemental iron daily
• Iron supplementation resolves anemia by replenishing
iron stores to levels necessary for RBC production
and maturation.
• Reticulocytosis should occur in 7 to 10 days, and Hgb
values should rise by about 1.0 g/dL per week.
• Patients should be reassessed if Hgb does not
increase by 2.0 g/dL in 3 weeks.
• The preferred regimen for oral iron is 50 to 65 mg
of elemental iron two to three doses daily on an
empty stomach.
• Administration on an empty stomach (1 hour
before or 2 hours after a meal) is preferred for
maximal absorption.
• If patients develop intolerable GI side effects (ie,
heartburn, nausea, bloating) after taking iron on
an empty stomach, they should be advised to take
it with meals.
• After absorption, iron binds to transferrin in the
plasma and is transported to the muscles (for
myoglobin), liver(for storage), or bone marrow
(for red cell production).
• Common toxicities associated with oral iron
include abdominal pain, nausea, heartburn,
constipation, and dark stools.
 Interaction
• Potentially clinically significant drug interactions
involving iron products include fluoroquinolones,
tetracyclines, and mycophenolate mofetil.
• Iron decreases the absorption of these drugs.
• The absorption of iron is influenced by gastric acidity.
• Limited data support drugs that decrease gastric acidity
(antacids, proton pump inhibitors, and H2-receptor
antagonists) may impair the absorption of iron.
• If concurrent administration cannot be avoided, to
minimize this effect oral iron should be administered at
least several hours before or after the affected drug.
 • Parentral treatment
• Parenteral iron therapy is indicated when
patients cannot tolerate oral formulations, are
noncompliant, or fail to respond to oral iron
because of malabsorption syndromes
• The following formula can be used to estimate
the total dose of parenteral iron needed to
correct anemia:
• Dose of iron (mg) = whole blood hemoglobin
deficit (g/dL) × body weight (lb) or
• Dose of iron (mg) = whole blood hemoglobin
deficit (g/L) × body weight (kg) × 0.22
 • Parenteral
• Iron can be given parentarally in the form of ferric
gluconate, iron dextran (INFeD and Dexferrum),
iron sucrose, and feru- moxytol.
• Iron dextran, the oldest of the parenteral iron
agents, is US Food and Drug Administration (FDA)-
approved for the treatment of iron deficiency
when oral supplementation is impossible or
ineffective
 • Parenteral
• Iron dextran can be administered undiluted very
slowly as an intravenous (IV) injection at a rate
not to exceed 50 mg (i.e., 1 mL) per minute.
• iron dextran injection is commonly diluted in 250
to 1,000 mL of 0.9% NaCl and administered by IV
infusion.
• The upper limit of each daily dose is based on the
patient’s weight and is not to be greater than 100
mg/day.
 • Parenteral
• Because of the potential for anaphylaxis with iron
dextran, an intramuscular (IM) or IV test dose
should be given.
• The test dose for adults is 25 mg of iron dextran.
Although anaphylactic reactions usually are
evident within a few minutes when they occur, it
is recommended that a period of 1 hour or longer
elapse before the remaining portion of the initial
dose be given.
 • Parenteral
• Some formulations of iron dextran may be given
IM, and in a few instances, IM iron dextran is the
preferred treatment (e.g., patients with limited IV
access).
• In these cases, undiluted drug should be
administered using a Z-track technique to avoid
staining the skin
 • Parenteral
• Iron sucrose can be administered undiluted as a
slow IV injection (rate not to exceed 20
mg/minute) or as an IV infusion (dilute in a
maximum of 100 mL of 0.9% NaCl and infuse at
a rate of 100 mg for 15 minutes)
 • Parenteral
• Ferumoxytol can be administered (undiluted at a
rate of 1 mL/second) at an initial dose of
ferumoxytol 510 mg administered by IV injection;
a second dose of 510 mg is administered by IV
injection 3 to 8 days after the initial dose.
• A test dose is not indicated for these agents
because of the lower incidence of serious
anaphylactoid reactions.
 Megaloblastic anemia

• Anemia from vitamin B12 or folic acid deficiency is

treated by replacing the missing nutrient.
• Both folic acid and vitamin B12 are essential for
erythrocyte production and maturation.
 vitamin B12 deficiency
• Vitamin B12 deficiency can result from decreased
supply (reduced intake, absorption, transport, or
utilization) or increased requirement (greater
metabolic consumption, destruction, and excre-
tion).
• Pernicious anemia develops from a lack of gastric
intrinsic factor production, which causes vitamin B 12
malabsorption and ultimately vitamin B12 deficiency
• Life-long maintenance therapy (1000 mcg/month)
is required for patients with pernicious anemia or
surgical resection of the terminal ileum
• Strict vegetarians most frequently present with
signs and symptoms of vitamin B12 deficiency.

• This population also can be iron deficient, and the

microcytosis of iron deficiency anemia can mask
the vitamin B12 deficiency–induced macrocytic
appearance of RBCs.
• Oral and parenteral vitamin B12 (cyanocobalamin)
replacement therapies are equally effective.
• Vitamin B12 is absorbed completely following
parenteral administration, whereas oral vitamin B12
is absorbed poorly via the GI tract.
• Consequently, cyanocobalamin is commonly
administered as an intramuscular or subcutaneous
injection of 1000 mcg/day for 1 week, followed by
1000 mcg/week for a month or until the Hgb
normalizes.
• If the etiology was a dietary deficiency or
reversible malabsorption syndrome, treatment
can be discontinued after the underlying cause is
corrected and vitamin B12 stores normalized.
• A common oral dosing regimen is from 1000 to
2000 mcg/ day.
• If parenteral cyanocobalamin is used initially, oral
vitamin B12 can be useful as maintenance therapy
• Typically, resolution of neurologic symptoms,
disappearance of megaloblastic RBCs, and
increased Hgb levels occur within a week of
therapy
• Vitamin B12– and folic acid–deficiency anemias can
be caused by inadequate dietary intake,
decreased absorption, and inadequate utilization.

• Vitamin B12 is well tolerated. Reported adverse

effects include injection-site pain, pruritus, and
rash.
 • Folic acid deficiency anemia
• Folic acid–deficiency anemia can be caused by
hyperutilization due to pregnancy, hemolytic
anemia, myelofibrosis, malignancy, chronic
inflammatory disorders, long-term dialysis, or
growth spurt.
• Drugs can cause anemia by reducing absorption of
folate (eg, phenytoin) or through folate
antagonism (eg, methotrexate).
• The effective dose of folic acid is 1 mg/day by
mouth.
• Absorption of folic acid is rapid and complete.
However, patients with malabsorption syndromes
may require doses up to 5 mg/day.
• Resolution of symptoms and reticulocytosis
occurs within days of commencing therapy.
• Typically a patient’s Hgb will start to rise after 2
weeks of therapy and normalize after 2 to 4
months of therapy.
 • Side effect
• Folic acid is well tolerated. Nonspecific adverse
effects include allergic reactions, flushing, and
rash.
• A small study evaluating the effect of folic acid
doses of 10 mg/day on phenytoin levels reported
decreased phenytoin levels in 3 of 4 subjects.
• However, the occurrence of this interaction at
folic acid doses of 1 mg/day has not been
reported
 Anemia of chronic disease (ACD)
• Decreased RBC transfusion requirements is an
outcome achieved in patients with ACD treated
with the erythropoietin stimulating agent (ESAs)

• the FDA-labeled dosing regimens for patients

whose anemia is related to cancer chemotherapy,
CKD, or zidovudine treatment
• Epoetin, a recombinant human EPO, and
darbepoetin, a synthetic EPO analog, bind to the
EPO receptors on RBC precursor cells in the bone
marrow and result in increased RBC production.
• Clinical practice guidelines consider epoetin and
darbepoetin to be therapeutic equivalents

• ESAs should only be used to prevent a transfusion

and should not be initiated unless the
hemoglobin is less than 10.0 g/dL and
chemotherapy is planned for a minimum of two
additional months.
 Sickle Cell Disease
• Sickle cell syndromes, which can be divided into
sickle cell trait (SCT) and sickle cell disease (SCD),
are hereditary conditions characterized by the
presence of sickle hemoglobin (HbS) in red blood
cells (RBCs).
• SCT is the heterozygous inheritance of one
normal β-globin gene producing hemoglobin A
(HbA) and one sickle gene producing HbS (HbAS)
gene.
• Individuals with SCT are asymptomatic.
• SCD can be of homozygous or compounded
heterozygous inheritance. Homozygous HbS
(HbSS) has historically been referred to as sickle
cell anemia (SCA).
 Pathogenesis
• Hgb is a quaternary structure composed of two α-
globin chains and two β-globin chains (α2β2) in adults.
• During fetal development, the γ-globin is the primary
β-globin expressed, forming fetal Hgb (HbF or α2γ2).
• Normally, the period from birth to approximately 3 to
6 months of age is marked by the replacement of γ-
globin with β-globin, giving rise to the adult form of
Hgb (HbA, α2β2).
• Low levels of γ-globin persist throughout life, and HbF
may account for approximately 1% of the total Hgb
content.
• Sickle cell anemia is an inherited, autosomal
recessive Hgb disorder characterized by a DNA
substitution at the β-globin gene.

• The α-chains of HbS, HbA, and HbC are

structurally identical. The chemical differences in
the β-chain are responsible for RBC sickling and its
associated sequelae.
• The Hgb produced from this substitution has a
more negative charge than normal HbA, and in the
deoxygenated state will aggregate and polymerize,
forming sickled RBCs

• Sickled RBCs are more rigid and may become

“lodged” when passing through the
microvasculature, resulting in vascular occlusions.
 PATHOPHYSIOLOGY

• Clinical manifestations of SCD are due to impaired

circulation, RBC destruction, and stasis of blood
flow and ongoing inflammatory responses.

• In addition to sickling, other factors contributing

to the clinical manifestations include functional
asplenia (and increased risk of bacterial
infection), deficient opsonization, and coagulation
abnormalities.
• Polymerization allows deoxygenated hemoglobin
to exist as a semisolid gel that protrudes into the
cell membrane, distorting RBCs into sickle shapes.

• Sickle-shaped RBCs increase blood viscosity and

encourage sludging in the capillaries and small
vessels, leading to local tissue hypoxia that
accentuates the pathologic process.
• Repeated cycles of sickling, upon deoxygenation,
and unsickling, upon oxygenation, damage the
RBC membrane and cause irreversible sickling.

• Rigid, sickled RBCs are easily trapped, resulting in

shortened circulatory survival and chronic
hemolysis.
 CLINICAL PRESENTATION
• Cardinal features of SCD are hemolytic anemia and
vasoocclusion.
• Symptoms are delayed until 4 to 6 months of age when
HbS replaces fetal hemoglobin (HbF).
• Common findings include pain with fever, pneumonia,
splenomegaly, and, in infants, pain and swelling of the
hands and feet (eg, hand- and-foot syndrome or dactylitis).
• Usual clinical signs and symptoms of SCD include chronic
anemia; fever; pallor; arthralgia; scleral icterus; abdominal
pain; weakness; anorexia; fatigue; enlarged liver, spleen,
and heart; and hematuria.
• .
 • CLINICAL PRESENTATION
• Acute complications of SCD include fever and
infection (eg, sepsis caused by encapsulated
pathogens such as Streptococcus pneumoniae),
stroke, acute chest syndrome, and priapism.

• Acute chest syndrome is characterized by

pulmonary infiltration, respiratory symptoms, and
equivocal response to antibiotic therapy
 • CLINICAL PRESENTATION
• Acute episodes of pain can be precipitated by
infection, dehydration, stresses, and sudden
temperature changes.
• Acute splenic sequestration is the sudden massive
enlargement of the spleen due to sequestration of
sickled RBCs.
• The trapping of sickled RBCs by the spleen leads to
hypotension and shock, and can cause sudden
death in young children.
 • CLINICAL PRESENTATION
• Repeated infarctions lead to autosplenectomy;
therefore, incidence declines as adolescence
approaches.
• Chronic complications involve many organs and
include pulmonary hypertension, bone and joint
destruction, ocular problems, cholelithiasis,
cardiovascular abnormalities, depression, and
hematuria and other renal complications.
• Children experience delayed growth and sexual
maturation.
• Patients with SCT are usually asymptomatic, except
for rare painless hematuria
 DIAGNOSIS
• SCD is usually identified by routine neonatal
screening programs using isoelectric focusing,
high- performance liquid chromatography, or
electrophoresis.
• Laboratory findings include low hemoglobin;
increased reticulocyte, platelet, and white blood
cell counts; and sickled red cell forms on the
peripheral smear.
 TREATMENT

• Goals of Treatment: The goals are to reduce

hospitalizations, complications, and mortality.
 General principle
and treatment

• Patients with SCD require lifelong multidisciplinary

care that combines general symptomatic
supportive care, preventative medical therapies
and specific disease modifying therapies.
• Routine immunizations plus influenza,
meningococcal, and pneumococcal vaccinations are
recommended.
 • General principle
and treatment
• Prophylactic penicillin is recommended until at
least 5 years of age.
• An effective regimen is penicillin V potassium,
125 mg orally twice daily until 3 years of age and
then 250 mg orally twice daily until age 5 years.
 • General principle
and treatment
• HbF directly effects polymer formation.
Increases in HbF correlate with decreased RBC
sickling and adhesion.
• Patients with low HbF levels have more frequent
pain and higher mortality.
• HbF levels of 20% or greater reduce the risk of
acute sickle cell complications.
 • General principle
and treatment
• Hydroxyurea, a chemotherapeutic agent,
stimulates HbF production and increases the
number of HbF-containing reticulocytes and
intracellular HbF.
• It is indicated for patients with frequent painful
episodes, severe symptomatic anemia, acute
chest syndrome, or other severe vasoocclusive
complications.
• The starting dose is 15 mg/kg as a single daily
dose
 • General principle
and treatment
• Chronic RBC transfusions are indicated for
primary and secondary stroke prevention in
children.
• Transfusions are usually given every 3 to 4 weeks
or as needed to maintain desired HbS levels.
• The optimal duration of primary prophylactic
transfusion therapy in children is unknown.
 • General principle
and treatment
• Risks include alloimmunization, hyperviscosity, viral
transmission (requiring hepatitis A and B vaccination),
volume and iron overload, and transfusion reactions.
• Allogeneic hematopoietic stem cell transplantation
is the only curative therapy for SCD.
• The best candidates are younger than 16 years, have
severe complications, and have human leukocyte
antigen– matched donors. Risks must be carefully
considered and include mortality, graft rejection, and
secondary malignancies.
 TREATMENT OF COMPLICATIONS

• Educate patients to recognize conditions that

require urgent evaluation.
• Balanced fluid status and oxygen saturation of at
least 92% are important to avoid exacerbation
during acute illness.
• RBC transfusions are indicated for acute
exacerbation of baseline anemia (eg, aplastic crisis,
hepatic or splenic sequestration, or severe
hemolysis), severe vasoocclusive episodes, and
procedures requiring general anesthesia.
 • TREATMENT OF COMPLICATIONS
• Transfusions can be useful in patients with
complicated obstetric problems, refractory leg
ulcers, or refractory and protracted painful episodes
and for primary or secondary stroke prevention.
• Promptly evaluate fever of 38.5°C (101.3°F) or
higher.
• Empiric antibiotic therapy should provide coverage
against encapsulated organisms (eg, ceftriaxone for
outpatients and cefotaxime for inpatients;
clindamycin for cephalosporin-allergic patients).
 • TREATMENT OF COMPLICATIONS
• Priapism has been treated with analgesics,
antianxiety agents, and vasoconstrictors to force
blood out of the corpus cavernosum (eg,
phenylephrine and epinephrine), and
vasodilators to relax smooth muscle (eg,
terbutaline and hydralazine).
• Treatment of aplastic crisis is primarily
supportive. Blood transfusions may be indicated
for severe or symptomatic anemia.
 • TREATMENT OF COMPLICATIONS

• Treatment options for splenic sequestration

include observation alone, especially for adults
because they tend to have milder episodes;

• chronic transfusion in children younger than 2

years of age to delay splenectomy; and
splenectomy after a life-threatening crisis, after
repetitive episodes, or for chronic hypersplenism.
 • TREATMENT OF COMPLICATIONS

• Hydration and analgesics are mainstays of

treatment for vasoocclusive (painful) crisis.

• Administer fluids IV or orally at 1 to 1.5 times the

maintenance requirement; monitor closely to
avoid volume overload.

• Consider an infectious etiology and initiate

empiric therapy if indicated.
 • TREATMENT OF COMPLICATIONS
• Treat severe pain aggressively with an opioid, such
as morphine, hydromorphone, fentanyl, or
methadone.
• Meperidine should be avoided because
accumulation of the normeperidine metabolite
can cause neurotoxicity, especially in patients with
impaired renal function.

• Treat severe pain with an IV opioid titrated to pain

relief and then administered on a scheduled basis
with as-needed dosing for breakthrough pain.