Anemia.pdf

Bassant M. Barakat
Professor
Al Baha University, College of Clinical Pharmacy

LEARNING OBJECTIVES
Upon completion, students will be able to:
1. Identify common causes of anemia.
2. Describe common signs and symptoms of anemia.
3. Describe diagnostic evaluation required to determine the etiology of anemia.
4. Recommend a treatment regimen considering the underlying cause and
patient-specific variables.
5. Compare and contrast oral and parenteral iron preparations.
6. Explain the optimal use of folic acid and vitamin B12 in patients with
macrocytic anemia.
7. Evaluate the proper use of epoetin and darbepoetin in patients with anemia
caused by cancer chemotherapy or chronic kidney disease.
8. Develop a plan to monitor the outcomes of pharmacotherapy for the
treatment of anemia.

Intro
• Anemia is on of the most under diagnosed conditions and if left untreated can
lead to many serious complications such as CV diseases and compromised
immune function.
• Anemia is a manifestation of an underlying disease process and is not a diagnosis
in itself. A wide array of diseases, including inflammations, infections, and
malignancies, may at some point be associated with anemia.

Epidemiology
• It is considered a serious global public health problem that
particularly affects young children and pregnant women. WHO
estimates that 42% of children less than 5 years of age and
40% of pregnant women worldwide are anaemic.
• Prevalence of anemia varies widely based on age, gender, and
race/ethnicity.

Definition
Anemia is a reduction in the concentration of hemoglobin (RBCs
protein that carries oxygen to body's organs and tissues and
transports carbon dioxide from organs and tissues back to lungs)
resulting in reduced oxygen carrying capacity of the blood to body’s
tissues.
Normal range= 14-18 gm/100ml
Normal range= 12-16 gm/100ml
Normal range= 11.5-15.5 gm/100ml

To understand the Anemias, it is better to
learn some basics about RBCs and
Hemoglobin.

RBCs
• Mature RBCs are flexible bioconcave discs
that lacks nucleus.
• 2.4 million erythrocytes are produced/sec.
• Over 200 billion new blood cells per day in
the normal person and even greater in people
with conditions that cause loss or destruction
of blood cells are produced by this process.
• Each cell contains app. 270 million of Hb
molecules.
• RBCs develop in the bone marrow and
circulate for about 100-120 days in the body
before their components are recycled by
macrophages.
• The process of erythrocytes production is
called Erythropoiesis.

RBCs
• Erythropoiesis begins with a pluripotent stem cell in the bone marrow undergoing several
steps of differentiation to produce reticulocytes.
• Reticulocytes are then released to the peripheral circulation & become erythrocytes after 1 to
2 days in the bloodstream.

1) Erythropoietin (EPO), a hormone secreted
by the kidney in response to detection of
decreased oxygen-carrying capacity of blood
and is responsible for catalyzing and
stimulating RBCs production process.
• Optimum level of the hormone are kept in
circulation for erythropoiesis, and an efficient
feedback mechanism controlling the secretion
of erythropoietin.
• Hypoxia, which may be caused by anaemia,
stimulates renal production of erythropoietin
leading to increased RBC production. The
resultant increase in circulating RBCs relieves
the hypoxia.
• A lack of erythropoeitin, which is seen most
commonly in renal failure, can result in
profound reticulocytopaenia with consequent
reduction in RBCs and anaemia.
Regulation of Erythropoiesis

2) Special maturation factors, like vitamin B12 and folic acid; which are key
components of DNA synthesis and hence are required for RBC maturation.
•The deficiency of either can lead to failure of maturation of the nucleus, cells remain large
and become more fragile, and cell division also decreases significantly resulting in
decreased RBC production and hence certain types of anemia.
•Poor diet and malabsorption syndroms can contribute to folic acid and vitamin B12
deficiencies.
•Also, hoemonal influence; Androgens and thyroxine also exert a stimulatory effect on
erythropoiesis.

3) Factors necessary for hemoglobin formation such as proteins like
globin, and elements such as iron, cobalt, copper, calcium,
pyridoxine and bile salts.
• RBCs of an average adult human utilize about 65-70% of total iron
contained in the body.
• Deficiency (poor diet or loss), inadequate absorption, can result in
decreased RBC production and hence anemia.

Red blood cells’ indices
Mean Corpuscular Volume (MCV)
• An MCV blood test measures the average size
of red blood cells. Allow for classification of
anemia.
• Normal MCV is between 80 to 100 fL.
• Hct is proportion of red blood cells in blood. It
is normally 40.7–50.3% for males and 36.1–
44.3% for females.

Mean corpuscular hemoglobin concentration (MCHC)
• MCHC, It's a measure of the average concentration of hemoglobin in a given
volume of packed RBCs
• The reference range for MCHC in adults is 33.4–35.5 grams per deciliter
(g/dL).
Mean corpuscular hemoglobin (MCH)
• MCH, It's the average amount hemoglobin in each red blood cell.
• The normal values for MCH are 29 ± 2 picograms (pg) per cell.
Red blood cells’ indices

Clinical Presentation
Signs and Symptoms
Generally, the signs and symptoms of anemia are nonspecific and may include
the following:
• Fatigue, lethargy, dizziness
• Shortness of breath
• Headache
• Edema
• Tachycardia
• Pale or yellowish skin
• Cold hands and feet.
• Leg cramps
• Chest pain
Other findings that may be present in some
patients include:
• Dry skin, chapped lips
• Nail brittleness
• Hunger for ice, starch, or clay (termed pica)

The underlying cause of anemia must be determined and used to guide
therapy.
• PMH, PE
• CBC is the laboratory evaluation that provides objective characteristics of
RBCs useful in determining etiology and appropriate treatment.
• Determination of iron, ferritin, folate, and vitamin B12 levels are required to
correctly diagnose a patient’s anemia.
Diagnosis

Past Medical History
Inquire about the following conditions:
• History of blood loss, such as hemorrhoids, melena, or menorrhagia (Iron Defficiency
Anemia)
• Malnourished or recent weight loss (vitamin B12 or folate deficiency)
• Alcoholism (folate deficiency)
• Cancer or chronic kidney disease (CKD)
• Chronic autoimmune disorders or infections, such as HIV infection or rheumatoid
arthritis (anemia of chronic disease-ACD).
Physical Examination
• Orthostatic hypotension and tachycardia secondary to volume depletion
• Cutaneous changes such as pallor, jaundice, and nail brittleness
• These findings aid in determining the severity of the anemia:
Diagnosis

Laboratory Evaluation
• CBC. 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.
• 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

Laboratory Evaluation
Diagnosis

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.
• It is important to note that continuation of therapy should be assessed primarily
by resolution of clinical symptoms.
• Patients who experience a resolution in their symptoms (eg, shortness of
breath, tachycardia, fatigue, dizziness,) may not require aggressive therapy to
maintain their Hgb values within normal limits.
• Hypoxia and cardiovascular sequelae due to anemia can be avoided if Hgb
levels are greater than 7.0 g/dL (70 g/Lor 4.34 mmol/L).11

Nonpharmacologic Therapy
1) The primary nonpharmacologic treatment of anemia is transfusion of RBCs.
• For many decades, the decision to transfuse red blood cells (RBCs) was based upon the "10/30
rule": transfusion was used to maintain Hgb above 10 g/dL (100 g/L) and a Hct above 30%.
• Safety concerns, cost, and the limited availability of this therapy support efforts to establish the
“optimum” threshold for administering RBC transfusions in different settings.
These thresholds are not a substitute for direct assessment of the patient and clinical judgment.
Condition Hgb threshold for transfusion
Symptomatic patient (eg, myocardial ischemia, hemodynamic instability) 10 g/dL
Hospitalized patient
Preexisting coronary artery disease 8 g/dL
Acute coronary syndromes, including acute MI 8 to 10 g/dL
ICU (hemodynamically stable) 7 g/dL
Gastrointestinal bleeding (hemodynamically stable) 7 g/dL
Orthopedic surgery 8 g/dL
Cardiac surgery 7.5 g/dL
Ambulatory outpatient
Oncology patient in treatment 7 to 8 g/dL
Palliative care setting As needed for symptoms

Nonpharmacologic Therapy
2) Diet; Anemia can be attributed to diets poor in iron, folic acid, or
vitamin B12.
• However, in the United States, nutrient-poor diets rarely cause
anemia.
• Therefore, ingesting a diet that is rich in iron, folic acid, or vitamin
B12 should be encouraged, but is rarely the sole modality of
treatment.

Iron deficiency Anemia
• Is the most common cause of chronic
anemia.
• Iron forms the nucleus of the iron-
porphyrin heme ring, which together
with globin chains forms hemoglobin.
• In the absence of adequate iron, small
erythrocytes with insufficient hemoglobin
are formed, giving rise to microcytic
hypochromic anemia.
• Low MCV & MCH
Iron deficiency is commonly seen in populations with increased iron requirements:
• Infants, especially premature infants; children during rapid growth periods
• Pregnant and lactating women;
• Patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis
• Inadequate iron absorption due to severe small bowel disease.
• Heavy menstrual bleeding

1) Oral iron therapy:
• The initial treatment of IDA.
• It corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption
from the GIT is normal.
• Reticulocytosis should occur in 7 to 10 days, and Hgb values should rise by about 1.0 g/dL (10 g/L or
0.62 mmol/L) per week.
• Patients should be reassessed if Hgb does not increase by 2.0 g/dL (20 g/L or 1.24 mmol/L) in 3 weeks.
• Requirements: 150 to 200 mg of elemental iron daily.
• The preferred regimen is 50 to 65 mg of elemental iron two to three doses daily on an empty stomach (1
hour before or 2 hours after a meal) 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.
Common toxicities/side effects:
• Abdominal pain, nausea, heartburn, constipation, and dark stools.
• Some patients have less severe gastrointestinal adverse effects with
one iron salt than another and benefit from changing preparations.

1) Oral iron therapy:
Clinically significant drug interactions:
1. Iron products + fluoroquinolones, tetracyclines, eltrombopag, and mycophenolate. Iron decreases
the absorption of these drugs.
2. The absorption of iron is enhanced by gastric acidity. Drugs that decrease gastric acidity (antacids,
proton pump inhibitors, and H2-receptor antagonists) may impair the absorption of iron. limited
data.
• 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.
Commonly prescribed oral iron products and the
amount of elemental iron provided by each.

2) Parenteral iron therapy:
• Is reserved & indicated when patients cannot tolerate oral formulations, are noncompliant, or fail to respond to
oral iron because of malabsorption syndromes.
• Iron products that are administered parenterally include the following:
o Ferric carboxymaltose (Injectafer)
o Ferric derisomaltose (Monoferric)
o Ferric gluconate
o Ferric pyrophosphate citrate (Triferic)
o Ferumoxytol (Feraheme)
o Iron dextran complex
o Iron sucrose (Venofer)
• They are expensive and has greater morbidity than iron preparations taken orally.
• High molecular weight iron dextrans are associated with increased risks (anaphylactic-like reactions), so their
use for IV therapy should be avoided. If used, a test dose of iron dextran (0.5 mL over at least 30 seconds)
must be administered to patients before their first dose, monitored for signs of anaphylaxis for at least 1 hour
before administering the total dose.
• The second- and third-generation IV irons are considered equally efficacious in treating iron deficiency in
equivalent doses, but iron isomaltoside seems to have a lower frequency of serious and severe hypersensitivity
reactions.
Very important:
• For patients treated chronically with parenteral iron, it is important to monitor iron storage levels to avoid the
serious toxicity associated with iron overload.

Vitamin B12 deficiency anemia/ Pernicious anemia
• Deficiency of vitamin B12 leads to
megaloblastic macrocytic anemia
Main Hematological findings:
• Decreased (RBC) count and hemoglobin
levels.
• Increased MCV and MCH.
• Often associated with mild or moderate
leukopenia or thrombocytopenia (or both).
Signs and symptoms:
• The neurologic syndrome associated with
vitamin B12 deficiency includes:
 Confusion, paresthesias in peripheral
nerves and weakness that might
progresses to spasticity & ataxia
Causes:
• Inadequate supply in the diet (unusual).
• Inadequate absorption of dietary vitamin B12
(more common /especially older adults).
• A special protein, called intrinsic factor (IF),
binds vitamin B12 so that it can be absorbed in
the intestines.
• This protein is released by cells in the stomach.
When the stomach does not make enough
intrinsic factor, the intestine cannot properly
absorb vitamin B12.

Treatment:
• 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 i.m or s.c injection.
• Parentral dosing: 1000 mcg/day for 1 week, followed by 1000 mcg/week for a month or until
the Hgb normalizes.
• Life-long maintenance therapy (1000 mcg/month) is required for patients with pernicious
anemia or surgical resection of the terminal ileum.
• 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.
• Oral dosing regimen: 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 is well tolerated. Reported adverse effects include injection-site pain, pruritus,
and rash.
Vitamin B12 deficiency anemia

Folic acid deficiency anemia
• Folate deficiency is relatively
common, even though the
deficiency is easily corrected by
administration of folic acid.
• The consequences of folate
deficiency go beyond the problem
of anemia because it is implicated
as a cause of:
 Congenital malformations in
newborns
 May play a role in
cardiovascular disease
For the anemia:
• Folate deficiency results in a
megaloblastic anemia that is
microscopically indistinguishable
from the anemia caused by vitamin
B12 deficiency.
What is the difference???
• Folate deficiency does not cause the
characteristic neurologic syndrome
seen in vitamin B12 deficiency.

Causes of Folic acid deficiency:
• Often: inadequate dietary intake.
• Patients with alcohol dependence and with
liver disease because of poor diet and
diminished hepatic storage of folates.
• Pregnant women and patients with hemolytic
anemia have increased folate requirements
and may become folic acid-deficient,
especially if their diets are marginal.
• Patients with malabsorption syndromes.
• Patients who require renal dialysis because
folates are removed from the plasma during
the dialysis procedure.
• Folic acid deficiency can be caused by drugs.
Methotrexate
Treatment:
• Parenteral administration of folic acid is rarely necessary, since
oral folic acid is well absorbed even in patients with
malabsorption syndromes.
• 1 mg folic acid orally daily is sufficient to reverse
megaloblastic anemia, restore normal serum folate levels, and
replenish body stores of folates in almost all patients. 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.
• Therapy should be continued until the underlying cause of the
deficiency is removed or corrected.
• Therapy may be required indefinitely for patients with
malabsorption or dietary inadequacy.
• Folic acid supplementation to prevent folic acid deficiency
should be considered in high-risk patients, including pregnant
women, patients with alcohol dependence, hemolytic anemia,
liver disease, or certain skin diseases, and patients on renal
dialysis.
• Folic acid is well tolerated. Nonspecific adverse effects include
allergic reactions, flushing, and rash.
Folic acid deficiency anemia

Anemia of Chronic Disease
1) Anemia Due to Chemotherapy in Patients with Cancer (ASCO/ASH clinical practice
guideline update- 2019)
Erythropoiesis stimulating agent (ESAs) administered i.v or sc.
• 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.
• Darbepoetin differs from epoetin in that it exhibits a longer half-life (three times), allowing
for a longer dosing interval, but, they are considered therapeutic equivalents.
• The FDA is requiring all drugs called (ESAs) to be prescribed and used under a risk
management program, known as a risk evaluation and mitigation strategy (REMS), to
ensure the safe use of these drugs.
• Why??? because studies show that ESAs can:
• Increase the risk of tumor growth (tumor grow faster)
• Shorten survival in patients
• Increase the risk of heart attack, heart failure, stroke and blood clots

1) Anemia Due to Chemotherapy in Patients with Cancer
Erythropoiesis stimulating agent (ESAs)
• Key concept: ESAs should only be used to prevent a transfusion and should not be initiated unless the
hemoglobin is less than 10.0 g/dL (HgB has declined to < 10 g/dL) and chemotherapy is planned for a
minimum of two additional months
• Clinical question: Among adult patients who will receive an ESA for chemotherapy-associated anemia, What
are recommendations for ESA dosing and dose modifications?
• Monitor weekly.

1) Anemia Due to Chemotherapy in Patients with Cancer
Erythropoiesis stimulating agent (ESAs)
• Clinical question: Among adult patients who will receive an ESA for chemotherapy-associated anemia,
What is the recommended target HgB level?
• Recommendation: HgB may be increased to the lowest concentration needed to avoid or reduce the
need for RBC transfusions, which may vary by patient and condition.
• Clinical question : Among adult patients with chemotherapy-associated anemia who do not respond to
ESA therapy (< 1 to 2 g/dL increase in HgB or no decrease in transfusion requirements), Does
continuation of ESA therapy beyond 6 to 8 weeks provide a benefit?
• Recommendation: ESAs should be discontinued in patients who do not respond within 6 to 8 weeks.
Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression,
iron deficiency, or other etiologies for anemia.
• Clinical question: Among adult patients with chemotherapy-associated anemia, Does iron
supplementation concurrent with an ESA reduce transfusion requirements?
• Recommendation: Iron replacement may be used to improve HgB response and reduce RBC
transfusions for patients receiving ESA with or without iron deficiency. Baseline and periodic
monitoring of iron, total iron-binding capacity, transferrin saturation, or ferritin levels is recommended.

2) Anemia Due to CKD
• Anemia is common in patients with CKD. Early treatment of anemia in patients with CKD on dialysis
has been associated with slower disease progression and lower risk of death.
• It is essential to evaluate and treat anemia in patients before they progress to stage 5 CKD (glomerular
filtration rate [GFR] of less than 15 mL/min/1.73 m2 [0.14 mL/s/m2]).
• Patients with CKD typically develop normocytic, normochromic anemia as a result of EPO deficiency.
However, a thorough workup of anemia should be performed to rule out other etiologies.
• The target Hgb range in patients with CKD is 11.0 g/dL in patients on hemodialysis and to 10.0 g/dL in
CKD patients not on hemodialysis and this is to decrease the risk of serious adverse cardiovascular
events (hypertension, stroke...).
• Although EPO deficiency is the primary cause of CKD anemia, iron deficiency may also exist. Iron
stores in patients with CKD should be maintained so that transferrin saturation is greater than 20%
(0.20) and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L).
• If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective. Most CKD
patients will require iron supplementation.

3) Anemia Due to Zidovudine (azidothymidine (AZT) in HIV-Infected Patients
• Early clinical trials documented that nearly 50% of patients treated with zidovudine develop anemia
requiring RBC transfusions.
• Blood transfusion used to be the only treatment option for severe anemia in HIV/AIDS patients.
• In 1991, epoetin, was approved as treatment for patients with HIV whose anemia is due to therapy with
AZT.
• Epoetin resulted in statistically significant decreases in transfusion requirements for patients with serum
EPO levels less than 500 mUnits/mL (500 U/L).
• Currently, epoetin has a labeled indication for the treatment of anemia in patients with EPO levels less
than 500 mUnits/mL (500 U/L) and administered zidovudine doses less than 4200 mg/week

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