Here is part two of Anemia pharmacotherapy using a case based approach

1. Week
Anemia
Part Two
Anas Bahnassi
1

2. Lecture Outline
Folic acid deficiency anemia
Sickle cell anemia
Complications of sickle cell anemia
Anemia of chronic diseases
Human Recombinant Erythropoietin Therapy
Renal insufficiency-related anemia
Malignancy-related anemia

3. 41
Folic acid deficiency anemia
The average diet
provides 50 to 2,000
mcg of folate per day
Excessive cooking
(>15 minutes) in large
quantities of water
destroys a high
percentage of the
folate that is
contained in food.
Generally humans
require a daily intake
of 3 mcg/kg/day of
folate.
Predisposing factors:
a) Alcoholism: Enterohepatic recirculation of folate can
become impaired by the toxic effect of alcohol
b) Rapid cell turnover Folate coenzymes are required for
most metabolic pathways (Fig. 86-2). Therefore, folate
deficiency will develop in any condition of rapid cellular
turnover (e.g., hemolytic anemias, hemoglobinopathies,
sideroblastic anemia, leukemias, lymphomas, multiple myeloma)
Dietary deficiency Can develop during the third trimester of
pregnancy as a result of a marginal diet and the rapid metabolism
of the fetus.

4. A case approach understanding for folate deficiency anemia
A22-year-old woman, malnutritioned-appearing
pregnant in her 2rd trimester, .
Chief complaints
Presents for regular pregnancy check-up.
Complains of dyspnea on exertion, palpitations, and diarrhea.
PMD
7-year history of excessive alcohol intake,
3-year history cocaine use,
Lost 8-10lbs in the 1st trimester due to nausea, vomiting, and
anorexia.
Current Meds
Denies taking and Rx med.
FH
Ran away from home when she was 16 yr old.

5. A case approach understanding for folate deficiency anemia
A22-year-old woman, malnutritioned-appearing
pregnant in her 2rd trimester, .
Relevant laboratory findings;
Hct, 25.5% (normal, 40% to 44%);
MCV, 112 µm3 (normal, 76 to 100);
MCH, 34 pg (normal, 27 to 33);
RBC, 1.1 ×106/mm3 (normal, 3.5 to 5.0);
Folate, 30 ng/mL (normal, in RBC 140 to 960);
serum vitamin B12, 250 pg/mL (normal, 200 to 1,000);
Reticulocytes, 1% (normal, 0.5 to 1.5);
Platelets, 75,000/mm3 (normal, 130,000 to 400,000);
WBC count, 2,000/mm3 (normal, 3,200 to 9,800) with
hypersegmented PMN;
LDH, 450 U/L (normal, 50 to 150);
Bilirubin, 1.5 mg/dL (normal, 0.1 to 1).

6. A case approach understanding for folate deficiency anemia
What are the factors predisposing this patient to Folate
Deficiency Anemia?
The patient has more than one risk factor for folate deficiency.
(a) Cocaine and alcohol, together with multiparity complicated by anorexia,
nausea, and vomiting, could lead to poor nutrition.
(b) Alcohol has toxic effects on the intestinal mucosa and interferes with
folate utilization by the bone marrow.
(c) The patient should be asked specifically about her dietary habits and
recent weight history.
(d) She may have a folate-poor diet for financial reasons or because she is
overcooking her food.
(e) Cocaine may be causing anorexia.
(f) The nutritional intake of people who abuse alcohol and drugs is often
poor.

7. A case approach understanding for folate deficiency anemia
What laboratory values support the diagnosis of folate
deficiency anemia?
Values reflect macrocytic anemia (Hct, 25.5%; MCV, 112 µm3) with
pancytopenia (reduced number of RBC, WBC, and platelets).
Normal serum vitamin B12 conc., but folate stores are inadequate.
Serum folate conc. generally reflect folate balance over 3 wks,
One balanced meal can raise serum levels and provides false (+).
Tissue folate stores reflected by the RBC polyglutamated folate
content, is more accurate, which is approximately 10- 30 times serum
folate concentrations.
Hemolysis or vitamin B12 deficiency causes leakage of monoglutamated
folates from cells, thereby falsely elevating serum folate levels.

8. A case approach understanding for folate deficiency anemia
What is the treatment plan this patient?
(a) Counsel the patient about her nutritional diet.
(b) Provide 1 ug folic acid daily for 2-3 weeks.
(c) 5ug might be needed if folate absorption is compromised due to
alcohol.
(d) She should continue to take folate supplement throughout her
pregnancy and lactation periods.
(e) Reassess to ensure response to supplement.
(f) Continue folate supplement as long as the risk factors are present.

9. A case approach understanding for iron deficiency anemia
How can you monitor response to therapy?
(a) Bone marrow aspirates (not performed regularly)
(b) RBC morphology should begin to revert back to normal within 24 to
48 hours after therapy is initiated.
(c) Hypersegmented neutrophils should disappear in the periphery in
about 1 week.
(d) The reticulocyte count should increase by day 2 to 3 and peak by
day 10.
(e) LDH and bilirubin values should normalize in 1 to 3 weeks.
(f) Anemia should be corrected in 1 to 2 months.
(g) Once anemia is corrected, 0.1 mcg of folate as a nutritional
supplement should be adequate for maintenance.
(h) Patients with underlying vitamin B12 deficiency are inappropriately
treated with folate, neurologic sequelae will persist, and macrocytic
anemia will abate but will not resolve completely.

10. Sickle cell anemia
An inherited hemoglobin disorder characterized by a
DNA substitution where the β-globin gene is located.
Sickle cell anemia results from a DNA substitution of
thymidine for adenine in the glutamic acid codon,
forming a B6 valine instead of glutamic acid.
The hemoglobin produced from such a substitution has
a more negative charge than normal HbA, and the
deoxygenated state favors hemoglobin aggregation and
polymerization, which forms sickled RBC.
Sickled RBC are more rigid and may become “lodged”
when passing through microvasculature, resulting in
vascular occlusions.

11. Laboratory evaluation of sickle cell anemia
Patients are diagnosed by electrophoretic procedures
that separate different forms of Hgb.
WBC , MCV, and platelet counts often are elevated,
Reticulocyte count can range from 5% to 15%,
If MCV values are within the normal range, iron deficiency or BOthalassemia must be considered.
In patients with sickle cell BO-thalassemia, hematologic
abnormalities vary, depending on the amount of HbA present.
This form may be difficult to distinguish from sickle cell anemia;
RBC microcytosis may be the only differentiating parameter

12. Management of sickle cell anemia
The kidney is commonly affected and lose it's ability to
concentrate urine.
During pregnancy, an increased frequency of urinary tract
infections and hematuria are seen.
Vaso-occlusive events are uncommon.
Sickle cell HbC disease is usually associated with few clinical
complications.
These patients may have normal physical examination findings with only splenomegaly.
Patients are at risk for bacterial infections and, because of elevated Hgb levels, they may
suffer from ocular, orthopedic, and pulmonary vaso-occlusive events.

13. Management of sickle cell anemia
Treatment of sickle cell anemia is largely directed toward
prophylaxis against infections and supportive management
of vaso-occlusive crises.
The clinical course among patients with sickle cell disease
is variable and difficult to predict.
Some patients suffer from a multitude of health problems.
Organs such as the kidneys, retina, spleen, and bones are
frequent sites of vaso-occlusive events because these
sites have a relatively low pH and oxygen tension.

14. Management of sickle cell anemia
Complications (e.g., pain, anemia, and
infections) as well as cardiac, pulmonary,
neurologic, hepatobiliary,
obstetric/gynecologic, ocular,
dermatologic, or orthopedic complications
can occur.
The management of these complications is
organ specific and aimed at supportive
interventions.

15. Hemolytic anemia
Caused by splenic sequestration of abnormal RBC.
Sequestration reduces RBC life span from 120 to 15-25
days and elevates the reticulocyte count.
Some patients may experience aplastic anemia (bone
marrow failure) due to hemolysis accompanied by
inadequate bone marrow response.
Human parvovirus (HPV) B19 is a common cause of
transient red cell aplasia (TRCA) with up to 67% of
infections resulting in a hematologic change typical of
aplasia.

16. Hemolytic anemia
Nearly 70% of all cases of homozygous sickle cell patients
are HPV B19 seropositive by 20 years of age.
Hemolytic anemia can also present in patients with
glucose-6-phosphate dehydrogenase deficiency.
Cardiac manifestations include:
High-output failure secondary to anemia.
Management of the underlying anemia may include
splenectomy following the first splenic sequestration event.
Alternatively, patients can be treated with transfusions
and careful observation.

17. Infections
Infections commonly occur in patients with sickle cell anemia due to:
(a) Complement pathway
(b) Granulocyte function
(c) Alteration of B-cell immunity
(d) Impaired splenic function increases the risk for infection.
Bacteria involved:
(a) Streptococcus pneumoniae
(b) Haemophilus influenzae
(c) Neisseria meningitidis
(d) Salmonella typhimurium.
Pneumonia can worsen hypoxia, causing progression to vaso-occlusion and acute
chest syndrome (chest pain in the presence of a local infiltrate).

18. Infections
Prophylactic administration of penicillin is recommended in children up to 5 yrs.
Pulmonary complications may lead to right-sided heart failure.
Other common infections include osteomyelitis or urinary tract infections.
Antibiotic therapy should be instituted at the earliest sign of infection.
Vaccines that are recommended for patients with homozygous sickle cell include
all standard pediatric vaccines as well as pneumococcal 23-valent
polysaccharide vaccine at 2 and 5 years of age with a booster every 10 years.
Because patients with sickle cell typically respond poorly, only 50% of patients
will be protected by vaccination

19. Vascular occlusive crisis:
Also called “sickle cell crisis”, they cause severe pain and organ damage.
The pain typically lasts 2 to 6 days and should be managed with narcotic
analgesics.
Treatment of frequent vaso-occlusive crisis:
Hemoglobin F (HbF) has a protective effect against hemoglobin
polymerization.
Hydroxyurea has been found to increase HbF synthesis.and used
prophylactically not in treatment. It is a cytotoxic agent associated with
bone marrow suppression.
Other effects include GI effects, dermatologic effects, and potential
risk of developing a secondary neoplasm (leukemia).
Dose is 15 to 35 mg/kg/day. blood counts should be monitored.

20. A case approach understanding for sickle cell anemia
18-year-old man with sickle cell anemia,
Chief complaint
Rapid onset of abdominal pain and shortness of breath.
PMH
Since infancy, he’s been severely incapacitated by his
disease.
During early childhood, he experienced several episodes of
acute pain, swelling of the hands and feet, and jaundice.
Three years before this admission, he required a left hip
replacement secondary to bony infarctions.
Recently, frequent blood transfusions have reduced the
frequency of sickling crises.

21. A case approach understanding for sickle cell anemia
18-year-old man with sickle cell anemia,
Physical examination
Thin black man in acute distress and with scleral icterus. Pulse
=110 beats/min, a RR=18 breaths/min, temp= 37°C. Lungs are
clear, hyperdynamic pericardium and a systolic murmur at the left
sternal edge. Splenomegaly, and cardiomegaly.
Laboratory Findings
Hgb, 5.5 g/dL (normal, 14 to 18). Hct, 25% (normal, 42% to 52%)
WBC count, 5,000/mm3 (normal, 3,200 to 9,800)
Platelets, 325k/mm3 (normal, 130k – 400k)
Reticulocyte count, 1% (normal, 0.5-1.5%)
Bilirubin, 5.8 mg/dL (normal, 0.1 to 1.0);
SrCr 3.0 mg/dL (normal, 0.6 to 1.2)
BUN 52 mg/dL (normal, 1 to 18).
The peripheral
blood smear
shows target
cells with an
occasional
sickled cell

22. A case approach understanding for sickle cell anemia
What are the signs and symptoms that are
consistent with sickle cell anemia?
The presence of splenomegaly and anemia with target and sickled
cells
What is the current sickle cell anemia complication?
Splenic sequestration crisis.
Splenomegaly rapidly evolves over several hours and is
accompanied by progressive anemia.
The low reticulocyte count is consistent with acute
sequestration because a reticulocyte response would
be expected if the anemia had developed in recent
days.

23. A case approach understanding for sickle cell anemia
What is the treatment plan for this patient?
Signs and symptoms are sufficiently serious to justify
transfusion therapy.
Hydration is needed due to SrCr and BUN levels.
Sickle cell anemia patients lose the ability to concentrate urine,
they may become dehydrated, which further contributes to cell
sickling.
Pain control also should be aggressively instituted
Splenectomy may be indicated in instances of
severe splenomegaly, repeated infarction, or pain in
adults, and it is indicated when crises occur in
children.
Patients with sickle cell anemia who are bedridden
should be placed on chronic heparin therapy to
prevent vascular occlusions and deep vein
thrombosis

24. Chronic disease related anemia
Mild to moderate anemia associated with a number of
disorders (e.g., rheumatoid arthritis [RA], systemic
lupus erythematosus, chronic infections, chronic renal
failure, acquired immunodeficiency syndrome [AIDS],
neoplastic disease).
Management of mild to moderate ACD usually
focuses on the underlying disease process. Anemia of
chronic disease is not usually progressive or lifethreatening, although it generally affects a patient's
quality of life.
Patients may require blood transfusions for symptomatic anemia.
Recombinant human EPO (rhEPO) has been used successfully to treat

25. Human Recombinant Erythropoietin Therapy
Human recombinant erythropoietin therapy is indicated for use in anemia
associated with end-stage renal disease, drug-induced anemia (chemotherapy
and zidovudine therapy), AIDS; in patients with low endogenous EPO
levels; and with autologous blood transfusions for elective surgery.
Therapeutic Uses and Regimens for Recombinant Human Erythropoietin
Epoetin Alfac
Darbepoetin Alfac
Anemia
Time to Respond Overall Response
Pathogenesis
Dose (U/kg)
Frequency
Dose (mcg/kg)
Frequency
(wk)
Rate (%)
Acquired immuno100
3× /wk
8–12
17–35
deficiency
syndrome (AIDS)
Chemotherapy- 150 or 40,000 U 3× /wk or once a 2.25 or 500 mcg Once a week or
2–8
32–61d
induced malignancy (total dose)
week,
(total dose)
once every 3
48–83e
respectively
weeks,
respectively

26. A case approach of renal insufficiency-related anemia
A 35-year-old man with a 25-year history of diabetes mellitus,
is diagnosed with renal failure and placed on hemodialysis three
times weekly.
One year later, he is noted to have become increasingly
transfusion dependent for correction of his anemia.
Significant laboratory values include the
following: Hgb, 7 g/dL (normal, 14 to 18);
Hct, 26% (normal, 42% to 52%); ferritin, 360
ng/mL (normal, 15 to 200); and serum iron, 98
µg/dL (normal, 50 to 160). In addition, K.S.
complains of constant fatigue, poor appetite,
and a low energy level.

27. A case approach of renal insufficiency-related anemia
What is the treatment plan to correct his anemia?
The cause of the anemia is complex but involves reduced EPO production
and a shortened RBC life span.
Previously, these patients were treated with transfusions and
androgens.
Although effective, repeated transfusions cause complications,
such as iron overload, infections, reactions to leukocyte
antigens, or the development of cytotoxic antibodies.
Because EPO is secreted in the kidney in response
to anoxia and is responsible for normal differentiation
of RBC from other stem cells, rhEPO is used to
treat anemia in patients with renal failure who are
undergoing hemodialysis,,

28. A case approach of malignancy-related anemia
A 45 year-old woman with non-Hodgkin's lymphoma diagnosed 2
months ago.
She is being seen for her third of six cycles of chemotherapy.
She complains of shortness of breath and fatigue when she walks
up stairs.
Her only medication is ibuprofen 200 mg PRN for occasional
headaches.
Her CBC indicates the following: Hgb, 9.7 g/dL
(normal, 12 to 16); Hct, 29% (normal, 40% to 44%);
MCV, 90 µm3 (normal, 81 to 99); MCHC, 30% (normal,
33% to 37%); serum erythropoietin, 29 U/L (normal, 4 to
26). The peripheral smear shows normochromic and
normocytic RBC.

29. A case approach of malignancy-related anemia
What is the most likely cause of this patient's anemia?
Malignancy-related anemia, which is often characterized as anemia of
chronic disease or is chemotherapy induced.
It is generally normocytic and normochromic and develops when a disease
has persisted for >1 to 2 months. the anemia is often asymptomatic or
mildly symptomatic .
What is the treatment plan this patient's anemia?
Number of anemia management options.
Course of chemotherapy can be delayed to allow for
hematologic recovery and resolution of anemia symptoms.
RBC transfusion can be given to relieve her symptoms and allow
her to better tolerate chemotherapy.
Erythropoietic therapy with epoetin alfa or darbepoetin alfa also
should be considered.

30. Pharmacottherapy
Anas Bahnassi PhD CDM CDE
abahnassi@gmail.com
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