Anemia Pharmacotherapy: Part-2

Anemia Part Two

Anas Bahnassi

1 Week

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

Folic acid deficiency anemia

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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.

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.


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).


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.


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.


(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.

What is the treatment plan this patient?

A case approach understanding for iron deficiency anemia

(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.

How can you monitor response to therapy?

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.

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 BO-thalassemia 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

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.


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.


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.

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.

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.

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).

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

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.

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.


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


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.


What is the treatment plan for this patient?

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

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

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 life-threatening, 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

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.

Anemia Pathogenesis

Epoetin Alfac Darbepoetin Alfac Time to Respond (wk)

Overall Response Rate (%) Dose (U/kg) Frequency Dose (mcg/kg) Frequency

Acquired immuno-deficiency

syndrome (AIDS)

100 3× /wk 8–12 17–35

Chemotherapy-induced malignancy

150 or 40,000 U (total dose)

3× /wk or once a week,

respectively

2.25 or 500 mcg (total dose)

Once a week or once every 3

weeks, respectively

2–8 32–61d 48–83e

Therapeutic Uses and Regimens for Recombinant Human Erythropoietin

A case approach of renal insufficiency-related 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.

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.

A case approach of renal insufficiency-related anemia

What is the treatment plan to correct his anemia?

Although effective, repeated transfusions cause complications, such as iron overload, infections, reactions to leukocyte antigens, or the development of cytotoxic antibodies.

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.

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,,

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.

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.

Pharmacottherapy Anas Bahnassi PhD CDM CDE

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Anemia Pharmacotherapy: Part-2

Health & Medicine

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