Lecture 23: Anemia

Question 1

ANEMIA: CAUSES

Answer 1

• Chronic blood loss
• Bone marrow abnormalities
• Increased hemolysis
• Renal failure
• Other diseases
• Many drugs may cause anemia.
• Nutritional anemias are caused by deficiencies of substances which are necessary for normal erythropoiesis such as:
  
  • Iron
  • Folic acid
  • Vitamin B12

Question 2

Acute iron toxicity

Answer 2

• Acute iron toxicity is seen mainly in young children who accidentally ingest iron tablets.
• Iron poisoning leads to necrotizing gastroenteritis, with vomiting, abdominal pain, and bloody diarrhea which may be followed by shock, metabolic acidosis, coma, and death.

Question 3

Deferoxamine

Answer 3

• ACUTE IRON TOXICITY: TREATMENT
• an iron-chelator, can be given to bind iron that has already been absorbed and to promote its excretion in urine and feces.

Question 4

CHRONIC IRON TOXICITY

Answer 4

Causes

• Most commonly occurs in patients with inherited hemochromatosis, a genetic disorder characterized by excessive iron absorption
• Also in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major).

Rx

• Chronic iron overload in the absence of anemia is most efficiently treated by phlebotomy.
• Chelation therapy with parenteral deferoxamine or deferasirox may be needed in patients with thalassemia major to retard the accumulation of iron.

Question 5

VITAMIN B12: Chemistry

Answer 5

• Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans.
• Cyanocobalamin, hydroxocobalamin and other cobalamins found in food are converted to the active forms.

PK

• The normal daily requirements of vitamin B12 are only about 2 μg.
• It would take 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped.
• Vitamin B12 deficiency in humans most often results from malabsorption.
• Malabsorption is due either to lack of intrinsic factor or to loss or malfunction of the transporter.
• Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products.

PD

1. Methylcobalamin transfers a methyl group from N5-MTHF to homocysteine, forming methionine. In the process, N5-MTHF is converted to THF, the precursor of folate cofactors. Depletion of THF prevents synthesis of dTMP and purines required for DNA synthesis. The accumulation of folate as N5-MTHF and the associated depletion of THF cofactors in vitamin B12 deficiency is called the “methylfolate trap.”
2. other reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl- CoA by the enzyme methylmalonyl-CoA mutase.

In vitamin B12 deficiency, methylmalonyl-CoA, and methylmalonate accumulate.

Question 6

VITAMIN B12: CLINICAL PHARMACOLOGY

Answer 6

• Folic acid can partially reverse some of the hematologic abnormalities of vitamin B12 deficiency, and thus, mask the B12 deficiency.
• As a consequence, the neurologic complications will worsen.

Most common causes of vitamin B12 deficiency

• Pernicious anemia
• Gastrectomy
• Malabsorption syndromes
• IBS
• Small bowel resection.

Question 7

Folic acid: PK/PD

Answer 7

• Cofactors of THF participate in several essential reactions.
• One of these reactions produces dTMP needed for DNA synthesis.
• N5-MTHF is required for the vitamin B12- dependent reaction that generates methionine from homocysteine.
• Also, THF cofactors are essential in the de novo synthesis of purines.

Clinical

• Folate deficiency does not cause a neurologic syndrome
• Folic acid deficiency can be caused by drugs including Methotrexate, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may cause megaloblastic anemia.

Question 8

HEMATOPOIETIC GROWTH FACTORS

Answer 8

• ERYTHROPOIETIN: member of the JAK/STAT superfamily of cytokine receptors.
• MYELOID GROWTH FACTORS
  
  • FILGRASTIM
  • SARGRAMOSTIN
• MEGAKARYOCYTE GROWTH FACTORS: INTERLEUKIN-11

Question 9

EPO: PK/PD

Answer 9

PD

• An inverse relationship exists between the hemoglobin level and the serum erythropoietin level.
• **The most important exception to this inverse relationship is the anemia of chronic renal failure. In patients with renal disease, erythropoietin levels are usually low because the kidneys cannot produce it. **
• **Darbepoetin is a long-acting version of erythropoietin. **

Adverse: Hypertension and thrombotic complications.

Question 10

FILGRASTIM AND SARGRAMOSTIN

Answer 10

• MYELOID GROWTH FACTORS:
• Stimulate production and function of neutrophils

Uses

Used to accelerate recovery of neutrophils after cancer chemotherapy.

Question 11

INTERLEUKIN-11

Answer 11

• MEGAKARYOCYTE GROWTH FACTORS
• Increases the number of peripheral platelets.
• Used for patients undergoing cancer chemotherapy.
• Reduces the need for platelet transfusions.

Question 12

HYDROXYUREA

Answer 12

• AGENTS USED TO TREAT SICKLE-CELL DISEASE
• can relieve the painful clinical course of sickle-cell disease
• In sickle-cell disease, the drug apparently increases HbF, thus diluting HbS.
• This process takes several months.

Adverse: Bone marrow suppression and cutaneous vasculitis.