Cytopenias and Anemia Drugs

• Study notes on Cytopenias and Drugs for Anemia

Hematopoiesis

• Requires iron, folic acid, B12, and hematopoietic growth factors.
• Anemia is defined as a deficiency in oxygen-carrying red cells.

Iron

• Dietary ferric iron (Fe3+) must be reduced to ferrous iron (Fe2+) for absorption.
• The enzyme ferrireductase helps reduce the iron in most foods.
• Iron in hemoglobin binds oxygen and is the mechanism for delivering oxygen to tissues
• Iron deficiency anemia leads to microcytic, hypochromic (pale) red cells.
• Ferritin is the storage form of iron and is located in the liver.
• Transferrin protein in plasma transports iron into cells.
• Ferrous salts are used as drug supplements.
• Ferrous salt is typically administered orally (PO), while intravenous (IV) ferric can be toxic.
• IV dosage forms use chemical complexes enabling a slow release of iron, which converts to ferrous in the body.
• IV iron is available as iron dextran, sodium ferric gluconate complex, and iron sucrose
• Low serum iron in plasma < 30 mcg/dL indicates iron deficiency
• Low serum ferritin levels < 20 mcg/L indicates an iron deficiency

Iron Toxicity

• Toxicity occurs when unbound iron precipitates into tissues and destroys them.
• Free unbound iron is highly toxic and does not exist in the body
• Overdoses are most commonly seen in children who ingest vitamin tablets.
• As few as 10 tablets can be lethal in children.
• Deferoxamine is administered intravenously to bind and remove iron from the body.
• Free iron is toxic; an overdose can overwhelm iron-binding proteins, leading to iron precipitation in tissues.

Chronic Iron Toxicity

• Chronic iron toxicity is hemochromatosis.
• It can result from inherited excess iron absorption.
• Treatment involves intermittent phlebotomy, like monthly blood donations.

Vitamin B12

• B12 drugs include Hydroxocobalamin and cyanocobalmin
• Cobalamin is another name for Vitamin B12.
• Deficiency leads to megaloblastic anemia.
• Deficiency can cause neurological, and behavioral symptoms as the first sign.
• Major source found in meat and dairy products, synthesized by microbes
• Sources include red meats and dairy products
• Deficiency causes megaloblastic anemia, GI symptoms, and neurological abnormalities
• B12 deficiency = Megaloblastic Anemia
• B12 deficiency due to lack of Intrinsic Factor = Pernicious Anemia
• Macrocytic normochromic anemia can also be caused by B12 deficiency
• Low serum B12 < 100 pmol/L indicates B12 deficiency

Vitamin B12 Absorption

• Intrinsic factor protein in the stomach is required for B12 absorption.
• It takes approximately 5 years to deplete B12 body stores if dietary intake stops.
• B12 is stored in the liver, and it would take about 5 years to use up all the stored B12
• B12 is essential for two major reactions:
  • Serves as an intermediate in methyl group transfer from N5 methyltetrahydrofolate to homocysteine
  • Required for the isomerization of methylmalonyl-CoA to succinyl-CoA
• Folic acid can mask B12 deficiency, but does not reverse neurological symptoms.
• Deficiency can be screened for via B12 and folic acid serum levels.
• The Schilling test uses radioactive B12 to measure absorption rates.
• Pernicious anemia (PA) results from a defect in intrinsic factor (IF).
• Gastritis can reduce IF secretion, lowering IF levels.
• B12 deficiency is mostly due to absorption issues; injections are required since oral B12 will not absorb if IF is lost.

Folic Acid

• Functions similarly to Vitamin B12 in the context of anemia and hematopoiesis.
• A vitamin required for the synthesis of DNA and biochemical reactions.
• Replenished with oral folic acid if serum levels are low.
• Richest sources are yeast, liver, kidney, and green vegetables
• Stores are rapidly depleted within 1-6 months, leading to megaloblastic anemia.
• Macrocytic normochromic anemia can be a sign of folic acid deficiency
• Low serum folic acid indicates folic acid deficiency
• Public Health considerations exist regarding folic acid.

Overview of Anemia

• Can be caused by deficiencies in B12, folic acid, and/or intrinsic factor.
• Low serum folic acid is treated with oral folic acid.
• Low serum B12 indicates a need for B12 supplementation, and a Schilling Test should be performed to evaluate Intrinsic Factor levels.
• If IF is normal, oral B12 can be given, if deficient, B12, which is a protein, should be administered via injection.
• B12 vs Folic Acid caused anemia presents with the same symptoms, but B12 deficiency is associated with neurological symptoms, not folic acid anemia

Hematopoietic Growth Factors

• Hormones which stimulate the production of red cells, white cells, and platelets.

Normal Blood Cell Counts

• Red Blood Cells (RBCs): 5,000,000/uL
• Platelets: 500,000/uL
• White Cells: 5,000/uL
• These numbers are general guidelines

Erythropoietin

• Erythropoietin, a protein hormone, produced by the kidney, stimulates red cell production.
• Kidney measures blood volume and triggers release of erythropoietin.
• Considered the first "orphan drug" to become a blockbuster.
• Hormone erythropoietin travels to the bone marrow, stimulating red cell production.
• Chronic kidney failure patients on dialysis often develop severe anemia due to lack of erythropoietin, requiring blood transfusions.
• Erythropoietin injections have largely replaced the need for transfusions in dialysis patients.
• Epoetin alfa: Administered intravenously up to three times per week
  • Alpha signifies the first letter of the Greek alphabet and indicates the protein is recombinant.
• Darbepoetin: Glycosylated form, administered once per week.
• Methoxy polyethylene glycol epoetin beta: Has PEG attached, once per month.
• Drug modification with PEG slows absorption and increases its half-life.

Reticulocyte Count

• Used to monitor therapy, effects are typically seen 10 days after treatment begins.
• Reticulocytes are immature red cells containing some residual DNA.
• All mature red cells do not have a nucleus which is removed during bone marrow release.
• The number of reticulocytes in the blood stream is a marker of how many immature red cells are being released after
• Epoetin drugs activate red cell production and immature red ells are released

Hct and Hb

• Hematocrit (Hct) and Hemoglobin (Hb) levels increase within 2-6 weeks.
• Hct, commonly called "the crit," represents the percentage of red cells, white cells, and platelets in the blood
  • Normally, blood is 50% water and 50% cells
• If the "crit" is 23%, it indicates anemia.
• Hemoglobin presents the total amount of red cell hemoglobin per 100 mL of blood, with a normal range of 12-15 g/dL.
• Hct is measured by centrifuging blood in a capillary tube, separating cells from plasma where you measure the height.

Myeloid Growth Factors

• Peptide hormones stimulate the bone marrow to produce white cells (neutrophils) when injected
• Applications in clinical medicine are numerous.
• Includes Granulocyte-Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF).
• G-CSF is also known as rHuG-CSF, or Filgrastim (G-CSF)
• Stimulates neutrophil production, administered via daily subcutaneous injections
• GM-CSF is also known as rHuGM-CSF, or Sargramostin.
• CSF stands for colony stimulating factor
• Pegfilgrastim consists of PEG on filgrastim.
• All myeloid growth factors are proteins, administered intravenously (IV) or subcutaneously (SC).
• G-CSF stimulates neutrophil production and increases peripheral stem cell numbers in the blood.
• GM-CSF stimulates granulocytes as well as red cells.
• Can cause serious viral infections like hepatitis and HIV

Stem Cells

• Stem cells (CD34 white cells) are present in low numbers in the bloodstream, accessible, and always measurable
• To become a stem cell donor may take a myeloid growth factor once a day for 2-3 days, after donation, CD34 cells are extracted and used for patients to recover after cancer chemotherapy
• This process is common of a "bone marrow donor" donation

Megakaryocyte Growth Factors

• Megakaryocyte is a platelet.
• Platelet transfusions are common but carries bacterial infection risks and die at 37 degrees C
• Thrombocytopenia indicates reduced platelet count
• Thrombopoietin and Interleukin-11 (IL-11) are proteins that stimulate platelet production.
• IL-11 is also known as oprelvekin.
• Oprelvekin activates IL-11 receptors and stimulates the production of platelets, injected subcutaneously daily.
• Romiplostim consists of peptibodies; a peptide linked to an antibody fragment to stimulate platelet production and extend their half-life.
• All drugs reduce the need for transfusions, but may not totally replace depending on the condition.