Pharmacology of Hematopoiesis

Question 1

What is the definition of anemia?

Answer 1

Signficant reduction in functional red cell mass with a consequent reduction in oxygen carrying capacity

Can be due to blood loss, reduced red cell production, or production of abnormal cells

Question 2

Where is erythropoietin made?

Answer 2

Primarily in the proximal tubular cells of the kidney epithelium, minor in liver

Question 3

What are the three major functions of erythropoietin? What happens in its absence

Answer 3

Control the:

1. Synthesis of erythroblasts (stimulates CFU-E line)
2. Maturation of erythroblasts
3. Release of mature reticulocytes from the bone marrow

In its absence: severe anemia

Question 4

What conditions favor the renal synthesis and secretion of erythropoietin?

Answer 4

Anemia or hypoxia

Conditions like pulmonary insufficiency will do this, or renal cancer which synthesizes more

Question 5

What are the major myeloid growth factors?

Answer 5

GM-CSF - granulocyte / macrophage colony stimulating factor

G-CSF = granulocyte only
M-CSF = monocyte only
IL-3 = stimulates formation of most lines

Question 6

What produces the major myeloid growth factors?

Answer 6

GM-CSF / IL-3 = T-lymphocytes

All others (other than erythropoietin) made by monocytes, fibroblasts, and endothelial cells

Question 7

What four lines does GM-CSF stimulate the production of?

Answer 7

In the presence of IL-3: CFU-E, CFU-G, CFU-M, and CFU-Meg (karyoblasts)

Question 8

Other than synthesis and release of specialized cells, what is the function of the myeloid growth factors?

Answer 8

They also help stimulate the mature granulocytes into functioning (i.e. G-CSF enhances neutrophil phagocytic and cytotoxic properties)

Question 9

What are the primary indications for erythropoietin?

Answer 9

Anemia resulting from chronic renal failure or those on hemodialysis (lack of erythropoeitin secretion)

Also in anemia associated with AZT or cancer chemotherapy

Question 10

What is needed to be done when administering erythropoeitin?

Answer 10

Titrate the dose carefully to avoid an excessively rapid increase in hematocrit -> raise it slowly while monitoring blood pressure

Also, make sure the patient has adequate iron supply

Question 11

What are the most common toxicities and side effects of erythropoietin?

Answer 11

All adverse effects associated with increased hematocrit

• > increased clotting / thrombotic phenomena
• > hypertension

Question 12

What is the signalling pathway for erythropoietin release?

Answer 12

Gs pathway causes increased cAMP which activates PKA and causes more erythropoietin production

Question 13

What are the major clinical utilities of myeloid growth factors?

Answer 13

1. Restoration of normal hematopoiesis in patients with diseases impacting bone marrow production
2. Recovery from severe neutropenia
3. Augmentation of host defenses vs infection
4. Adjunct role in chemotherapy to improve cytotoxicity vs tumor cells

Question 14

What are the less serious and more dose-limiting toxicities of myeloid growth factors?

Answer 14

Less serious: injection site reaction, fever, myalgias

Serious / dose-limiting: Pericarditis, pleuritis, pulmonary emboli, possible oncogenesis

Question 15

What myeloid growth factor is thought to have fewer untoward effects?

Answer 15

G-CSF

Question 16

What is the primary problem in patients with sickle cell disease?

Answer 16

Deoxygenated HbS chains form polymeric structures causing deformation of erythrocytes and membrane permeability changes. They thus aggregate in the microvasculature and cause veno-occlusive damage

Question 17

What drug is approved in the US for treatment of veno-occlusive events and how does it work?

Answer 17

Hydroxyurea

-> increases production of fetal hemoglobin, interfering with polymerization of HbS

Question 18

What is the most common nutritional anemia in man and what does it do to the RBCs?

Answer 18

Iron deficiency, causes a microcytic, hypochromic anemia due to drop in hemoglobin synthesis

Question 19

What is iron status largely dependent on and why?

Answer 19

Economic status of the population

• > high intake comes from expensive foods like meats, egg yolks, oysters, and dried beans / fruits
• > smaller intake comes from milk products and non-green vegetables

Question 20

What is the cause of most nutritional iron deficiency in the US?

Answer 20

Blood loss, especially in females due to menstruation.

Is also caused by increased requirements during pregnancy (6x as much iron needed per day in pregnancy)

Question 21

What is the most absorbable form of iron? What helps its absorption?

Answer 21

Heme iron, although it represents a minority of iron in the diet.

Iron is also more absorbable in the ferrous state -> vitamin C (Ascorbate) helps reduce iron to this form

Question 22

In what form does the majority of the body’s iron content exist in?

Answer 22

70% in hemoglobin, 10% in myoglobin, and other than trace amounts in cytochromes and enzymes, about 10-20% is stored in ferritin

Question 23

Where is ferritin found and what does it do?

Answer 23

24 polypeptide chain which forms an outer shell and storage cavity for iron, found in reticuloendothelial system + liver

Question 24

How is iron moved around the body to specific cells?

Answer 24

Via the glycoprotein transferrin, which delivers iron to sites on cellular plasma membranes

Question 25

In high and low iron states, what is the relative expression of ferritin and transferrin receptors?

Answer 25

Low iron - tissues need it:
Low ferritin, high transferrin receptors

High iron - need to store it:
High ferritin, low transferrin receptors

Question 26

What is the most common iron therapy, its percent absorption, and its adverse effects?

Answer 26

Oral ferrous sulfate, about 25% is absorbed.

Adverse effects: GI distress

Question 27

When is parenteral iron therapy warranted?

Answer 27

Patients who cannot absorb iron or those with chronic blood loss

Question 28

Aside from blood loss, what is really the only way our body loses iron?

Answer 28

Loss of ferritin during exfoliation

Generally we just need more iron as we grow

Question 29

Why is vitamin B12 dependent on folate?

Answer 29

B12-dependent synthesis of methionine from homocysteine requires a methyl from methyl-tetrahydrofolate

Question 30

What is folate specifically required for?

Answer 30

Synthesis of purines and metyhlation of dUMP to dTMP

Question 31

What will deficiency in either B12 or B9 cause?

Answer 31

Decreased synthesis of methionine and S-adenosylmethionine, leading to interference with numerous methylation “one-carbon metabolism reactions”

-> stores are directed away from nucleic acid synthesis, halting production of new cells

Question 32

How is B12 absorbed?

Answer 32

Instrinsic factor secreted by parietal cells, B12-intrinsic factor complex is absorbed in distal ileumm

Question 33

What moves B12 around the body?

Answer 33

Transcobalamin II

Question 34

What is the primary source of B12? Where is it stored and how much do we have?

Answer 34

The diet -> originally from microorganisms
We store it in the liver and have enough for 3-4 years
-> if we run out of cobalamin (B12), it’s probably due to a defect, not a dietary deficiency

Question 35

How is folate absorbed?

Answer 35

In the early small intestine, typically in the MeFH4 form, via receptor-mediated endocytosis of reduced polyglutamates

Question 36

What is folate present in, and why is it easy to have a deficiency?

Answer 36

Virtually all foods especially green vegetables. However, cooking destroys up to 90% of folate content in foods, and we don’t eat enough folates to handle that destruction (dietary requirement is 50 micrograms per day, and we eat at a minimum that much, before destruction)

Question 37

What does B12 deficiency do to the body?

Answer 37

Causes abnormal hematopoeitic and nervous systems, since the proper amount is required to carry out DNA synthesis (B12 deficiency will lead to trapping of folate)

Question 38

What is the characteristic anemia found in B12 deficiency and why?

Answer 38

Megaloblastic anemia - hematopoietic stem cell will still go through a series of cell divisions.

Even though cytoplasmic maturation occurs at a normal rate, defect in chromosomal replication causes abnormally large red blood cells or cells dying in maturation

Question 39

What causes B12 deficiency and what is the treatment?

Answer 39

Deficiency in instrinsic factor or defect in absorption at distal ileum (i.e. due to bariatric surgery with ileal resection)

Treatment is parenteral injections of B12

Question 40

How is B12 deficiency diagnosed (differentiate it from B9)?

Answer 40

Measurements of serum B12 or serum methylmalonic acid (goes up in parallel to decreasing B12 levels because B12 is needed for synthesis of succinyl-CoA from methylmalonic acid, made from propionyl-CoA)

Question 41

Who typically gets a folate deficiency?

Answer 41

Elderly patients, poor patients, and people with diets lacking vegetables, eggs, and meat.

Alcoholics + patients with liver disease are very susceptible due to diminished capacity for folate stores in liver

Question 42

What type of anemia does folate cause?

Answer 42

Megaloblastic anemia, same as B12

Question 43

What happens if you treat a B12 deficient patient with folate?

Answer 43

Megaloblastic anemia is relieved, but neurological defects will persist

-> need to diagnose a B12 deficiency by measuring elevated serum methylmalonic acid