Pharmacology of Hematopoiesis Flashcards
What is the definition of anemia?
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
Where is erythropoietin made?
Primarily in the proximal tubular cells of the kidney epithelium, minor in liver
What are the three major functions of erythropoietin? What happens in its absence
Control the:
- Synthesis of erythroblasts (stimulates CFU-E line)
- Maturation of erythroblasts
- Release of mature reticulocytes from the bone marrow
In its absence: severe anemia
What conditions favor the renal synthesis and secretion of erythropoietin?
Anemia or hypoxia
Conditions like pulmonary insufficiency will do this, or renal cancer which synthesizes more
What are the major myeloid growth factors?
GM-CSF - granulocyte / macrophage colony stimulating factor
G-CSF = granulocyte only M-CSF = monocyte only IL-3 = stimulates formation of most lines
What produces the major myeloid growth factors?
GM-CSF / IL-3 = T-lymphocytes
All others (other than erythropoietin) made by monocytes, fibroblasts, and endothelial cells
What four lines does GM-CSF stimulate the production of?
In the presence of IL-3: CFU-E, CFU-G, CFU-M, and CFU-Meg (karyoblasts)
Other than synthesis and release of specialized cells, what is the function of the myeloid growth factors?
They also help stimulate the mature granulocytes into functioning (i.e. G-CSF enhances neutrophil phagocytic and cytotoxic properties)
What are the primary indications for erythropoietin?
Anemia resulting from chronic renal failure or those on hemodialysis (lack of erythropoeitin secretion)
Also in anemia associated with AZT or cancer chemotherapy
What is needed to be done when administering erythropoeitin?
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
What are the most common toxicities and side effects of erythropoietin?
All adverse effects associated with increased hematocrit
- > increased clotting / thrombotic phenomena
- > hypertension
What is the signalling pathway for erythropoietin release?
Gs pathway causes increased cAMP which activates PKA and causes more erythropoietin production
What are the major clinical utilities of myeloid growth factors?
- Restoration of normal hematopoiesis in patients with diseases impacting bone marrow production
- Recovery from severe neutropenia
- Augmentation of host defenses vs infection
- Adjunct role in chemotherapy to improve cytotoxicity vs tumor cells
What are the less serious and more dose-limiting toxicities of myeloid growth factors?
Less serious: injection site reaction, fever, myalgias
Serious / dose-limiting: Pericarditis, pleuritis, pulmonary emboli, possible oncogenesis
What myeloid growth factor is thought to have fewer untoward effects?
G-CSF
What is the primary problem in patients with sickle cell disease?
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
What drug is approved in the US for treatment of veno-occlusive events and how does it work?
Hydroxyurea
-> increases production of fetal hemoglobin, interfering with polymerization of HbS
What is the most common nutritional anemia in man and what does it do to the RBCs?
Iron deficiency, causes a microcytic, hypochromic anemia due to drop in hemoglobin synthesis
What is iron status largely dependent on and why?
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
What is the cause of most nutritional iron deficiency in the US?
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)
What is the most absorbable form of iron? What helps its absorption?
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
In what form does the majority of the body’s iron content exist in?
70% in hemoglobin, 10% in myoglobin, and other than trace amounts in cytochromes and enzymes, about 10-20% is stored in ferritin
Where is ferritin found and what does it do?
24 polypeptide chain which forms an outer shell and storage cavity for iron, found in reticuloendothelial system + liver
How is iron moved around the body to specific cells?
Via the glycoprotein transferrin, which delivers iron to sites on cellular plasma membranes
In high and low iron states, what is the relative expression of ferritin and transferrin receptors?
Low iron - tissues need it:
Low ferritin, high transferrin receptors
High iron - need to store it:
High ferritin, low transferrin receptors
What is the most common iron therapy, its percent absorption, and its adverse effects?
Oral ferrous sulfate, about 25% is absorbed.
Adverse effects: GI distress
When is parenteral iron therapy warranted?
Patients who cannot absorb iron or those with chronic blood loss
Aside from blood loss, what is really the only way our body loses iron?
Loss of ferritin during exfoliation
Generally we just need more iron as we grow
Why is vitamin B12 dependent on folate?
B12-dependent synthesis of methionine from homocysteine requires a methyl from methyl-tetrahydrofolate
What is folate specifically required for?
Synthesis of purines and metyhlation of dUMP to dTMP
What will deficiency in either B12 or B9 cause?
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
How is B12 absorbed?
Instrinsic factor secreted by parietal cells, B12-intrinsic factor complex is absorbed in distal ileumm
What moves B12 around the body?
Transcobalamin II
What is the primary source of B12? Where is it stored and how much do we have?
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
How is folate absorbed?
In the early small intestine, typically in the MeFH4 form, via receptor-mediated endocytosis of reduced polyglutamates
What is folate present in, and why is it easy to have a deficiency?
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)
What does B12 deficiency do to the body?
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)
What is the characteristic anemia found in B12 deficiency and why?
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
What causes B12 deficiency and what is the treatment?
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
How is B12 deficiency diagnosed (differentiate it from B9)?
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)
Who typically gets a folate deficiency?
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
What type of anemia does folate cause?
Megaloblastic anemia, same as B12
What happens if you treat a B12 deficient patient with folate?
Megaloblastic anemia is relieved, but neurological defects will persist
-> need to diagnose a B12 deficiency by measuring elevated serum methylmalonic acid
