Block V- Pulm Anemia/Hematopoietic Growth Factors

Question 1

What molecules store Iron?

Answer 1

Ferritin (macrophages, liver, spleen)

Hemosiderin

Question 2

What oxidation state of Iron is preferentially absorbed and what maintains this state?

Answer 2

Fe2+ (ferrous) form, maintained by acid produced by the gastric body

Question 3

What molecule brings Iron to the plasma/ liver/ spleen (storage)?

Answer 3

Ferritin

Question 4

What molecule takes Iron to the BM?

Answer 4

Transferrin

Question 5

Where is Iron absorbed?

Answer 5

duodenum and jejunum

Question 6

What are ferritin and transferrin levels in Iron Deficiency?

Answer 6

dec. ferritin

inc. transferrin

Question 7

What are ferritin and transferrin levels in Iron Overload?

Answer 7

inc. ferritin

dec. transferrin

Question 8

Hepcidin and Ferroportin:
hemochromatosis
anemia of chronic disease

Answer 8

ferroportin = gatekeeper. prevent iron from getting out or send it out! tell it where to go!

hemochromatosis = decreased hepcidin and increased ferroportin

ACD = inc hepcidin = down regulation of ferroportin = iron stuck in cell w/o normal gatekeeper

Question 9

What are indications for Iron therapy? (4)

Answer 9

1) prevention or treatment of iron deficiency anemia
2) Increased requirements (premature infants, children, pregnant and lactating women)
3) Inadequate absorption (small intestine or gastrectomy)
4) blood loss (period of chronic GI bleed)

Question 10

Oral Iron Therapy

Answer 10

• Ferrous sulfate, ferrous gluconate, ferrous fumarate
• quick response (1-3 months)
• Adverse Effects: nausea, vomiting, black stools

Question 11

Parenteral Iron Therapy (IM/IV)

Answer 11

• Iron dextran, iron sucrose, iron gluconate
• Indicated when oral iron not tolerated (post GI resection, malabsorption syndromes)
• Adverse Effects: pain, tissue staining (IM), HA, fever, N/V, back/joint pain, allergic rxn, anaphylaxis

Question 12

What is Acute Iron Toxicity?

Answer 12

• over ingestion of iron tablets
• fatal in children
• Necrotizing gastroenteritis

Question 13

What is Chronic Iron Toxicity?

Answer 13

• Hemochromatosis, multiple red cell transfusions

- organ failure

Question 14

How do you treat Acute Iron Toxicity?

Answer 14

• Gastric aspiration
• Gastric lavage (phosphate or carbonate)
• Iron chelation with deferoxamine

Question 15

How do you treat Chronic Iron Toxicity?

Answer 15

• intermittent phlebotomy (if no anemia)

- Iron chelation (deferoxamine, deferasirox)

Question 16

Where is Vitamin B12 absorbed?

Answer 16

The distal ileum

Question 17

What is Vitamin B12 bound to in the small intestine which permits its absorption?

Answer 17

Intrinsic factor (from the gastric parietal cells)

Question 18

What is B12 bound to in plasma?

Answer 18

Transcobalamin II

Question 19

What are the active forms of vitamin B12?

Answer 19

• deoxyadenosylcobalamin

- Methylcobalamin

Question 20

What are prodrugs of B12 and how are they given?

Answer 20

• Given IM
• Cyanocobalamin
• Hydroxycobalamin

Question 21

Where is folate stored?

Answer 21

-stored in the liver (1-6 months)

Question 22

Describe folic acid metabolism and absorption

Answer 22

• Dietary polyglutamates are hydrolyzed to mono glutamate

- Monoglutamate is absorbed in the blood stream

Question 23

What are symptoms of B12/Folic Acid deficiency seen in the Alimentary tract?

Answer 23

• atrophic glossitis
• chronic gastritis

seen here because these cells have lots of turnover!

Question 24

What are symptoms of B12/Folic Acid deficiency seen in the Blood and bone marrow?

Answer 24

• megaloblastic anemia
• Leukopenia with hypersegmetned granulocytes
• mild to moderate thrombocytopenia

Question 25

What are symptoms of B12 deficiency seen in the CNS?

Answer 25

Subacute Combined Degeneration: due to pile up of MMA - spastic paraparesis - sensory ataxia - lower limb paresthesias FOLATE = NO CNS! (VB12 can still convert MMA to SCoA)

Question 26

How is Vitamin B12 deficiency treated?

Answer 26

- IM injections of prodrugs - cyanocobalamin - Hydroxycobalamin - Response within 1-2 months

Question 27

How is folic acid deficiency treated?

Answer 27

-oral folic acid

Question 28

What are benefits of oral B12 therapy?

Answer 28

- works even with IF deficiency | - you can treat B12 def with folic acid and resolve the anemia but it won't fix the CNS sx!

Question 29

What is the action of Erythropoietin?

Answer 29

- glycoprotein - binds to its receptor and stimulates proliferation and differentiation of erythroid cells - Stimulates releases of reticulocytes from the bone marrow

Question 30

Where is EPO produced?

Answer 30

- The kidney | - the peritubular interstitial fibroblasts

Question 31

What is the normal relationship between EPO and Hb? What disease process will skew the normal relationship between EPO and Hb?

Answer 31

inverse relationship renal failure

Question 32

How is recombinant EPO produced?

Answer 32

- Epoetin alpha | - produced in a mammalian expression system

Question 33

What are indications for EPO therapy? (4)

Answer 33

1) Chronic renal failure 2) Patients with aplastic anemia, leukemias, HIV/ADS associated anemias, cancer 3) Anemia of prematurity 4) Post phlebotomy

Question 34

What are some EPO drug names?

Answer 34

- epoetin alpha - Epogen - Procrit - Aranesp

Question 35

How is EPO therapy delivered?

Answer 35

-IV or subcutaneous injection

Question 36

What is the response time for EPO therapy?

Answer 36

- reticulocytes seen in 10 days | - increase in Hb seen in 2-6 weeks

Question 37

What are the Adverse Effects of EPO therapy?

Answer 37

- HTN - thrombotic complications - allergic reactions - Black Box warning for increased tumor progression or recurrence!! - Cardiovascular events

Question 38

What are the growth factors that stimulate proliferation and differentiation of myeloid cells?

Answer 38

G-CSF and GM-CSF

Question 39

What is the growth factor that stimulates proliferation and differentiation of erythroid and megakaryocytic cells?

Answer 39

GM-CSF

Question 40

What is the growth factor that promotes release of hematopoietic stem cells from the bone marrow into peripheral circulation?

Answer 40

G-CSF better than GM-CSF

Question 41

How is recombinant G-CSF produced?

Answer 41

- Filgrastim - produced in a bacterial expression system - Pegfilgrastim - conjugated to polyetheylene glycol for a longer half life

Question 42

How is recombinant GM-CSF produced?

Answer 42

- Sargramostim | - produced in a yeast expression system

Question 43

What are indications for G-CSF/GM-CSF therapy? (5)

Answer 43

1) After intensive chemotherapy 2) after chemotherapy for acute myeloid leukemia 3) treatment of congenital neutropenia, cyclic neutropenia, neutropenia associated with myelodysplasia and aplastic anemia 4) High dose chemotherapy with autologous stem cell rescue 5) (G-CSF) mobilization of peripheral blood stem cells for autologous transplant

Question 44

Describe the pattern (graph) of neutrophil release following G-CSF/GM-CSF therapy

Answer 44

- bimodal spike | - immediate early release followed by a later, sustained release

Question 45

What are the Adverse Effects of G-CSF Therapy?

Answer 45

- Bone pain - splenic rupture (rare) - allergic reactions - preferred in general

Question 46

What are the Adverse Effects of GM-CSF Therapy?

Answer 46

- fever - arthralgia, myalgia - peripheral edema - pleural/pericardial effusion - allergic reactions

Question 47

Where is IL-11 produced?

Answer 47

bone marrow stromal cells

Question 48

How is recombinant IL-11 produced?

Answer 48

- Oprelvekin | - produced by a bacterial expression system

Question 49

What is the function of IL-11?

Answer 49

- promotes proliferation of megakaryocytic progenitors | - Increases peripheral platelet counts

Question 50

What are indications for IL-11 therapy?

Answer 50

- Patients with thrombocytopenia after chemotherapy - prevent adverse reactions of platelet transfusions - for patients who are refractory to platelet transfusions

Question 51

When is IL-11 therapy administered?

Answer 51

2-3 weeks after chemotherapy or until platelets rise to 50,000/uL

Question 52

What are Adverse Effects of IL-11?

Answer 52

- fatigue - HA - Dizziness - Dyspnea - Arrhythmias - Hypokalemia

Question 53

What is Romiplostim?

Answer 53

- New agent for thrombocytopenia - peptibody with an antibody and Fc domain - increased half life - used for ITP AE = HA, myalgia and bone marrow fibrosis.

Question 54

What is Eltrombopag?

Answer 54

- New agent for thrombocytopenia - small molecule thrombopoietin receptor agonist - used for ITP AE = HA, myalgia and bone marrow fibrosis.