Block V- Pulm Anemia/Hematopoietic Growth Factors Flashcards
What molecules store Iron?
Ferritin (macrophages, liver, spleen)
Hemosiderin
What oxidation state of Iron is preferentially absorbed and what maintains this state?
Fe2+ (ferrous) form, maintained by acid produced by the gastric body
What molecule brings Iron to the plasma/ liver/ spleen (storage)?
Ferritin
What molecule takes Iron to the BM?
Transferrin
Where is Iron absorbed?
duodenum and jejunum
What are ferritin and transferrin levels in Iron Deficiency?
dec. ferritin
inc. transferrin
What are ferritin and transferrin levels in Iron Overload?
inc. ferritin
dec. transferrin
Hepcidin and Ferroportin:
hemochromatosis
anemia of chronic disease
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
What are indications for Iron therapy? (4)
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)
Oral Iron Therapy
- Ferrous sulfate, ferrous gluconate, ferrous fumarate
- quick response (1-3 months)
- Adverse Effects: nausea, vomiting, black stools
Parenteral Iron Therapy (IM/IV)
- 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
What is Acute Iron Toxicity?
- over ingestion of iron tablets
- fatal in children
- Necrotizing gastroenteritis
What is Chronic Iron Toxicity?
- Hemochromatosis, multiple red cell transfusions
- organ failure
How do you treat Acute Iron Toxicity?
- Gastric aspiration
- Gastric lavage (phosphate or carbonate)
- Iron chelation with deferoxamine
How do you treat Chronic Iron Toxicity?
- intermittent phlebotomy (if no anemia)
- Iron chelation (deferoxamine, deferasirox)
Where is Vitamin B12 absorbed?
The distal ileum
What is Vitamin B12 bound to in the small intestine which permits its absorption?
Intrinsic factor (from the gastric parietal cells)
What is B12 bound to in plasma?
Transcobalamin II
What are the active forms of vitamin B12?
- deoxyadenosylcobalamin
- Methylcobalamin
What are prodrugs of B12 and how are they given?
- Given IM
- Cyanocobalamin
- Hydroxycobalamin
Where is folate stored?
-stored in the liver (1-6 months)
Describe folic acid metabolism and absorption
- Dietary polyglutamates are hydrolyzed to mono glutamate
- Monoglutamate is absorbed in the blood stream
What are symptoms of B12/Folic Acid deficiency seen in the Alimentary tract?
- atrophic glossitis
- chronic gastritis
seen here because these cells have lots of turnover!
What are symptoms of B12/Folic Acid deficiency seen in the Blood and bone marrow?
- megaloblastic anemia
- Leukopenia with hypersegmetned granulocytes
- mild to moderate thrombocytopenia
What are symptoms of B12 deficiency seen in the CNS?
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)
How is Vitamin B12 deficiency treated?
- IM injections of prodrugs
- cyanocobalamin
- Hydroxycobalamin
- Response within 1-2 months
How is folic acid deficiency treated?
-oral folic acid
What are benefits of oral B12 therapy?
- 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!
What is the action of Erythropoietin?
- glycoprotein
- binds to its receptor and stimulates proliferation and differentiation of erythroid cells
- Stimulates releases of reticulocytes from the bone marrow
Where is EPO produced?
- The kidney
- the peritubular interstitial fibroblasts
What is the normal relationship between EPO and Hb?
What disease process will skew the normal relationship between EPO and Hb?
inverse relationship
renal failure
How is recombinant EPO produced?
- Epoetin alpha
- produced in a mammalian expression system
What are indications for EPO therapy? (4)
1) Chronic renal failure
2) Patients with aplastic anemia, leukemias, HIV/ADS associated anemias, cancer
3) Anemia of prematurity
4) Post phlebotomy
What are some EPO drug names?
- epoetin alpha
- Epogen
- Procrit
- Aranesp
How is EPO therapy delivered?
-IV or subcutaneous injection
What is the response time for EPO therapy?
- reticulocytes seen in 10 days
- increase in Hb seen in 2-6 weeks
What are the Adverse Effects of EPO therapy?
- HTN
- thrombotic complications
- allergic reactions
- Black Box warning for increased tumor progression or recurrence!!
- Cardiovascular events
What are the growth factors that stimulate proliferation and differentiation of myeloid cells?
G-CSF and GM-CSF
What is the growth factor that stimulates proliferation and differentiation of erythroid and megakaryocytic cells?
GM-CSF
What is the growth factor that promotes release of hematopoietic stem cells from the bone marrow into peripheral circulation?
G-CSF
better than GM-CSF
How is recombinant G-CSF produced?
- Filgrastim
- produced in a bacterial expression system
- Pegfilgrastim - conjugated to polyetheylene glycol for a longer half life
How is recombinant GM-CSF produced?
- Sargramostim
- produced in a yeast expression system
What are indications for G-CSF/GM-CSF therapy? (5)
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
Describe the pattern (graph) of neutrophil release following G-CSF/GM-CSF therapy
- bimodal spike
- immediate early release followed by a later, sustained release
What are the Adverse Effects of G-CSF Therapy?
- Bone pain
- splenic rupture (rare)
- allergic reactions
- preferred in general
What are the Adverse Effects of GM-CSF Therapy?
- fever
- arthralgia, myalgia
- peripheral edema
- pleural/pericardial effusion
- allergic reactions
Where is IL-11 produced?
bone marrow stromal cells
How is recombinant IL-11 produced?
- Oprelvekin
- produced by a bacterial expression system
What is the function of IL-11?
- promotes proliferation of megakaryocytic progenitors
- Increases peripheral platelet counts
What are indications for IL-11 therapy?
- Patients with thrombocytopenia after chemotherapy
- prevent adverse reactions of platelet transfusions
- for patients who are refractory to platelet transfusions
When is IL-11 therapy administered?
2-3 weeks after chemotherapy or until platelets rise to 50,000/uL
What are Adverse Effects of IL-11?
- fatigue
- HA
- Dizziness
- Dyspnea
- Arrhythmias
- Hypokalemia
What is Romiplostim?
- New agent for thrombocytopenia
- peptibody with an antibody and Fc domain
- increased half life
- used for ITP
AE = HA, myalgia and bone marrow fibrosis.
What is Eltrombopag?
- New agent for thrombocytopenia
- small molecule thrombopoietin receptor agonist
- used for ITP
AE = HA, myalgia and bone marrow fibrosis.
