Anemia (pt 1/3) Iron, B12, Folic Acid, IL Flashcards
1
Q
What is Hematopoiesis?
A
Process by which RBCs are made
-happens in the bone marrow
2
Q
_____+ _____ = Hematopoietic Cell
A
Essential Nutrients + Growth Factors = Hematopoietic cells
3
Q
What are the Essential Nutrients?
A
Iron
Vitamin B12
Folic Acid
4
Q
What is a Hematopoietic Cell?
A
Immature cell that can develop into all types of blood cells
5
Q
What is the most common cause of anemia?
A
Iron Deficiency
6
Q
How do we get iron?
A
-Iron is recycled from damaged RBCs (don’t need a large intake usually)
-Only a small amount of iron is lost each day therefore dietary requirements are low
7
Q
Iron requirements increase in what situations?
A
-Growing children
-Pregnant women
-Menstruating women
8
Q
What is Hepcidin?
A
A peptide produced primarily by the liver.
-Regulates the absorption, transport and storage of iron.
9
Q
How does low iron cause anemia?
A
-Iron forms the nucleus of the iron-porphyrin heme ring → hemoglobin
-↓iron = small RBCs with insufficient hemoglobin
-Microcytic (small) Hypochromic (less red) Anemia
10
Q
What are S/Sx of Iron Deficiency?
A
-Fatigue, weakness
-pale/yellowish skin
-Dizziness/lightheadedness
-Irregular heartbeat
-Shortness of Breath
-Cold hands/feet
-Chest pain
-HA
11
Q
What kind of anemia does low Iron cause?
A
Microcytic, Hypochromic
12
Q
What are the laboratory abnormalities associated with Iron-deficiency anemia?
A
-Low serum Fe (<30 mcg/dl), increased transferrin iron-binding capacity
-% Transferrin saturation of <10%
-Low serum ferritin levels (stored iron) <20 mcg/L
13
Q
What type of anemia occurs with Folic Acid Deficiency?
A
-Macrocytic Normochromic Anemia
14
Q
What are the laboratory abnormalities associated with Folic Acid Deficiency Anemia?
A
Low Serum Folic Acid level
-< 4 ng/mL
15
Q
What type of anemia occurs with Vitamin B12 deficiency?
A
-Macrocytic Normochromic Anemia
16
Q
What are the laboratory abnormalities associated with Vitamin B12 deficiency anemia?
A
-Low Serum Cobalamin
-Increased Serum Homocysteine
-Increased Serum Methylmalonic Acid
-Increased Urine Methylmalonic Acid
17
Q
What is Serum Homocysteine?
A
-Can be used to establish a diagnosis of Vit B12 deficiency.
-Methylcobalamin is required for the conversion of homocysteine to methionine.
-B12 deficiency decreases the formation of methylcobalamin, thereby increasing homocysteine levels (because it’s not being used to convert).
18
Q
What is the stored form of Iron?
A
Ferritin
19
Q
How is iron transported into the blood?
A
By Ferroportin (Fp)
20
Q
How is iron actively transported in the blood?
A
By Transferrin (Tf)
21
Q
In the blood, what are the two locations iron is transported to?
A
1) Erythroid precursors in the bone marrow for synthesis of hemoglobin
2) Hepatocytes for storage as Ferritin
22
Q
How is iron reclaimed after it is used?
A
Macrophages that phagocytize senescent (old) erythrocytes (RBC) reclaim the iron (in the spleen or other tissues, macrophages) from the RBC hemoglobin and either export it or store it as ferritin.
23
Q
What offers negative feedback by inhibiting ferroportin (the active transporter than pulls iron into the blood)?
A
High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin (the active transporter)
24
Q
What conditions require additional iron therapy?
A
-Infants especially premature infants
-Children during rapid growth periods
-Pregnant and lactating women
-Chronic Kidney Disease (2/2 RBC loss during hemodialysis)
-Inadequate absorption: Malabsorption post-gastrectomy for pts with severe small bowel disease; Normal process of iron function occurs in intestinal epithelial cells.
-Blood loss (Most common cause of iron deficiency anemia in adults):
Menstruating women lose 30 mg of iron with each menstrual period. Those with heavy bleeding can lose much more.
In men/post-menopausal women, the most common site of bleeding is the GI tract.
25
Describe the facts regarding the Ferrous Salts (Sulfate/Gluconate/Fumarate)?
-Oral or IV iron preparations
-PO corrects anemia just as rapidly and completely as parenteral IF iron absorption from the GI tract is normal (malabsorption issues = use IV form)
-Continue for 3-6 months so we don’t rapidly go back to anemia (replenishes iron stores)
-For patients on dialysis, IV therapy is preferred
26
What are the adverse effects associated with the Ferrous Salts (Sulfate/Gluconate/Fumarate)?
Dose related:
-Lower the dose
-Take with/after meals
-Change preparations
Nausea, epigastric discomfort, ABD cramps, constipation, diarrhea
Black stools:
-Not clinically significant
-May obscure GI bleed
27
What is Parenteral Iron Therapy (Iron Dextran) reserved for?
Reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron.
-Pts with extensive chronic anemia who cannot be maintained with oral iron alone
-Advanced chronic kidney disease on requiring hemodialysis
-Post-gastrectomy patients
-Inflammatory bowel disease of the small bowel
-Malabsorption Syndromes
28
Why is the IV route preferred over IM for iron therapy?
IV is preferred – eliminates pain, tissue staining and allows full dose administration (absorb 100% of the dose).
IM is painful, stains tissue, and has limits in dosing.
29
What are the adverse effects associated with Parenteral Iron therapy?
HA
dizziness
fever
arthralgias
nausea, vomiting
back pain
flushing
urticaria
bronchospasm
anaphylaxis
death
30
What are two formulations in clinical use for Parenteral Iron therapy?
Low Molecular Weight Form
-INFed
High Molecular Weight Form
-Dexferrum
31
Inorganic free ferric iron has serious ______ _____________ toxicity.
Inorganic free ferric iron has serious dose dependent toxicity.
32
What are the special formulations of parenteral iron therapy?
-Colloid containing particles
-Iron Dextran: Risk of hypersensitivity reaction
-Sodium Ferric Gluconate Complex
-Iron-sucrose Complex
33
What is important to know about the Colloid containing particles (Parenteral Iron therapy)?
Colloid containing particles = stability and slow release of bioactive iron
Core of Oxyhydroxide surrounded by a core of Carbohydrate
34
What is important to know regarding Iron Dextran?
-Risk of hypersensitivity reaction increases with repeated treatments or strong history of allergy
-Clinical anecdotal evidence indicates that the risk of anaphylaxis is largely associated with the HIGH Molecular Weight Forms!!
35
Why do you need to monitor iron STORAGE levels during parenteral Iron therapy? (Blue Box!!)
-Monitor Iron Storage Levels!
-IV therapy bypasses the regulatory mechanism provided by instestinal uptake.
-IV can deliver more iron than can be safely stored.
36
How can acute Iron Toxicity occur?
Children that ingest iron tablets
-10 tablets of any of the oral iron preparation can be lethal to young children
37
What are the S/Sx of ACUTE Iron Toxicity?
-Necrotizing gastroenteritis
-vomiting
-ABD pain
-bloody diarrhea
-shock
-lethargy
-dyspnea
-Metabolic acidosis
-coma
-death
38
What is the antidote for acute iron toxicity?
Deferoxamine
39
How does Deferoxamine work?
A binding agent usually administered IV.
-Binds to iron that has not been absorbed.
-Excreted in urine and feces
40
What is the other name for chronic iron toxicity (iron overload)?
Hemochromatosis (Excess iron in the organs: heart, liver, pancreas, etc)
41
How can chronic iron toxicity occur?
Can be inherited or develop in pts who receive a lot of RBC transfusions over a long period of time (Beta thalassemia)
-Can lead to organ failure and death
42
What is the treatment for chronic iron toxicity?
-Intermittent phlebotomy is used for patients with chronic iron overload in the absence of anemia (remove 1 unit blood/week)
-For patients with refractory anemia (Ex. Thalassemia major, sickle cell, aplastic) chelation therapy is the better option: More complicated, expensive and hazardous
43
What are the drugs used in Iron Chelation Therapy?
-Deferoxamine (IV)
-Deferasirox (PO)
-Deferiprone (PO)
44
What is Vitamin B12?
-Also called Extrinsic Factor
(Intrinsic Factor is a protein secreted by the stomach that is required for GI uptake of Vit B12)
-Cofactor for several essential biochemical reactions in humans
-Deficiency leads to megaloblastic anemia, GI symptoms and neurologic abnormalities
45
What are the symptoms of Vitamin B12 Deficiency?
-Often associated with mild to moderate leukopenia or thrombocytopenia
Neuro symptoms: (unique)
-Paresthesias in peripheral nerves
-Weakness progressing to spasticity, ataxia, other CNS dysfunction
-Treatment will stop the progression of neuro symptoms but may not reverse it
46
What are the causes of Vitamin B12 deficiency?
Usually malabsorption.
-Deficiency due to inadequate diet (less common, can occur in older adults)
-Inadequate absorption
-Gastrectomy: Needs therapy for life
Common Causes:
-Pernicious anemia – caused by defective secretion of Intrinsic Factor from gastric mucosal cells
-Partial or Total gastrectomy
-Malabsorption Syndrome
-Inflammatory Bowel Disease
-Small Bowel Resection
-Strict Vegan Diet
-Congenital deficiency of intrinsic factor
47
What are the chief dietary sources of Vitamin B12?
Meat
Eggs
Dairy products
48
What are the Vitamin B12 options administered as treatment?
Cyanocobalamin
Hydroxycobalamin
49
Which form of Vitamin B12 is preferred?
-Hydroxycobalamin
-Preferred b/c highly protein bound = longer circulation time
50
Why is Folic Acid necessary?
Folic Acid = Pteroylglutamic Acid (Vit B9)
-Required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines and DNA.
51
What are sources of Folic Acid?
-Various forms of folic acid are present in a wide variety of plant and animal tissues.
-Richest sources are yeast, liver, kidney and green vegetables.
-5-10 mg of folates is stored in the liver and other tissues
-Excreted in the urine/stool, and destroyed by catabolism → serum levels fall within a few days when intake is diminished
52
What are causes of Folic Acid Deficiency?
Common and easily corrected. Often the result of poor diet, inadequate intake or diminished hepatic stores.
-Pregnancy
-Alcohol dependence
-Liver disease
-Renal dialysis patients
-Malabsorption syndromes
-Methotrexate therapy (deficiency of folate cofactors)
53
T/F: PO Folic Acid therapy is not absorbed in patients with Malabsorption.
False; PO folic acid is well absorbed, even in pts with malabsorption.
54
What does Folic Acid Deficiency cause?
-Causes megaloblastic anemia that is microscopically indistinguishable from that caused by Vit B12 deficiency
-Does not cause the neuro symptoms seen in Vit B12 deficiency
-Definitive cause determined by labs especially RBC folate levels
55
What is the treatment for Folic Acid Deficiency (Megaloblastic Anemia)?
-1mg PO daily → reverse Megaloblastic Anemia
-Restore serum folate levels & replenish stores
-Prevention therapy with oral supplementation is recommended for high-risk patients
56
T/F: We store a lot of Folic Acid in our bodies, so it never really becomes deficient.
False; Stores are relatively low compared to the high daily requirement = folic acid deficiency and anemia can develop within 1-6 months after ↓intake
57
What are Hematopoietic Growth Factors?
Glycoprotein hormones that regulate the proliferation and
differentiation of hematopoietic progenitor cells in the bone marrow.
58
What eventually becomes RBCs?
Erythropoietin (epoetin alfa & epoetin beta)
59
What eventually becomes WBCs?
Granulocyte Colony-Stimulating Factor (G-CSF)
60
What eventually becomes platelets?
Interleukin-11 (IL-11)
61
What is Recombinant DNA Technology?
-Uses enzymes to cut and paste together DNA sequences of interest. For creation of blood component growth factors.
-The recombined DNA sequences can be placed into vehicles called vectors that ferry the DNA into a suitable host cell where it can be copied or expressed.
62
What was the first human hematopoietic growth factor to be isolated?
Erythropoietin
63
What is Erythropoietin?
-Originally purified from the urine of patients with severe anemia
-Glycoprotein that promotes RBC production
-Endogenous erythropoietin is produced in the kidney
-Inverse relationship between Hct/Hgb levels and serum erythropoietin levels
-Normal serum erythropoietin < 20 IU/L
-Mod-severe anemia = 100-500 IU/L
-Severe anemia can be in the 1000s
-Kidney disease is the exception to the inverse relationship
-Binds to specialized receptors on red cell progenitors
-Induces release of reticulocytes (immature RBCs) from the bone marrow
-Commonly used by endurance athletes to enhance performance
64
What is Recombinant Human Erythropoietin?
(rHu-EPO, epoetin alpha)
Produced by mammalian cell expression system.
65
What are the uses for Erythropoietin Stimulating Agents (ESAs)?
-Treat anemia secondary to chronic kidney disease
-↓RBC transfusion in myelosuppressive cancer treatments
-Myelodysplastic Syndrome
-Anemia requiring blood transfusions
-Pts with serum erythropoietin levels < 100 IU/L have the best response
66
What are the toxicity effects associated with Erythropoietin Stimulating Agents (ESAs)?
-HTN
-Thrombotic complications ↑ with Hgb > 11 g/dL (makes blood viscous)
-Allergic reactions are rare
-Long term SQ administration can cause pure red cell aplasia (PRCA)
67
What are the 3 example drugs of the Erythropoietin Stimulating Agents (ESAs)?
1) Epoetin Alpha (3 x’s per week)
-Half-life 4-13 hours in CRF Pts
-Not cleared by dialysis
2) Darbepoetin Alpha (weekly)
-Modified erythropoietin
-↑ glycosylation
-2-3 times longer half-life
3) Methoxy Polyethylene Glycol-Epoetin Beta (every 2 wks or monthly)
-Isoform of erythropoietin
-Extensive half-life
-IV or SQ
68
What are the effects of the Erythropoietin Stimulating Agents (ESAs)? (Blue Box!)
Blue Box:
-Reticulocyte counts ↑ in 10 days
-Hgb & Hct ↑in 2-6 wks
-Target Hgb is pt specific (No greater than 10-12 g/DL)
-CKD Pts require PO or parenteral Iron supplements
-Folic Acid supplements PRN
Not in Blue box:
-Conservative use in cancer patients with Hgb < 10 and not to exceed 11g/dL in CKD pts.
-Hgb should kept at the lowest dose necessary to avoid transfusion (don’t overcorrect)
-Do not use when cancer therapy is curative
69
What is the MOA of the G-CSF and GM-CSF?
Cause differentiation and proliferation by agonism of myeloid progenitor cells.
70
What are Myeloid Growth Factors?
-Myeloid = bone marrow
-Subclass of Hematopoietic Growth Factors
-Includes Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
-Originally purified from cultured human cells
-Currently recombinant
-Half-lives are 2-7 hours
-Admin either IV or SQ
-Recombinant human G-CSF (rHuG-CSF, Filgrastim or Tbo-Filgrastim) is produced in a bacterial suspension system
-Pegfilgrastim = conjugation product of Filgrastim with polyethylene glycol has a longer half-life
-Lenograstim = used in Europe
-Recombinant human GM-CSF (rHuGM-CSF, Sargramostim) is produced in a yeast expression.
71
What does G-CSF do?
-Promotes differentiation of neutrophils
-Activates phagocytic actions of mature neutrophils
-Mobilizes peripheral blood stem cells (Allows for transplantation of peripheral blood stem cells vs. bone marrow)
72
What does GM-CSF do?
-Broader actions than G-CSF
-Early & late granulocytic progenitors
-Erythroid & megakaryocyte progenitors
-Stimulates mature neutrophils
-Works with IL-2 on T-cells
-Mobilizes peripheral blood stem cells (↓efficacy & ↑ toxicity versus G-CSF)
73
What does G-CSF therapy in Chemotherapy induced Neutropenia do?
-Accelerates the rate of neutrophil recovery after dose-intensive myelosuppressive chemotherapy
-Reduces the duration of neutropenia
-Raises the nadir (lowest neutrophil count seen following a cycle of chemotherapy.)
-↓ episodes of febrile neutropenia (not true with GM-CSF because it itself can cause a fever).
-↓ requirements for broad spectrum antibiotics
-↓ infections
-↓ days of hospitalization
Used as Preventative therapy for pt’s receiving regimens with high risk for febrile neutropenia.
However, Clinical trials did not show improved survival in cancer patients treated with G-CSF.
74
What are the uses for G-CSF and GM-CSF?
-Congenital Neutropenia
-Cyclic Neutropenia
-Myelodisplasia
-Aplastic Anemia
-Autologous Stem Cell Transplant
75
Do G-CSF or GM-CSF stimulate the formation of erythrocytes and platelets? (Blue Box!)
Neither G-CSF nor GM-CSF stimulates the formation of erythrocytes and platelets, they are sometimes combined with other growth factors for treatment of pancytopenia.
76
What are the limits of use of G-CSF and GM-CSF?
-G-CSF and Pegfilgrastim are more used more frequently than GM-CSF. All have similar effects on neutrophil counts but G-CSF generally tolerated better
-G-CSF and Pegfilgrastim can cause bone pain. Clears when the drug is discontinued
-GM-CSF causes more severe side effects (Fever, malaise, arthralgias, myalgias and capillary leak syndrome (peripheral edema and pleural or pericardial effusions) )
-Allergic reactions are infrequent
-Splenic rupture is a rare but possible complication when G-CSF is given for autologous stem cell transplant
77
What does Interleukin 11 (IL-11) do?
-Stimulates the growth of multiple lymphoid and myeloid cells
-Acts in conjunction with other growth factors: Stimulating the growth of megakaryocytic progenitors
-↑peripheral platelets
-↑neutrophils
78
What is Megakaryocyte Growth Factor?
-Megakaryocyte are vital to the production of platelets
-Subclass of Hematopoietic Growth Factors
-Natural protein produced in the bone marrow by fibroplasts and stromal cells
-Oprelvekin = recombinant IL-11 produced by expression in Escherichia coli.
-Half-life 7-8 hours
-Administered SQ at 50 mcg/kg daily
-Given daily for 14-21 days or until the platelet count rises to more than 50,000/µL
-Use the smallest dose to keep platelets counts > 50,000/µL
79
What are the uses of Interleuken-11 (IL-11)?
-Prevention of thrombocytopenia in chemotherapy pts (Only in non-myeloid cancers)
-↓Platelet transfusions between chemotherapy cycles (Started 6-24 hours after chemo)
-No benefit on leukopenia due to myelosuppressive chemotherapy
80
What are the adverse effects associated with Interleuken-11 (IL-11)?
-Fatigue, headache, dizziness
-Anemia due to hemodilution
-Dyspnea due to fluid accumulation in the lungs
-Transient a-fib
-Hypokalemia
-All adverse effects are reversible!!
81
T/F: The adverse effects associated with Interleuken-11 are irreversible.
False; All adverse effects with IL-11 are reversible!!
