23 Agents used in Cytopenias: Hematopoietic Growth Factors Flashcards
Three essential nutrients for hematopoiesis
Iron
V B12
Folic acid
Proteins that regulate the proliferation and differentiation of hematopoeitic cells
Hematopoietic growth factors
Nonheme iron in food and in inorganic iron salts must be reduced by _____ to ____ before it can be absorbed by intestinal mucosal cells
Ferric reductase
Ferrous iron
Absorption of iron takes place in the _____
Duodenum and proximal jejunum
Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms
Active transport of ferrous iron by divalent metal transporter (DMT1)
Absorption of iron complexed with heme
Actively transports newly absorbed iron into the blood across the basolateral membrane
Ferroportin
Oxidizes iron to ferric iron
Feroxidase hephaestin
Iron is stored primarily as _____ in macrophages in the liver, spleen and bone and parenchymal liver cells
Ferritin
Controls mobilization of iron from macrophages and hepatocytes
Inhibits intestinal cell iron release by binding to ferroportin and triggering its internalization and destruction
Hepcidin
Most common cause of IDA in adults
Blood loss
Ferrous salts
Ferrous sulfate/gluconate/fumarate
Amount of elemental iron should be given daily to correct IDA most rapidly
200-400 mg
Treatment of iron should be continued for _____ to ensure stores are replenished
3-6 months
Contains 50 mg of elemental iron/mL of solution
Given through deep IM injection or IV infusion
Iron dextran
Before administering of iron dextran, this should be performed
Test dose (risk of hypersensitivity reaction)
Other parenteral iron forms
Na ferric gluconate complex
Iron-sucrose complex
Potent iron-chelating compound
Given IV to bind iron that has already been absorbed and to promote its excretion in urine and feces
Deferoxamine
Lead to organ failure and death
Excess iron is deposited in heart, liver, pancreas and other organs of the body
Hemochromatosis (chronic iron toxicity)
Treatment for hemochromatosis
Intermittent phlebotomy (1 unit of blood/week) Iron chelation therapy
Oral chelator
Deferasirox
Extrinsic factor
Cofactor for several essential biochemical reactions in human
Deficiency leads to megaloblastic anemia, GI symptoms, and neurologic abnormalities
Cobalamin
Active forms of Vitamin B12
Deoxyadenosylcobalamin
Methylcobalamin
Form of Vitamin B12 found in food sources
To be converted into the active form
Cyanocobalamin
Hydroxocobalamin
Normal daily requirement for Vitamin B12
2 micrograms
Average adult has a total storage pool of ____
3-5mg
IF combines with V12 that is liberated from dietary sources in the stomach and duodenum, and the complex is absorbed in the ___ by a highly selective receptor-mediated transport system
Distal ileum
Serves as intermediate in the transfer of methyl group of N-methyltetrahydrofolate to homocysteine, forming methionine
Methylcobalamin
Disruption of ____ is thought to be the cause of the neurologic manifestations of Vitamin B12 deficiency
Methionine synthesis pathway
Isomerization of methylmalonyl-CoA to _______ by the enzyme _____
Succinylcholine-CoA
Methylmalonyl-CoA mutase
Accumulation of folate as N-methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency
Methylfolate trap
Determine whether the cause of megaloblastic anemia is due to B12 deficiency or folic acid def
Serum levels of vitamins
Measures absorption and urinary excretion of radioactively labeled vitamin B12
Used to defined the mechanism of V12 malabsorption
Schilling test
Most common causes of V12 deficiencies
Pernicious anemia (defective secretion of IF and individuals frequently have autoantibodies for IR)
Partial or total gastrectomy
Conditions affecting distal ileum
Parenteral injection is available as ___
Cyanocobalamin or hydroxycobalamin
Preferred because it is highly protein-bound and remains longer in the circulation
Hydroxycobalamin
Initial therapy for V12 def
100-1000 micrograms IM daily or every other day for 1-2 weeks
Maintenance therapy for V12 def
100-1000 micrograms IM once a month for life
Required for essential biochemical reactions that provide precursors for the synthesis of AA, purines and DNA
Folic acid
Indicated in the cause of congenital NTD
Relatively common
Folic acid deficiency
Folic acid deficiency can be caused by drugs
Methotrexate
Trimethroprim and pyrimethamine
Phenytoin
Inhibits dihydrofolate reductase and may result in a deficiency of folate cofactors
Methotrexate
Long-term use may also cause folic acid deficiency
Rarely causes megaloblastic anemia
Phenytoin
Dose for treating folic acid deficiency
1 mg orally
Gp (34-39 kDa)
Serum half-life of 4-13 hours in px with chronic renal failure
EPO
Modified form of EPO that is more heavily glycosylated resulting to a twofold to three fold longer half-life than epoetin alfa
Darbepoetin alfa
Isoform of EPO covalently attached to a long polyethylene glycol polymer administered at 2-week or monthly intervals
Methoxypolyethylene glycol-epoeitin beta
EPO receptor is a member of ____
Use phosphorylation and transcription factor activate to regulate cellular function
JAK/STAT cytokine receptors
Adverse effects of EPO
HPN
Thrombotic complications
Allergic reactions
Pure red cell aplasia
Consistently improve hematocrit and hemoglobin level
Often eliminate the need of transfusion
Erythropoiesis-stimulating agents (ESAs)
Originally purified from cultured human cell lines
G-CSF
GM-CSF
Covalent conjugation product of filgastrim and a form of polyethylene glycol
Longer serum half -life than recombinant G-CSF
Pegfilgrastim
Glycosylated form of recombinant G-CSF
Lenograstim
Stimulates progenitors committed to neutrophil lineage
Activates phagocytic activity of mature neutrophils and prolongs their survival
G-CSF
Multipotential hematopoeitic growth factor
Stimulates proliferation and differentiation of earlly and late granulocytic progenitor cells, and erythroid and megakaryocyte progenitors
GM-CSF
Also mobilizes PB stem cells, but significantly less efficatious and more toxic
GM-CSF
Common adverse effect of the cytotoxic drugs used to treat cancer, and they increase the risk of serious infection in patients receiving chemotherapy
Neutropenia
Treatment regimen for neutropenia
G-CSF
Can be an alternative to preventing chemotherapy-induced neutropenia
Administered once per chemotherapy cycle
Shortens period of severe neutropenia slightly more than G-CSF
Pegfilgrastim
Potent hematopoietic stem cell mobilizer
Plerixafor
Key endogenous regulators of platelet production
TPO and IL-11
TPO agonists
Romiplostim
Eltrombopag
68-85 kDa protein produced by fibroblasts and stromal cells in the bone marrow
Half-life is 7-8 hours
IL-11
Recombinant form of IL-11 approved for medical use and is produced by expression in E. coli
Oprelvekin
Acts through a specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cells
IL-11
Approved for the secondary prevention of thrombocytopenia in px receiving cytotyoxic chemotherapy for treatment of nonmyeloid cancers
IL-11
IL-11 dosing
Subcutaneous injection at a dose of 50 mcg/kg/d
Started 6-24 hours after completion of chemotherapy and continued for 14-21 days or until the platelet count passes the nadir
Approved for therapy for patients with chronic immune thrombocytopenia and inadequate response to other therapies
Romiplostim
After subcutaneous administration, romiplostim is eliminated by the ____ with an average half life of ____
RES
3-4 days
Orally active small nonpeptide thrombopoeitin agonist
For tx of thrombocytopenia in patients with hep C to allow initiation of IFN therapy
Eltrombopag
