6.

01 ERYTHROPOIESIS & ANEMIA

DR. De Castro, April 13, 2021
Elysian Trans by Tanya Treyes
CLINPHARMA
Outline Absorption
 Iron absorption is increased in the presence of iron deficiency,
I. Hematopoiesis
bleeding, active hemolysis
II. Iron
 Decreased when in a state of iron overload, chronic
III. Vitamin B12
inflammation
IV. Folic Acid
 5-10% is absorbed from the 10-15mg of elemental iron daily
(0.5-1mglday)
*source Doc’s ppt
 Duodenum and proximal jejunum
*gray - side notes
Hematopoiesis  Total iron increases to 1-2mg/day on normal menstruating
 Production from undifferentiated stem cells of circulating women and be as high as 3-4mg/day in pregnant women
erythrocytes, platelet, leukocytes  Red Meat - abundant source of iron
 Machinery resides in the bone marrow  Iron crosses the intestinal mucosa via active transport for
o 3 Basic parts ferrous iron (Fe2+) and absorption of iron complex with heme
o Red (Erythrocytes)  DMT1(divalent metal transporter)
o White (leukocytes) o Transport iron across intestinal membrane
o platelets o Ferroportin: Basolateral export of ferrous iron
 Requires 3 essential nutrients (Hematinics)  Together with iron split from absorbed heme, the newly
o Iron absorbed iron can be actively transported into the blood via
o Vit B12 IREG1 (ferroportin)
o Folic acid  Excess iron stored as ferritin (water soluble complex
o Plus presence of hematopoietic growth factors consisting of core of ferric hydroxide covered by storage
Agents used in Anemia protein apoferritin
Iron o Ferritin: measure of stored iron
 IDA: mc cause of anemia worldwide o One of the most reliable indicator of Iron deficiency
 Its deficiency is the most common cause of chronic anemia  Transferrin
 CVS- tachycardia, increase cardiac output, vasodilation o Where iron binds to be transported in the plasma
 Hemoglobin o Beta globulin that binds 2 molecules of ferrous iron
o Formed by iron-porphyrin heme ring plus globin chains o Increases in Fe deficiency anemia
o State of prolonged IDA; seen in PBS as ...  Transferrin-Iron complex enters erythroid cells via the
o Microcytic Hypochromic anema transferrin receptors( integral membrane glycoproteins present
in erythroid cells) thru endocytosis
Pharmacokinetics  Iron is released for hemoglobin synthesis while the
transferrin-transferrin receptor complex is recycled to the
 Uses specialized transport and storage proteins and the
plasma membrane
concentration are controlled by body’s demand for
 Increase erythropoiesis results to an increase in number of
hemoglobin synthesis and adequate iron stores transferrin receptors on developing erythroid cells
 Iron is reclaimed from damged or senescent red cell o The time when the body needs ample amount of iron to
 Growing children, pregnant women (increase demand) work very well
Storage
 Primarily stored as Ferritin in macrophages in the liver,
spleen,and bone and in parenchymal liver cells
o Hgb Iron: tretrameric form, almost 2g in content
o Storage iron: Ferritin, Hemosiderin
o Myoglobin iron: monomeric. least amount
o Ferritin: best measure of stored iron
 Apoferritin synthesis is regulated by levels of free iron (low free
iron inhibited apoferritin synthesis and so iron goes with
transferrin)
 Serum Ferritin levels can be used to estimate total body iron
stores
o Can be an Acute phase reactant
o Only true reflection of Iron stores if pxt doesn’t have
infection or inflammation
o e.g.ESRD pxts different cut off level

*photo taken from google

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 6.01 ERYTHROPOIESIS

Elimination Acute Toxicity

 No mechanism for excretion  Deferoxamine
 Low levels are lost in feces, bile, urine, and sweat (<1mg of o Iron chelating compound
iron/day) o Binds absorbed iron and excretes it via urine or feces
o Desquamation of intestinal cells o Parenteral chelator of choice
o Males: 1mg/day physiologic iron loss o SE: flushing, abdominal discomfort, rash, ARDS
o Females: as high as 2mg/day on heavy menses o Appropriate therapy for bleeding, acidosis and shock
Indications for Iron Use o Goal of treatment in IDA: normalize Hgb levels
 Treatment or prevention of iron deficiency anemia o Goal of treatment in thalassemia: alleviate symptoms
o Only clinical indication Chronic Toxicity
 Seen in infants, rapid growth of children ,pregnant and  Aka Hemochromatosis
lactating women, CKD (increase requirement) o Results when excess iron is deposited in the liver, heart,
 Gastrectomy, severe small bowel disease (inadequate pancreas abd other organs
absorption)  Seen as inherited disorder or those with many red cell
 Blood loss is the most common cause of Iron deficiency in transfusion over long time (thalassemia major)
adults
 Tx: if without anemia: intermittent phlebotomy (1 unit of
 Menstruating women loss 30mg / menstrual period
blood/week)
 In men and post menopausal women GIT is most common
 Deferasirox
site of blood loss
o Men with Iron deficiency, suspect GI bleeding o Oral treatment for iron overload (BT, Thalassemia, MDS)
o Tridentate chelator
Treatment
o Binds iron and the complex iecreted in the bile
PREPARATION ELEMENTAL IRON TABS/DAY o SE: GI disturbance and skin rash
Ferrous SO4 65mg 3-4
hydrated 325mg Vit B12
FeSO4 dessicated 65mg 3-4  Prophyrin ring with central cobalt atom attached to a nucleotide
Ferrous gluconate 36mg 3-3  Deoxy adenosylcobalamin and theylcobalamin are active
Ferrous fumarate 33mg 6-8 forms of the vitamins in humasn
Ferrous 106mg 2-3  Microbial synthesis - ultimate source of vitamin B12
fumarate325  Chief dietary source is microbially derived vit B12 in meat (liver)
 Blood tranfusion egg and dairy products
o Fastest way to increase the Hgb of a pxt with IDA  Called extrinsic factor
o Only if pxt is symptomatic Pharmacokinetics
o Frank bleeding  5-30mcg of B12 per day, 1-5mcg of which is absorbed
 About 50-100mg iron can be incorporated into the Hgb daily  Stored avidly in the liver, with an average adult having a pool of
and 25% of oral iron given as ferrous salts can absorbed 3000 - 5000 mcg
o Best absorbed on empty stomach  5 years to exhaust all B12 in the blood (2mcg daily
o Can also be taken 2 hrs after a meal requirement)
 Thus 200-400 mg of elemental iron should be given daily for  B12 is absorbed with intrinsic factor (parietal cells of gastric
3-6months mucosa) in the distal ileum via receptor mediated transport
o To replenish ferritin inside the bone marrow system
 SE: cramps, constipation, diarrhea, black stools  Transported throughout the body via plasma glycoprotein
 Parenteral Iron Therapy transcobalamin II
o For patients who cannot tolerate or absorb oral iron or  Liver as storage for the excess B12
those with extensive chronic blood loss (post gastrectomy,
IBD, malabsorption syndrome CRD)
 Iron dextran - ferric hydroxide + LMW
 IV Deferoxamine
o Need test dose
 Oral Deferiprone
 Oral Deferasirox
 Dextran with 50mg elemental iron/ml of solution
o Deep IM or IV
o SE: light headedness, fever, arthralgias, nausea, vomiting,
flushing, urticaria, rarely anaphylaxis and death (Due to
dextran; develops after 48-72hrs thus testing is needed) Pharmacokinetics
 Iron sucrose complex or iron sodium gluconate complex  Megaloblastic anemia
 Given IV route o Most characteristic clinical manifestation of B12 deficiency
 Less hypersensitivity  Poor absorption: mc reason
 Periodically monitor iron storage since it bypasses the  FA def: inadequate intake
regulatory system by the intestinal uptake system

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 6.01 ERYTHROPOIESIS

o Macrocytic anemia often with mild to moderate leukopena
or thrombocytopenia and hypercellular marrow with
accumulation of megaloblastic erythroid
o Begins with paresthesias and weakness in peripheral
nerves and progresses to spasticity and ataxia (B12 will not
totally reverse the condition)
 Schilling Test - measures absoprtion and urinary excretion of
radioactive labeled vit B12
 Pernicious anemia, partial or total gastrectomy, malabsorption
syndromes, IBD, small bowel resection
o Most common causes f B12 deficiency
 PA - defective secretion of intrinsic factor by gastric mucosa
cells
 PA patients have gastric atrophy (Schilling test shows
decreased absorption of radioactive B12)
 If distal Ileum is affected, the Schilling test will show
radioactive B12 is not absorbed even if IF is added
o Indirect way: check homocysteine level of patients
o Identify megaloblastic anemia due to B12 deficiency
o PBS: hypersegmentation of neutrophils
o Prolonged intake of PPI: lead to blunting of villi in GIT:
impair absorption of Vit B12
 Almost all cases of B12 deficiency are caused by
malabsorption thus parenteral injection of B12 are required for
therapy
 100-1000mcg IM daily or every other day for 2 weeks (with
neuro problems 1-2weeks for 6 months before switching)
 Maintenance is 100-1000mcg IM per month for life
o Best route: sublingual
 For every one mole of dTMP produced, one more of
tetrahydrofolate is consumed
 Thus for DNA synthesis to continue, continued regeneration of
tetrahydrofolate by reduction or dihydrofolate (from folic acid)
must occur
 Enzymed in the dTMP cycle are targets of Methotrexate
dihydrofolate reductase and 5FU (thymidylate synthase)
MTX: most powerful inhibitor of FA synthesis
Clinical Pharmacology
 Folate deficiency results to megaloblastic anemia that is
indistinguishable from anemia of B12 deficiency
 No neurologic manifestation is seen
 Caused by inadequate dietary intake
 Seen in alcohol dependence and liver disease (poor diet and
diminished storage)
 It is also linked to occurence of fetal neural tube defects
(others with low folates)
 Dialysis patients (folates removed during procedure)
 Drugs: Methotrexate, trimethoprim and phenytoin
Treatment
 Oral folic acid is well absorbed
 1mg daily will restore serum levels, reverse anemia and
replenishes body stores
 Supplementation for high risk mothers, alcohol dependence,
liver disease, hemolytic anemia and renal dialysis
 No FA overdose: can give up to 2x a day

Folic Acid End of Transcription

 Reduced forms are needed for essential biochemical
reactions that provide precursors for synthesis of amino acis,
purine and DNA
o Best absorbed in the duodenum, proximal jejunum
o Only take months to be depleted in the body
 Or Pteroylglutamic acid
o Composed of pteridine, paraaminobenzoic acid and
glutamic acid
o Folate reductase - converts folic acid to dihydrofolate form
o Thymidylate synthase - converts dUMP to dTMP

Pharmacokinetics
 Average diet containss 500-700 mcg of folate per day
 Pregnant women absorbs 300-400 mcg of folic acid daily
 Richest source are yeast, liver kindye and green vegetables.
o Minimum dietary allowance: 50mcg
 Normaly 5-20mg are stored in the liver
 Readily and completely absorbed in the proximal jejunum
 N5-methyltetrahydrofolate is converted to tetrahydrofolate
requiring B12
 Excreted in urine and stool

Pharmacodynamics
 Tetrahydrofolate cofactors participate in one carbon transfer
reaction
 Enzyme thymidylate synthase catalyzes transfer of one
carbon unit of N5-N10 methylenetetrahydrofolate to dUMP to
form dTMP
 Average diet contains 500-700 mcg of folate per day

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