211

Pharmacotherapy in patients with anemia

hemoglobin hematocrit
oxygen

200 3-6
EPO

1.

2.
3.

1.
2.
3.

1.
2.
3.
 212

Pharmacotherapy in patients with anemia

oxygen

(Function of blood)
1. (Transportation)
(Nutrition transportation)


gas (Gases transportation) hemoglobin
oxygen oxyhemoglobin hemoglobin
oxygen carbon
dioxide
(Waste product transportation)
metabolism urea, uric acid, creatinine

(Hormone transportation)
(endocrine gland) 1
2. (Regulation)
(regulation of pH)
metabolism
- lactic acids
buffer

(Regulation of body temperature)

(Regulation of water balance)

3. (Protection)
 213

(Protection of blood loss)

(Protection of foreign body)

antibody

1 Blood transportation (Frank , 1997)

 214

(Blood components)
(connective tissue) (liquid)

1. Plasma
plasma
plasma 55
2. (Corpuscles formed element)
45

(Blood characteristic)
(Viscosity) 4.5-5.5 ()
(temperature) 37-38
- (pH) 7.35-7.45
0.9%
(weigh) 8%
(volume)
5-6
4-5

(Hemopoiesis)

1. (embryonic or prenatal hemopoiesis)
3
mesoblastic
2
mesenchymal cell (york sac)
(differentiate) (blood vessel)
(hemopoietc precursor cell)
primitive histoblasis
hemoglobin
normoblast
(undifferentiated primitive cell)
(intravascular heopoiesis) 7.8

 215

hepatic
mesoblastic
6 2 4 5
2-3
5
lymphocyte
(thymus gland) lymphocyte
(lymphatic organ) lymphocyte

lymphocyte
4 5
modullary

(bone marrow) 5
mesenchymal
granulocyte
normoblast
granulocyte 3
granulocyte 20 lymphocyte

2. (Post-natal hemopoiesis)
lymphocyte

myeloid period
(red marrow)

(fat cell) (yellow marrow)
(flat bone)
(vertebrae ribs) (sternum) (pelvis) (scapulae)
(skull) (proximal of humerous) (femur)
3. (extramedullary hemopoiesis)




 216

mesenchymal (thyroid gland) (adrenal

gland)

(Corpuscles formed elements)

1. (Erythrocyte, red blood cell)
(biconcave)

hemoglobin, enzyme
ion oxygen carbon dioxide
buffer
oxygen
erythropoietin 120

5.5-6.0 /
4.5-5.0 /
erythropoietin
Hemoglogin (Hb) oxygen
beffer hemoglobin 4
1 heme peptide 1 (Fe) 1 hemoglobin
oxygen oxyhemoglobin hemoglogin
carbondioxide oxygen 2

2 hemoglobin (Mader, 1997)

 217

(red blood cell destruction)

120

( 1 )

polycythemia
(anemia)
reticuloendothlial system
(spleen) hemoglobin heme globin heme
biliverdin bilirubin

2. (Leucocyte, white blood cell) 3

3
1.
(Diapedesis)
2.

3. phagocytosis
2
1. granule (granulocytic
polymorphonuclear cell) granule 3

Neutrophil poloymorphonuclear cell, PMN) 2

Eosinophil 12 neutrophil
Basophil neutrophil 2-5 lobe
2. granule (agranulocytic mononuclear cell)
granule 2
Monocyte 3

Lymphocyte
3. (Thrombocyte, platelet)
megakareocyte

 218

(Anemias)
(World health organization) (anemias)
hemogloblin (Hgb) 13 g/dL 12 g/dL

3.4
African-american national health
nutrition examination survey (NHANES) 5.7%, 5.9%
4.4% retrospective and observational (CKD)
hemodialysis (congestive heart failure)

oxygen
hemoglobin hematocrit

( 1)
 219

3 (http://en.wikipedia.org/wiki/File:Illu_blood_cell_lineage.jpg)
 220

1 (Ineck et al., 2011)

Macrocytic
Megaloblastic anemias Vitamin B12 deficiency anemia
Folic acid deficiency anemia
HgB
Hypochromic, microcytic Iron deficiency anemia
Genetic anomaly
Sickle cell anemia
Thalassemia
Normocytic anemias Recent blood loss
Hemolysis
Bone marrow failure
Anemias of chronic disease
Renal failure
Myeloblastic anemias
Endrocrine disorders

folate vitamin B12 Vitamin B12 deficiency anemia

Folic acid deficiency anemia
Anemia of chronic disease
Malignant bone marrow disorders
(bleeding) Bleeding anemia
Hemolytic anemia

Trauma, peptic ulcer, hemorrhoid

vaginal bleeding, peptic ulcer, intestinal parasites, drugs
(e.g., nonsteroidal anti-inflammatory agents; NSAIDs)
RBC antibodies
Drugs
Excessive sequestration in the spleen
Heredity
Iron deficiency anemia
Vitamin B12 deficiency anemia
Folic acid deficiency anemia

hypothyroid, adrenal insufficiency

 221

Vitamin B12
(anemias in chronic disease; ACD)


mucous membrane

1. Hemoglobin (HgB) 13.5-17.5 g/dL 12-16

g/dL hemoglobin androgen
HgB HgB
(WHO) HgB 2

2 anemia (Groopman et al.,1999)

HgB (g/dL)
0 11
1 (mild) 9.5-10.9
2 (moderate) 8-9.4
3 (severe) 6.5-7.9
4 (life-threatening) < 6.5

2. Hematocrit (Hct)
41-53% 36-46%
plasma
3. Red blood cell count HgB
4.5-5.9 million/mm3 4-4.9 million/mm3
4. RBC indices mild anemia
RBC indices
4.1 mean corpuscular volume (MCV) 80-100 m3
(nomocytic) (macrocytic) (microcytic)
coulter counter MCV Hct MCV Hct

 222

4.2 Mean corpuscular hemoglobin (MCH) 26-34 pg

HgB MCH 2
(microcytic) HgB 2
(hypochromic) HgB
4.3 Mean corpuscular hemoglobin concentration (MCHC) 31-37%
HgB ( )
MCHC (hypochromic)
5. Total reticulocyte count 0.5-1.5%

6. Serum iron 50-160 g/dL 40-150 g/dL

transferrin
hemolytic anemia (iron
overload)
7. Total iron-binding capacity (TIBC) 250-400 g/dL
serum tranferrin serum iron
TIBC
8. Percent transferring saturation serum iron TIBC
13 serum iron TIBC

9. Serum ferritin 15-200 ng/mL 12-150

ng/mL ferritin (storage iron)

10. Folic acid level 2-10 ng/mL
50-800 ng/mL folate

11. Vitamin B12 level 200-1,000 pg/mL

vitamin B12
12. Schilling test vitamin B12
intrinsic factor vitamin B12
pernicious anemia vitamin
B12 cobalt vitamin B12 vitamin
B12 cobalt intrinsic factor cobalt
33% 24 pernicious anemia
5
 223

13. Erythropoietin (EPO) level 100-1,000

(hypoxia)
14. Coombs test antiglobutin 2 indirect direct coombs
test indirect sensitized (In vitro
sensitization) direct sensitized
(In vivo sensitized) autoimmmune hemolytic anemia
3 (Ineck et al., 2011)
()

2-6 6-12 12-18 18-49
Hemoglobin (g/dL) 11.5-15.5 11.5-15.5 M 13.0-16.0 M 13.5-17.5
F 12.0-16.0 F 12.0-16.0
Hematocrit (%) 34-40 35-45 M 37-49 M 41-53
F 36-46 F 36-46
MCV (fL) 75-87 77-95 M 78-98 80-100
F 78-102
MCHC (%) --- 31-37 31-37 31-37
MCH (pg) 24-30 25-33 25-35 26-34
RBC (million/mm3) 3.9-5.3 4.0-5.2 4.5-5.3 4.5-5.9
Reticulocyte count, absolute --- 50-120 50-120 0.5-1.5
(%)
Serum iron (g/dL) --- 50-120 50-20 M 50-160
F 40-150
TIBC (g/dL) 250-400 250-400 250-400 250-400
RDW (%) --- --- --- 11-16
Ferritin (ng/mL) 7-140 7-1740 7-140 M 15-200
F 12-150
Folate (ng/mL) --- --- --- 1.8-16.0*
Vitamin B12 (pg/mL) --- --- --- 100-900*
Erythropoietin (mU/mL) --- --- --- 0-19
*
F=female, M=male

(Iron deficiency anemia; IDA)

(Epidemiology)

500 NHANES
1-2
 224

(Etiology)

rheumatoid arthritis, malabsorption syndrome

centers for disease
control (CDC) (30 mg/day)

gastrointestinal bleeding 50,
corticosteroids, aspirin, NSAIDs alcohol

T-cell humoral
immunity

motor co-
ordination

(Pathophysiology)
serum ferritin

HgB serum ferritin 12 ng/mL TIBC
serum iron Hct RBC indices HgB
Hct (microcytic hypochromic)
3
1
serum ferritin serum
ferritin serum ferritin
necrosis
2
serum iron
serum erythropoiesis serum iron
transferring (total iron binding capacity, TIBC) serum iron TIBC
transferring saturation (sensitivity) serum iron
TIBC tissue injury serum iron
 225

free erythrocyte protoporhyrin (FEP) heam

FEP FEP
(lead poisoning) 2 mean corpuscular
volume (MCV) RDW
3
hemoglobin
hemoglobin microcytic hypochromic



koilonychias (Spooning of nails)
(angular stomatitis) (glossitis) HgB 8-9 g/dL

1. Serum iron
2. Serum ferritin

3. TIBC
4. HgB 11 g/dL
5. Hct 38%
6. Transferrin saturation


15


PRC ( blood
component therapy)

1.

soluble ferrous iron salts




 226

ferrous sulfate,
ferrous succinate, ferrous lactate, ferrous fumarate, ferrous glutamate, ferrous gluconate
carbonyl iron carbonyl iron
iron overdose
200 mg elemental iron 2-3
200 mg ferrous sulfate 325 mg single dose
1


3-6

H2-blockers,
proton pump inhibitors
5

hemoglobin 1-2 g/dL
3 3 hemoglobin 2
g/dL




110-120 mg elemental iron
50
 227

4 elemental iron ferrous iron salts (Ineck et al., 2011)

elemental iron
Ferrous sulfate 20% 60-65 mg/324-325 tablet
18 mg iron/5 ml syrup
44 mg iron/5 ml elixir
15 mg iron/0.6 ml drop
Ferrous sulfate (exsiccataed) 30% 65 mg/200 mg tablet
60 mg/187 mg tablet
50 mg/160 mg tablet
Ferrous gluconate 12% 36 mg/325 mg tablet
27 mg/240 mg tablet
Ferrous fumarate 33% 33 mg/100 mg tablet
63-66 mg/200 mg tablet
106 mg/324-325 mg tablet
15 mg/0.6 ml drop
33 mg/5 ml suspension
Polysaccharide iron complex 100% 150 mg table
50 mg tablet
100 mg/5 ml elixir
Carbonyl iron 100% 50 mg caplet

5 (Ineck et al., 2011)

Al , Mg2+ Ca2+ (
3+
Levodopa ()
antacid)
Tetracycline doxycycline Methyldopa ()
H2-blockers Levothyroxine ()
proton pump inhibitors Pencillamine ()
Cholestyramine Fluoroquinolones ()
Tetracycline doxycycline (
)
Mycophenolate ()

(Parenteral iron therapy)

IDA

1.
2.
3.
 228

4. antacid
5. dialysis EPO
6.
parenteral iron therapy

parenteral iron
1. reticulo-endothelial system
2.
parenteral iron 3 iron dextran, sodium ferric
gluconate iron sucrose iron dextran iron sucrose (Venofer)
(bioavailability)
6
parenteral iron
7
Serum ferritin 100 mg/l 100 mg. 1-2
500-1,000 mg.
2
Serum ferritin Serum ferritin 100 mg/l
hematocrit 40-100 mg. 2-4
3 peritoneal dialysis
Hemodialysis 6
Serum ferritin 500-1,000 mg/l iron overload
Serum ferritin 500-1,000 mg/l 1
iron dextran test dose iron dextran 25
mg IM IV 5-10 IV infusion epinephrine,
hydrocortisone, diphenhydramine
IV infusion 2-6 IV iron dextran normal saline D5W
250-1000 ml
Sodium ferric gluconate gluconate
sucrose 4 289,000-440,000
(US-FDA) sodium ferric gluconate iron supplement
hemodialysis sodium ferric gluconate iron dextran
sodium ferric gluconate test dose 10 ml IV
(125 mg elemental iron) normal saline 100 ml IV infusion 1

 229

Iron sucrose polynuclear iron (III) hydroxide sucrose

34,000-60,000 Iron sucrose hemodialysis
IV 100 mg/ 3 / 1000 mg 10 dose iron sucrose
slow injection IV infusion test dose
normal saline ( 100 ml)
6 parenteral iron (Ineck et al., 2011)
Ferumoxytol Sodium Ferric glucose Iron dextran Iron Sucrose
elemental iron 30 mg/ml 62.5 mg iron/5 ml 50 mg iron/ml 20 mg iron/ml
75,000 289,000-444,000 165,000-267,000 34,000-60,000
Superparamagnetic iron Ferric oxide hydrate Complex of ferric Complex of
oxide that is coated boned to sucrose hydroxide and dextran polynuclear iron
with a carbohydrate chelates with gluconate hydroxide in sucrose
shell in a molecues to 1
gluconate molecule
Benzyl alcohol 9
(Preservative) mg/5ml 20% (975 mg
in 6.25 iron)


hemodialysis hemodialysis
EPO epoetin alfa therapy
hypersensitivity hypersensitivity
reaction reaction anaphylactic-type anaphylactic-type
reaction reaction
IM IM
510 125 mg (10ml) 100 mg normal 100 mg dialysis line
IV 510 100 ml normal saline saline D5W 250- 1 ml (20
IV 3-8 60 1000 ml rate mg iron)/
( 30 mg/) slow IV 50 mg (1 ml)/ dilute
injection (rate
12.5 mg/min)
2 doses x 510 mg 8 doses x 125 mg = 10 doses x 100 mg = 10 doses x 100
=1020 mg 1000 mg 1000 mg mg = 1000 mg



 230

7 Parenteral iron (Ineck et al., 2011)

15
Dose (ml) = 0.0442 (desired Hgb observed Hgb) x LBW +(0.26 x LBW)
LBW (male) = 50 kg + (2.3 x 5 )
LBW (female) =45.5 kg + (2.3 x 5 )
5-15
Dose (ml) = 0.0442 (desired Hgb observed Hgb) x W +(0.26 x W)
W =
Hgb = hemoglobin
LBW = lean body weigh
hemodialysis
mg of iron = blood loss (mL) X hematocrit

IV
IV iron dextran 5.0 anaphylaxis
0.1-0.6 anaphylactoid reaction , wheezing,
hypotension, angioedema 1.7
anaphylaxis
(25 mg) metallic taste iron
sucrose (colorectal cancer)
TSAT 60 oversaturation of
transferrin , ,
iron gluconate
( 62.5 mg) IV ( 4-4.5 )
2.



2 50

(megaloblastic anemias)

DNA RNA
cytoplasm
 231

"nuclear-cytoplasmic asynchronism" Vitamin B12 folate

DNA
(hyperlipidemia) hypothyroidism alcohol alcohol
90%

nucleic acid
folate vitamin B12 RNA DNA
vitamin B12 folic acid folate
5-methyl tetrahydrofolate (5-MTHF) tetrahydrofolate (THF)
vitamin B12 THF folate cofactor 5,10-methylene tetradrofolate
(5,10-METHF) thymidylate synthase nucleic acid 5,10-
METHF dihydrofolate (DHF) reduced dihydrofolate reductase
THF nucleic acid 4

4 nucleic acid (AACC, 2011)

vitamin B12 (Vitamin B12 deficiency anemia)

(Epidemiology)
Vitamin B12 deficiency anemia 100
1 40
vitamin B12
(cyanocobalamin)
 232

(Etiology)
Vitamin B12
1. vitamin B12
2. (malabsorption syndrome)
3. vitamin B12
Vitamin B12 vitamin B12
alcohol
vitamin B12 pernicious anemia ( vitamin B12
deficiency anemia intrinsic factor) intrinsic factor gastric
parietal cell autoimmune gastric parietal cell atrophy
gastric mucosa pernicious anemia African-american
intrinsic factor vitamin B12 bacteria
vitamin B12 vitamin B12 receptor
inflammatory bowel syndrome
(Pathophysiology)
Vitamin B12 DNA
(neurological system) vitamin B12 2-5
1-5
vitamin B12
vitamin B12 (free vitamin B12) free vitamin B12 intrinsic
factor (complex)
(duodenum) vitamin B12-intrinsic factor complex vitamin B12 receptor
vitamin B12-intrinsic factor complex
intrinsic factor vitamin B12 (cobalamine)
transcobalamine II serum heptocorrin
DNA


cardiac output vitamin
B12 (megaloblastic anemia)
spinal cord (paresthesia)
ataxia

 233

5 vitamin B12 (Robert, 2003)

1. RBC count
2. HgB Hct
3. RBC indices macrocyte MCV 100 m3
4.
5. Peripheral blood smear macrocyte hypersegmented
polymorphonuclear leukocytes
6. Reticulocyte
7. Serum vitamin B12
serum vitamin B12 150 pmol/L macrocyte,
hypersegmented polymorphonuclear leukocyte
vitamin B12 Schilling test
 234

serum vitamin B12 300 pmol/L vitamin

B12 220-300 pmol/L 1-3 220 pmol/L
Schilling test Schilling test vitamin B12
vitamin B12 300 pmol/L Schilling test
vitamin B12

vitamin
B12
vitamin B12 1-2
1-2 hemoglobin 1
vitamin B12 9
parenteral vitamin B12 1000 g 1 vitamin B12
hydroxylcobalamin ( vitamin B12) parenteral
vitamin B12 parenteral
vitamin B12 1 mg oral
parenteral vitamin B12 vitamin B12 nasal route intranasal
gel formulation
(dysphagia) intranasal gel
1

intranasal gel vitamin B12 pernicious
animias (PA) anemia vitamin B12 vitamin B12
vitamin B12 1000 mg IF vitamin B12
2-4
2 6 vitamin B12

serum vitamin B12 serum vitamin B12 8
8 serum vitamin B12 vitamin B12
Serum vitamin B12 (pmol/L)
vitamin B12
< 75
75-150
150-220
> 220

 235

1. vitamin B12 vitamin B12

2. serum vitamin B12
cobalamine- transporter protein

9 vitamin B12 (Ineck et al., 2011)

vitamin B12 (%)
3 oz 60
(breakfast cereal, fortified, 6
100%)
rainbow trout 3 oz 5.3
Sockeye salmon 3 oz 4.9
3 oz 2.1
(breakfast cereal, fortified, 25%) 1.5
(Hoddock) 3 oz 1.2
Clams, breaded and fried 1.1
Oysters, breaded and fried 6 1
3 oz 0.9
1 0.9
(Yogurt) 8 oz 0.9

folic acid (folic acid deficiency anemia)

(Epidemiology)
folic acid alcohol
folic acid
(Etiology)
folic acid
folic acid alcohol (alcohol
folic acid folic folic )
folate
dihydrofolate reductase dihydrofolate (DHF) active tetrahydrofolate (THF)
10
folic acid
hemolytic animia (crohns disease, rheumatoid arthritis,
psoriasis hemodialysis )
 236

10 folate (Ineck et al., 2011)

folate
Phenytoin Phenobarbital
Primidone Alcohol
Oral contraceptive Sulfasalazine
dihydrofolate reductase DHF THF
nucleic acid
Methrotrexate Trimethoprim
Triamterene

(Pathophysiology)
Folic acid vitamin folic acid
nucleic acid, protein, amino acid, purine, thymine DNA
RNA folic acid
folic acid
Folic acid polyglutamate form
monoglutamate folic acid
tetrahydrofolate vitamin B12 (cobalamine) folic acid 50-
100 g/day folic acid 400 g/day 600 g/day
500 g/day folic acid
5-10 mg hepatic circulation

11 folic acid (Ineck et al., 2011)

folic acid (g)
3.5 oz 770
0.5-1.5 100-400
Lentils 0.5 180
Chickpeas 0.5 141
Asparagus 0.5 132
(spinach) 0.5 131
Black bean 0.5 128
Pasta 2 oz 100-120
Kidney beans 0.5 115
Lima beans 0.5 78
0.75 60
1 48
Brussels srouts, 0.5 47
 237

vitamin B12
folate

vitamin B12
serum RBC folate level folate serum
folate level erythrocyte folate level folate
folate

folic acid 1 mg/day malabsorption
5 mg 4 folic acid

folic acid
megaloblastic anemia low
dose folic acid (500 g/day) folic acid
metabolism (enzyme inducer)

folic acid 800-1000

g/day neural tube defect


reticulocyte 2-3 5-8
Hct 2 2

(Anemia of chronic disease)

1-2

anemia of inflammation
12
(iron
homeostasis) proliferation of erythroid progenitor cell
erythropoietin
Tumor cell CD3+ T cell monocyte proinflammatory cytokines
 238

(free radical) erythro progenitor cell (bleeding)

(cobalamine folic acid) hypersplenic, autoimmune hemolysis

3
1. (Drug regulation of iron homeostasis)
proinflammatory cytokines
interleukin, interferon tumor necrosis factor- (TNF-) interleukin-1, 6 10
macrophage (uptake) , interferon- divalent metal
transporter 1 (DMT 1) macrophage ferrous iron (Fe2+)
ferroportin 1 (transmembrane exporter of iron) macrophage ferrous iron
(Fe2+) uptake
interleukin-6 lipopolysaccharide
hepcidine 25 hepcidine ferrous iron
(Fe2+) ferroportin 1 ferrous iron (Fe2+)
gene hemojuvelin hepcidine gene
erythroid progenitor cell heam
2. Impaired proliferation of erythroid progenitor cells
proliferation differentiation erythroid precursors
erythroid colony-forming unit interferon-, , TNF- interleukin-1
cytokine mediated precursors (erythroid colony-forming
unit) apoptosis cytokine mediated
erythropoietin cytokines (toxicity; cytokines free radical
nitric oxide superoxide anion) progenitor cell
3. erythropoietin
erythropoietin
lipopolysaccharide interleukin-6, TNF- hepcidin hepcidin
EPO interferon-, TNF- interleukin-1
EPO

iron
EPO serum iron , transferitin saturation ferritin
ferritin
13
 239

12 Anemia of chronic disease (Weiss et al., 2005)

ACD

HIV virus
bacteria 18-95


(Cancer)
(Hematologic) 30-77
Solid tumor
Autoimmune
Rheumatoid arthritis
SLE 8-71
Vasculitis
Sarcoidosis
8-70
23-50

13 (Weiss et al., 2005)

Iron
Transferin
Transferritin saturation
Ferritin
Soluble transferritin receptor
Ratio of soluble transferring (< 1) (> 2) (> 2)
receptor to log ferritin
Cytokine levels
 240

3 (Weiss et al., 2005)

 241

65

1. Coronary artery disease

2. Pulmonary disease
3. Chronic kidney disease

(Transfusions)
oxygen

(transfusion)

(severe anemia; Hb < 8 g/dL)
(life-threatening anemia; Hb < 6.5 g/dL) (myocardial
infraction)
multipleorgan failure
iron overload
Iron therapy

iron supplement
serum ferritin ( 100 ng/mL)

Erythropoietin agents
Erythropoietin agents
AIDs erythropoietin agents 3 epoetin alfa,
epoetin beta darbepoetin alfa
14 (Weiss et al., 2005)


yes yes
(Transfusions)* yes yes
Iron supplementation no yes
Erythropoietin agents yes Yes iron
*
 242

(Anemia of chronic renal failure)

(chronic renal failure : CRF)
creatinine 2 mg/dL (end-stage renal disease :
ESRD) hematocrit ESRD
25 normochromic normocytic red blood cell
CRF
left ventricular hypertrophy (LVH), ventricular dilatation ischemic
heart disease hemoglobin (HgB) 10 g/dL
CRF HgB 8 g/dL HgB 8
g/dL CRF

erythropoietin stimulating
agent (ESA)
(androgen hormone)

15 Stage of CKD (National Kidney Foundation, 2002)

1. Erythropoietin stimulating agent (ESA) epoietin (EPO) darbeproin

onset
5-7 Hgb Hct
2-6 National Foundations
Disease Outcomes Quality Initiative (NKF-K/DOQI)
Hct 33-36 Hgb 11-12 ESA 2
EPO
 243

-
pure red cell aplasia (PRCA) .. 2541

ESA
Hct, iron ferritin total iron binding capacity (TIBC), percent transferring
saturation (TSAT), , Hct 1.5-
3.5 2 33-36 Hgb 11-12 /
, vitamin
B12, folic acid, bone marrow fibrosis, , ,
hyperparathyroidism, , ACEIs,
theophylline ESA
ESA Hct 8
1 Hct Hgb

SC
K/DOQI serum ferritin 100 ng/ml
transferring saturation 20 ferritin acute phase reactant
malignancy TSAT TSAT = [serum iron X 100]/total iron
binding capacity
2. (Iron Supplement)

200 mg/day
enteric coat
100 mg/tab bioavailability


3 iron dextran, ferric
gluconate ferrous hydroxide sucrose complex iron dextran

test dose 25
30
delayed reaction anaphylactoid reactions
K/DOQI 1,000 8-10
absolute iron deficiency (serum ferritin 100 ng/ml TSAT 20)
1 course TSAT 20 / serum ferritin 100 ng/ml
 244

maintenance dose 25-100 / iron

balance ESA Hct/Hgb iron
maintenance dose
ESA iron overload TSAT
50 ferritin 800 ng/ml iron indices 3
TSAT 50 ferritin 800 ng/ml

3.
6 skin
hyperpigmentation periphreral neuropathy
hypervitaminosis A


4.
EPO

5. erythrokinetics Hct
Hgb

16 Parameter EPO 1

Parameter
(IV) (SC)
(Cmax) 0 / 104 / (100 IU/kg)
144 / (150 IU/kg)
242 / (200 IU/kg)
288 / (300 IU/kg)
(Tmax) 5-18
(t1/2) 3-6 28
bioavailability 21.5% (24 )
31% (72 )
(excretion) 10%

0.087 -1 0.025 -1
0.032-0.0085 (.//.)
(Vd) 21-107 (./.)
 245

17 hematocrit EPO
Hematocrit increase
Starting dose
Points/day Points/2week
50 units/kg 0.11 1.5
100 units/kg 0.18 2.5
150 units/kg 0.25 3.5

18 EPO
Initial Dose Dose adjustment
50 Units/kg 3 - 25% Hb = 12 g/dL Hb
IV SC 1g/dL 2
IV - 25% Hb 12 g/dL
8
50-100 3 - 25% Hb = 12 g/dL Hb
IV SC 1g/dL 2
IV - 25% Hb 12 g/dL
8
600 Units/kg 1 - 25% Hb = 12 g/dL Hb
IV (maximum 1g/dL 2
40,000 Units) - 900 Units/kg (maximum 60,000
units) Hb 12 g/dL 8
150 Units/kg 3 - 25% Hb = 12 g/dL Hb
/ Sc 40,000 1g/dL 2
Units/kg 1 - 300 Units/kg 3 /
Sc 60,000 Units/kg 1 Hb 12 g/dL
8

(Anemia of critical illness)

(Etiology)

sepsis
EPO

oxygen
 246

(Pathophysiology)
(homeostasis)
cytokines
serum protein

iron serum, TIBC serum
ferritin EPO
EPO

folic acid, vitamin B12

(parenteral
iron)
EPO
randomized control trial EPO (transfusion)
EPO
Hgb
oxygen

Hgb, Hct
EPO

(Anemia in the elderly)

(Epidemiology)
12
60 85
( 3 6 50-54
65 21 16 )


(Etiology)
3
1. ( 35)
2. ( 17)
 247

3. ( 15)
3
1. ( 36)
2. ( 23)
3. ( 17)

serum creatinine
vitamin B12
cross sectional

(Pathophysiology)

EPO GFR serum creatinine
EPO GFR 50

Hgb
hormone androgen CBC MCV > 100 fL
vitamin B12 folic acid MCV < 100 fL

iron supplement 50-100 mg elemental iron 3
vitamin B12 vitamin B12 folic acid folic acid
1 mg EPO 50-100 unit/kg 3
12

(Hemolytic anemia)

120
hemolytic anemia 120
membrane hemoglogbin metabolism
13
nitrofurantoin, cancer
chemotherapy, phenazopyridine, sulfone, amy nitrite, paraquat hydrogen peroxide
 248

19 hemolytic anemia (Ineck et al., 2011)

Intrinsic ()
membrane
Spherocytosis and elliptocytosis
hemoglobin
Sickle cell anemia
Thalassemia syndrome
Metabolic defect
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Many other enzyme deficiency
Extrinsic
membrane
Autoimmune hemolytic anemia
Oxidants, may cause unstable hemoglobin clump


membrane
120
1. membrane
sherocyte

reticuloendothelial cell (cholethiasis)
(cholecystitis)

2. Hgb sickle cell

anemia Thalassemia
3. metabolism dimension
Hgb metabolic pathway
metabolism hexose monophosphate shunt enzyme
Hgb reduced form methemoglobin Embden-Myerhof
pathway anaerobic glycolysis glucose lactic acid ATP
enzyme glucose-6-phosphate dehydrogenase (G-6-PD) Hgb oxidized
methemoblobin sulfhemoglobin Hgb Heinz body
membrane reticuloedothelial system
Mediterranean
antioxidant
 249

normocytic normochromic blood smear
sickle cell, target cell, sphrocytes, ellipocyte, lactate dehydrogenase

oxidation autoimmune hemolytic anemia
steroid

HIV (Anemia in HIV patients)

63-95 HIV HIV
1 CD4 200 /L
(opportunistic infection) HIV
Baker KR HIV
CD4 viral load
anemia HIV 3
1. HIV
anemia ACD
2. antiretroviral Zidovudine (AZT)
anemia AZT erythroid
colony formation AZT 1500 mg/day anemia
24 AZT 1500 mg/day
severe anemia (HgB < 7.5-8.0 g/dL) AZT
anemia antiretroviral
(myelotoxicity)
3. (opportunistic infection)
anemia Human parvovirus B19 (single-
stranded DNA virus) anemia virus erythroid
cell (TB)
anemia
- gangciclovir pancytopenia
- Amphotericin B erythropoietin
- Trimethoprim-sulfamethoxazole dapsone
magaloblastic anemia hemolytic anemia
G6PD
 250

HIV ACD
AZT anemia EPO 50-400 units/kg 2-3
IV SC hemoglobin
hemoglobin 12 g/dL 1 g/dL 2 25
hemoglobin 12 g/dL 8 25

Groopman
50-60 mild 29-44 severe

1.

2. (chronic disease)
cytokines interleukin-6 (IL-6)
TNF-, IL- EPO
3.

4. multiple
myeloma
5.

6. (hemolytic anemia)

1.


2. (erythropoiesis stimulating agents: ESAs) EPO

2-4 ESAs
serum ferritin ( 100 )

 251

Epoetin alpha 100-150 /. SC 3

reticulocyte 1 hemoglobin
0.5 / 2-4 hemoglobin 8
150-300 /. SC 3
Epoietin beta Epoetin alpha 150-300 /. SC 3
30,000-60,000 SC

Hemoglobin (Hb), Hematocrit (Hct)

oxygen




serum ferritin, serum iron, tranferritin saturation, Hgb, Hct
TIBC 3-6
12
12
intrinsic factor 12 pernicious anemia
12
neural tube defect

1-2
serum iron serum feritin
EPO

sepsis EPO

68 45 152
CC:
PMH: chronic kidney disease 3
 252

PI:
6
anemias
SH:
MH: Calcium carbonate 625 mg 1 x 3 po pc Renal function
Sodium bicarbonate 300 mg 1 x 3 po pc BUN (7-25): 17
Folic acid 5 mg 1 x 1 po pc sCr (0.7-1.4): 3.5
FeSO4 200 mg 1 x 3 po pc
Vitamin B 1-6-12 1 x 1 po pc
ALL: NKDA
Physical examination:
GEN: Thin, old female, pale Urinalysis
VS: T 38.0, P 86 /min, RR 20 /min, BP 95/65 mmHg Color: yellow
HEENT: glossitis Turbid: slightly
COR: no jugular venous distension, no murmurs WBC: 2-3
Chest: clear RBC: 3-5
ABD: + bowel sounds Epithelial: 0-1
EXT: normal Bacteria: -
Blood: hypochromic, microcytic red blood cell

Hematology
RBC: 1.24 Mono: 5.1 MCHC: 105
Hb: 6.2 Neu: 76.4 Serum ferritin: 75
Hct: 24 Eos: 0.7 TIBC: 400
WBC: 6.7 Baso: 0.2 Serum iron 75
Lym: 17.6 MCH: 39.4
Impression: Chronic kidney disease with anemia
1. CKD stage
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
2. anemia
.......................................................................................................................................................................................
.......................................................................................................................................................................................
 253

3. anemia
.......................................................................................................................................................................................
.......................................................................................................................................................................................
4. EPO
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
5. EPO
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
6.
.......................................................................................................................................................................................
.......................................................................................................................................................................................
7. EPO 2 Hb 7.5 g/dL

.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................

8.
.......................................................................................................................................................................................
.......................................................................................................................................................................................
9. Patient education
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
.......................................................................................................................................................................................
10. Future plan:

 254

1. Ineck BA, Mason BJ, Lyons WL. Anemias. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Well
BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 8th ed.
Appleton&Lange: Stamford; 2011.
2. Eschbach JW, Abdulhadi MH, Browne JK. Recombinant Human Erythropoietin In Anemic
Patients with ESRD. Ann Intern Med. 1989; 111 : 992-1000.
3. . .
, . Advance in Pharmaceutical care and
pharmacotherapeutics. : : 2547.
4. Kaitwatcharachi C. The Treatment of anemia of chronic renal failure. Songkla Med J 1997.
5. Weiss G, Goodnough LT. Anemia of Chronic Disease. N Engl J Med 2005; 352:1011-23.
6. Izaks GJ, Westendrop RG, Knock DL. The definition of anemia in older persons. JAMA
1999; 281 (18) : 1714-8.
7. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for chronic kidney
disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(suppl):S1-
S266.
8. Guideline and protocols advisory committee. Vitamin B12 deficiency investigation
management of vitamin B12 and folate deficiency. 2006.
9. Volberding PA, Baker KR., Levine AM. Human Immunodeficiency Virus Hematology. The
American Society of Hematology. 2003.
10. Lacy CF, Armstrong LL, Goldman PM, Lance LL. Drug information handbook. 12th ed. Ohio
: Lexi-Comp Inc; 2004.
11. . . . 2552;8(3) : 134-138.
12. Zlotkin SH Christofides AL, Hyder SMZ, Schauer CS. and Tondeur MC, et al. Controlling
iron deficiency anemia through the use of home-fortified complementary foods. Indian
Journal of Pediatrics, 2004; 71(11) : 1015-9.
13. Schwartzberg L, Burkes R, Mirtsching B, Rearden T and Silberstein P, et al. Comparison of
darbepoetin alfa dosed weekly (QW) vs. extended dosing schedule (EDS) in the
treatment of anemia in patients receiving multicycle chemotherapy in a randomized,
phase 2, open-label trial. BMC Cancer. 2010; 10(1): 581.
14. Frank H. Netter. Atlas of human anatomy. 10th edition. Hoechstetter printing company
inc. 1997.
15. Mader SS. Inquiry into Life, 8th ed. The McGraw-Hill. 1997.
16. AACC. Folate metabolism. available from : URL : http://www.aacc.org/publications/cln
/2011/january/Pages/FolateMetabolismFigure.aspx. Accessed: 20 May 2012.
17. Robert C, Brown DL. Vitamin B12 Deficiency. Am Fam Physician. 2003;67(5):979-86.
 255

18. Groopman JE, Itri LM. Chemotherapy-Induced Anemia in Adults: Incidence and
Treatment. J Natl Cancer Inst 1999;91:161634.
19. Groenveld HF, Januzzi JL, Damman K, Wijngaarden J, Hillege HL, Veldhuisen DJ. Anemia
and Mortality in Heart Failure Patients : A Systematic Review and Meta-Analysis. JACC
2008; 52(10):818-27.
20. Mozaffarian D, Nye R, Levy WC. Anemia Predicts Mortality in Severe Heart Failure The
Prospective Randomized Amlodipine Survival Evaluation (PRAISE). J Am Coll Cardiol
2003;41:19339.
21. Schneider JM, Fujii Mary L, Lamp CL, Lnnerdal B, Dewey KG, Cherr SZ. Anemia, iron
deficiency, and iron deficiency anemia in 1236-mo-old children from low-income
families. Am J Clin Nutr 2005;82:126975.
22. Sulaiman K, Prashanth P, Al-Zakwani I, Al-Mahmeed W, Al-Motarreb A, Al-Suwaidi J, et al.
Impact of Anemia on In-Hospital, One-Month and One-Year Mortality in Patients with
Acute Coronary Syndrome from the Middle East. Clinical Medicine & Research 2012; 10
(2) : 65-71.
23. Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y. Prevalence and management of
cancer-related anaemia, iron deciency and the specic role of i.v. iron. Annals of
Oncology. 2012; 9 : 1-9.
24. Winichagoon P. Forging Effective Strategies to Combat Iron Deciency Prevention and
Control of Anemia: Thailand Experiences. J. Nutr 2002;132: 862S866S,