Objectives

1
Overview of Anemia - I
Morey A. Blinder, M.D. Associate Professor of
Medicine and Pathology Immunology
Department of Internal Medicine Division of
Hematology
2
Anemia

• Anemia - I
• Overview
• Laboratory testing of anemia
• Hypoproliferative anemia

• Anemia - II
• Hemolytic anemia
• Peripheral smears
• RBC transfusions

3
Hematology Consults (BJH)
Evaluations No known hematologic illness n390
(74)
4
Hematology Consults (BJH)
Treatment of known hematologic illness n135 (26)
5
Hematology Inpatient Consults (BJH)
Evaluation of anemia (n79)
9
13
18
60
6
Regulation of Erythropoiesis
Kidney
Epo mRNA
Epo
Oxygen sensor
Blood vessel
7
Anemia

• Understanding anemia
• Disease - to be treated on its own merits
• Condition - a secondary manifestation of another
  disease
• Causes
• Decreased production
• Blood loss
• Hemolysis

8
Classification of Anemia

• Acute vs. chronic
• Signs and symptoms
• Red cell kinetics
• Determined by reticulocyte count
• Red cell size
• Determined by MCV

9
Laboratory Evaluation of Anemia

• Complete blood count
• Reticulocyte count
• Peripheral smear

10
Reticulocyte Count

• Relative reticulocyte count
• of all RBC (normal 0.8-1.5)
• Absolute reticulocyte count
• Relative reticulocyte count x RBC count
• Normal 50,000-75,000/µl
• Examples

1.1 x 4.96 x106 55,000/ml 12..2 x 2.05 x106
250,000/ml
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Classification of Anemia Based on RBC Kinetics
and Size
MCV
Microcytic Normocytic
Macrocytic Low Common Common
Common High Uncommon Common Uncommon
Retic count
12
Microcytic Hypochromic Anemia Diagnosis

• Mild (MCV gt 70 fl)
• Iron deficiency
• Thalassemia
• Lead toxicity
• Sideroblastic anemia
• Anemia of chronic disease

• Severe (MCV lt 70 fl)
• Iron deficiency
• Thalassemia

13
Thalassemia Impaired globin gene prouction
Hgb A tetramer
14
Globin chain synthesis
Development period
Globin chain component
a cluster - chromosome 16
of adult Hgb
Hgb name
a1
a2
z
z2e2 Gower 1 z2g2 Portland Embryonic a2e2 Gower
II a2g2 F Fetal lt1 a2d2 A2 1.5-3.5 Ad
ult a2b2 A gt95
e
Gg
d
b
Ag
b cluster - chromosome 11
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Thalassemia

• Decreased production of normal globin chains
• a thalassemia deficiency of a gene(s)
• b thalassemia deficiency of b gene(s)

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Alpha Thalassemia Laboratory Findings

• Hemoglobin
• ? chains Hgb (g/dl) MCV (fl) RDW Analysis
• ??/?? Normal Normal Normal Normal
• ??/-? 12-14 75-85 Normal Normal
• ?-/?- or 11-13 70-75 Normal with
• -/?? Hgb Barts
• -/- ? 7-10 50-60 Normal with
• Hgb Barts
• - -/- - - - - Not viable

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Alpha Thalassemia Clinical features

• Absence of 1-2 alpha chains
• Common
• Asymptomatic
• Does not require therapy
• Absence of 3 alpha chains
• Microcytic anemia (Hgb 7-10)
• Splenomegaly
• Absence of 4 alpha chains
• Hydrops fetalis (non-viable)

X
X
X
X
X
X
X
X
X
X
X
X
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Beta Thalassemia
Clinical Hgb Syndrome Genotype Hgb
(g/dl) analysis
Minor (Trait) ?/? or ?/? 10-13 Hgb A2,
Hgb F Intermedia ?/? 7-10 Hgb A2,
Hgb F Major (Cooleys) ?/? or ?/?
lt 7 Hgb A2, Hgb F
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Iron Deficiency Anemia

• A world-wide problem
• 3 of toddlers age 1-2 years
• 2-5 of women of child bearing age
• Iron metabolism
• Iron stores
• Laboratory findings of iron deficiency
• Causes of iron deficiency
• Treatment

20
Body Iron Distribution and Storage
Duodenum
Dietary iron
(average, 1 - 2 mg
Utilization
Utilization
per day)
Plasma
transferrin
(3 mg)
Bone
Muscle
marrow
(myoglobin)
(300 mg)
Circulating
(300 mg)
erythrocytes
Storage
(hemoglobin)
iron
(1,800 mg)
Sloughed mucosal cells
Desquamation/Menstruation
Other blood loss
(average, 1 - 2 mg per day)
Reticuloendothelial
Liver
macrophages
(1,000 mg)
Iron loss
(600 mg)
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Major Iron Compartments

• Metabolic
• Hemoglobin 1800-2500 mg
• Myoglobin 300-500 mg
• Storage
• Iron storage 0-1000 mg
• Transit
• Serum iron 3 mg
• Total 3000-4000 mg

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Development of Iron Deficiency

• Depletion of iron stores Ferritin low BM
  iron absent
• Compromised iron delivery Serum iron
  low TIBC high sTfR high
• Iron deficient anemia Hgb low MCV low

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Ferritin µg/l
Bone marrow iron stores
24
Systemic Manifestations of Iron Deficiency

• Behavioral and neuropsychiatric manifestations
• Pica (pagophagia)
• Angular stomatitis
• Glossitis
• Esophageal webs and strictures
• Koilonychia

25
Systemic Manifestations of Iron Deficiency
Glossitis
Koilonychia
Angular chelitis
26
Causes of Iron Deficiency

• Increased iron requirements
• Blood loss
• Gastrointestinal tract
• Genitourinary tract
• Blood donation
• Pregnancy and lactation

• Inadequate iron supply
• Insufficient dietary iron
• Impaired iron absorption
• Gastric surgery
• Intestinal malabsorption
• Celiac disease

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Unexplained iron deficiencyGastrointestinal
sideropenia

• Consider in patients with relapsed/refractory
  iron deficiency
• Celiac disease
• Atrophic body gastritis
• H. pylori infection
• Gastric bypass surgery

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Treatment with Oral Iron General Principles

• Ferrous salts are absorbed better than ferric
• All ferrous salts are absorbed to the same extent
• Ascorbic acid increases absorption and toxicity
• Iron is absorbed best on an empty stomach
• Iron should not be given with antacids
• Iron polysaccharide complex (Niferex) seems to be
  better tolerated than other iron salts

29
Use of Parenteral Iron

• Agents available
• Iron dextran (total dose replacement 1/300
  anaphylaxis)
• Iron polysaccharide (125 mg/d maximum 1/1000
  anaphylaxis)
• Indications
• Malabsorption
• Iron-limited response to erythropoietin
• Toxicity/noncompliance with oral iron
• Response
• Maximal increase in hemoglobin synthesis
• Rapid increase in iron stores

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Normal Hypochromic Microcytic
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Hypochromia without Anisocytosis Thalassemia
Trait
32
Severe Hypochromia Iron Deficiency Anemia
33
Mixed Population Treated Iron Deficiency Anemia
34
Microcytic Hypochromia Alpha Thalassemia (?-/--)
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Microcytic Hypochromia Beta Thalassemia Major
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Microcytic Hypochromia Beta Thalassemia Major
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Normocytic Anemia with Low Reticulocyte Count

• Decreased stimulation of bone marrow
• Anemia of chronic disease
• Chronic renal insufficiency
• Metabolic disorders
• Isolated decrease in RBC precursors
• Bone marrow damage
• Fibrosis
• Stem cell damage
• Infiltration with tumor/infection
• Intrinsic bone marrow disease
• Myelodysplasia/sideroblasticanemia

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Distinguishing iron deficiency from other anemias
with low reticulocyte count

• Decreased stimulation of RBC production in bone
  marrow
• Beta thalassemia
• Anemia of chronic disease
• Chronic renal insufficiency
• Isolated decrease in RBC precursors (Red cell
  aplasia)
• Bone marrow damage
• Fibrosis
• Stem cell damage
• Infiltration with tumor/infection
• Intrinsic bone marrow disease
• Myelodysplasia/sideroblastic anemia

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Anemia of Chronic Disease

• Associated conditions Prevalence
• Infection 20-95
• Viral, bacterial, TB, parasitic, fungal
• Autoimmune disease 8-17
• RA, SLE, Sarcoidosis, IBD, Vasculitis
• Cancer 30-77
• Chronic solid organ rejection 8-70
• Characteristics
• Anemia of variable severity (mild-severe)
• Low erythropoietin level
• Low reticulocyte count
• WBC and platelet counts are normal

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Laboratory diagnosis of iron deficiencySerum
transferrin receptor (STfR)

• Transferrin receptor located on surface of
  erythroid precursors in bone marrow
• Small amount of transferrin released into
  circulation (sTfR)
• Iron deficiency anemia associated with increased
  sTfR

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sTfR Distinguish iron deficiency from other
hypoproliferative anemias
Overall results of sTfR Sensitivity
100 Specificity 69 Accuracy 88
42
Iron Transfer Between Cells and TissuesImpaired
in Anemia of Chronic Disease
X
X
Blocked in Anemia of chronic disease
Hentze, et.al, Cell 117 285 (2004)
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Iron Transfer Between Cells and TissuesMediated
by Hepcidin
Iron overload Anemia of chronic disease Iron
deficiency Increased iron demand (hemolysis)
Hepcidin
Hentze, et.al, Cell 117 285 (2004)
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Summary

• Hepcidin plays a pivotal role in control of iron
• Increased hepcidin Anemia of chronic disease
• Decreased hepcidin Hemochromatosis
• Decreased hepcidin transcription in liver (HFE,
  Hemojuvelin orTfR2)

45
Anemia of Chronic Disease

• Treatment options
• Underlying condition
• RBC transfusion
• Erythropoietic agent
• Iron supplement not usually indicated
• Hepcidin inhibitors (?)

46
Anemia of Chronic Renal Disease

• Characteristics
• Widespread - 8 of US population has increased
  creatinine
• 23 of patients with chronic renal disease have
  HCT 30
• Long-term anemia is a risk for LVH
• Risk factor for mortality
• Etiology
• Insufficient production of erythropoietin

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Anemia in the Elderly

• General principles
• Anemia in elderly defined as Hgb lt13 g/dl for
  men Hgb lt 12 g/dl for women
• 3 million individuals in the US age gt65 are
  anemic
• Anemia more common in females lt75 years more
  common in males gt75 years

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Anemia in persons age 65 years
28.0
27.5
Male Female
25
20.4
20
15
11.5
11.0
10.2
9.2
9.3
10
8.7
7.5
5
Other
Non-hispanic White
Total population
Non-hispanic Black
Hispanic
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Distribution of types of anemia in US in persons
gt 65 years
Type of anemia Percent Blood
loss/nutritional 34 Iron deficiency B12
or Folate 20 Folate and/or B12
deficiency 14 Chronic disease (Epo
deficiency) 32 Chronic renal disease
8 Anemia of chronic disease 20 CRD
and ACD 4 Unexplained 34
NHANES III
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Potential Mechanisms of Anemia in the Elderly

• Dysregulation of the inflammatory response
• Blunting of hypoxia/erythropoietin sensing
  mechanism
• Sarcopenia
• Alterations in the stem cells
• Decrease in sex steroids (testosterone)
• Frequent co-morbid medical conditions
• Polypharmacy

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Pure Red Cell Aplasia

• Normocytic anemia with reticulocyte count lt 0.5
• Absent erythroid precursors in marrow
• Caused by Parvovirus B19
• Clinical setting
• Immunocompetent patients with chronic hemolysis
• Immunodeficient patients with persistent viremia

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Pure Red Cell AplasiaParvovirus B19 in an
immunocompetent host
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Macrocytic Anemia with Low Reticulocyte Count

• Megaloblastic anemia
• Vitamin B12 deficiency
• Folate deficiency
• Non-megaloblastic macrocytic anemia
• Liver disease
• Hypothyroidism
• Drug-induced (DNA synthesis block)
• Myelodysplastic syndrome

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Folate and Cobalamin Daily Requirements
Diet Vitamin B12 (Cobalamin)
Folate Source Animal products Widespread Bo
dy stores 5 mg 5 mg Daily requirement 2-5
µg 50-200 µg Daily intake 10-20 µg 400-800
µg Dietary deficiency Rare Common
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(No Transcript)
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Metabolic Testing for the Diagnosis ofVitamin
B12 and Folate Deficiency

• High Values
• Normal Vitamin B12 Folate Deficiency
  Deficiency
• Methylmalonic Acid lt 3 gt 95 lt 3
• Homocysteine lt 3 gt 95 gt 95

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Enteric Processing and absorption of Cobalamin
Food-Cbl
Stomach
Peptic digestion
H
Cbl R-binder
R-Cbl
Duodenum
Pancreatic enzymes
Cbl-TC complex
R-Cbl
IF Cb
OH -
Cbl-IF
Distal ileum
IF receptor
Cbl TC
Cbl-IF
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Vitamin B12 Deficiency Common Mechanisms

• Intragastric events
• Inadequate dissociation of cobalamin from food
  protein
• Total or partial gastrectomy
• Absent intrinsic factor secretion
• Proximal small intestine
• Impaired transfer of cobalamin from R protein to
  intrinsic factor
• Usurpation of luminal cobalamin
• Bacterial overgrowth
• Diphylobothrium latum (fish tapeworm)
• Distal small intestine
• Disease of the terminal ileum

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Pernicious Anemia

• Most common cause of vitamin B12 deficiency
• Occurs in all ages and ethnic backgrounds
• Associated with other autoimmune diseases
• Screen for thyroid disease every 1-2 years
• Pernicious anemia is a systemic disease
• Gastrointestinal tract involvement
• Neurologic involvement

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Pernicious Anemia Laboratory Diagnosis

• Anti-intrinsic factor antibodies
• Specific but not sensitive
• Anti-parietal cell antibodies
• Sensitive but not specific
• Schilling test
• Procedure
• Absorption of radiolabeled cobalamin Intrinsic
  factor
• Measure urinary excretion of radioactivity
• Specific but not sensitive

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Megaloblastic anemia
Macro-Ovalocytes
Hypersegmented Neutrophils
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Treatment of Vitamin B12 Deficiency

• Parenteral cobalamin
• 1 mg/day x 7 days
• 1 mg/week x 4 weeks
• 1 mg/month for life
• Oral cobalamin
• 1 mg/day for life