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Anemia and Abnormalities of

Red Blood Cells: Approach to


Diagnosis and Treatment

Section of Hematology-Oncology
Department of Medicine
University of Santo Tomas
Faculty of Medicine and Surgery
Case 1-01-01: 35 year old pre-
menopausic female with menorrhagia

 housewife
 complains of progressive easy fatigability of
about 3 months duration.
(-) epigastric pain, (-) hematochezia nor
melena
menses – 28 days cycle, 7 days duration,
3 days profuse flow , 5-6 fully soaked
pads/day
(-) bruises/ecchymoses
 P.E. Pale, no jaundice
(-) hepatosplenomegaly
Case 1-01-01

1. What other questions should you


ask of this patient who presents
with pallor?
2. What other findings should you
look for in the
physical examination?
Case 1-01-01

3. What laboratory examinations


would you request in this case?
4. What are red cell indices?
5. What information can you get
from the examination of the
peripheral smear?
6. What is the significance of the
reticulocyte count?
Case 1-01-01:
 CBC:
Hb: 60g/L Hct: .21
MCV: 80fL
MCH: 25 pg
MCHC: 28%
WBC: 6 x 109/L

seg: 70% lymph:


25%
eos: 3% mono:
2%
Platelets: adequate
 Reticulocyte count:
Interpretation?
 Microcytic (MCV low)
 Hypochromic (MCH low)
 Normal WBC
 Platelets normal quantity
 Reticulocyte count normal
 Peripheral smear: hypochromic,
microcytic red blood cells, varying sizes
(anisocytosis), varying shapes
(poikilocytosis), platelets adequate
Back
Case 1
Patient Normal value

Serum iron 10 9 - 27 umol/L


50 – 150
TIBC 60 μg/dL
54 – 64 umol/L
300 – 600
% transferrin 16.6% μg/dL
25 – 50%
saturation
Serum ferritin 8ug/L 30
μg/L(female)
100
Interpretation?
 Serum iron low
 TIBC normal
 Transferrin saturation low
 Serum ferritin low

 Iron deficiency anemia


Anemia
 Reduction below normal in the
concentration of hemoglobin or
RBC’s in the blood
 Anemia is not a diagnosis in itself, but
merely an objective sign of disease
 First step in its diagnosis is detection of its
presence
Symptoms of moderate to
severe anemia
 Fatigue
 Breathlessness
 Loss of stamina
 Palpitations, especially with physical exertion
 Headache
 Vertigo
 Lack of mental concentration
 Drowsiness
 Tinnitus
 Paresthesias
 Pica
History
Symptoms depend on:
2. Severity of the anemia
3. Rapidity of onset
4. Patient’s age and CV status
- capacity of the CV & pulmonary system
to compensate for the anemia
7. Associated manifestations of the underlying
disorder
- Endocrine disorder
- Renal disorder
- Hepatic disorder
History
 Onset & Duration of symptoms
 insiduous or acute
 Previous prescription for hematinics &
response
 Medication history
 Occupation, household customs & hobbies
 Symptoms of hemolysis
 jaundice, changes in urine color
 Symptoms of blood loss
 melena, hematochezia, epigastric pain
History
 Obstetric & Gynecologic history
 # of pads/day

 duration

 # of pregnancies, abortions -

interval
 Concomitant bleeding manifestations
 Dietary history
Back to questions
 Fever, Weight loss
Vital signs
 Blood pressure
 Hypotension

 Orthostatic hypotension

 Cardiac/pulse rate
 Tachycardia

 Respiratory rate
 Tachypnea

 Body temperature
Cardiac Signs
 Hemic murmurs: mid or
holosystolic often in the pulmonic
or apical area, due to increased
blood flow and turbulence
 Gallop rhythms
 Tachycardia/Cardiomegaly
 Strong peripheral pulses with wide
pulse pressure
Skin
 Pallor: <8 to 10 mg/dL hemoglobin
Affected by:
state of vasoconstriction/vasodilatation
degree & nature of pigmentation
nature & fluid content of the subcutaneous
tissues
Most constantly detected in:
mucous membranes of the mouth, pharynx,
conjunctivae, lips
nailbeds

* Areas where vessels are close to the skin


surface
Skin

 Dry, Shriveled skin


 Thinning, loss of luster,

premature graying of hair


 Brittle, lackluster nails, spooning
Gastrointestinal
manifestations
 Glossitis
 Atrophy of the papillae of the
tongue
 Dysphagia
 Oral ulcers
 Gingival hyperplasia
 Hepatosplenomegaly
 Sternal tenderness
 Lymphadenopathy
 Retinal hemorrhage

Back to questions
Complete blood count
 Red cells
 Hemoglobin

 Hematocrit

 Red cell count

 Morphology

 Red cell indices: MCV, MCH, MCHC

 White blood cells


 Total count

 Differential count

 Platelet count
Changes in Normal
Hemoglobin/Hematocrit Values with
Age and Pregnancy
Age/Sex Hgb (g/dl) Hct (%)
At birth 17 52
Childhood 12 36
Adolescence 13 40
Adult man 16(+2) 47(+6)
Adult woman 13(+2) 40(+6)
(menstruating)
Adult woman 14(+2) 42(+6)
(postmenopausal)
During pregnancy 12(+2) 37(+6)

Back to questions
Red cell indices
Index Normal Value

Mean Cell Volume(MCV)


(hematocrit x 10)/(red cell ct. x 106) 90 + 8 fL

Mean Cell Hemoglobin (MCH)


(hemoglobin x 10)/ (red cell ct. x 106) 30 + 3
pg

Mean Cell Hemoglobin Concentration 33 + 2%


(hemoglobin x 10)/ hematocrit,
or MCH/MCV
Back to questions
Morphology
Morphology
APPROACH TO THE DIAGNOSIS OF ANEMIA
Reticulocyte count
 Measure of bone marrow
compensation for anemia
 Normal Value
 0.5 – 1.5% (old)

 5 – 15 x 10-3 (SI)
 Corrected Reticulocyte
ct
=Patient’s Hct x
Reticulocyte 45
count (%)
 Reticulocyte production
index
Corrected Reticulocyte
2
Back to Algorithm
Back to case 1
Diagnosis of microcytic anemias
Tests Iron Inflammatio Thalassem Sideroblas
deficiency n ia tic anemia
Smear Micro/hypo Normal, Micro/hypo variable
micro/hypo with target
Serum <30 <50 Normal to Normal to
iron high high
TIBC >360 <300 normal norml

% <10 10-20 30-80 30-80


saturation
Ferritin <15 30-200 50-300 50-300

Hemoglob normal normal abnormal normal


in pattern
Adamson, J in Harrison’s Principles of Internal Medicine, 15th ed., 2001
Iron studies
 Serum iron: amount of circulating
iron bound to transferrin
 Total iron binding capacity:
indirect measurement of bound
transferrin
 Percent transferrin saturation:
 Serum iron level x 100

TIBC
 Serum ferritin: estimate of iron
stores
Stages of Iron Deficiency
Normal Negative Iron deficient Iron
iron erythropoiesi deficiency
balance s anemia
Marrow iron 1–3+ 0-1+ 0 0
stores
Serum ferritin 50- 200 <20 <15 <15
(ug/L)
TIBC (ug/dL) 300-360 >360 >380 >400
SI (ug/dL) 50-150 NL <50 <30
Saturation 30-50 NL <20 <10
(%)
Marrow 40-60 NL <10 <10
sideroblasts
(%)
RBC NL NL NL Microcytic
morphology hypochrom
ic
Treatment
 Severity and cause determine
approach to treament
 Elderly+/- cardiovasular

instability: RBC transfusions


 Younger individuals with

compensated anemia: iron


replacement
Oral Iron Therapy
 Optimal response occurs when about
200 mg of elemental iron given per day
 Absorption more complete on empty
stomach
 With or after a meal, absorption
decreases by 40 to 50%
 However gastric irritation is common,
hence, advisingpt to take tablet
immediately after a meal may increase
compliance
Oral Iron Therapy
 Absorption enhanced by orange juice,
meat, poultry, fish
 Absorption inhibited by cereals, tea,
milk
 Side Effects of Oral Iron:
gastrointestinal: heartburn, nausea,
abdominal cramps, diarrhea
 Related to dose

 Continue iron treatment 3 to 6 months


after anemia resolves
 Allows repletion of iron stores
Oral Iron Preparations

Preparation Size Iron Usual Adult


Content daily dose
Ferrous sulfate

tablets (hydrated) 300 mg 60 mg 3 tablets


tablets (exsiccated) 200 mg 60 mg 3 tablets
syrup & elixirs 40 8 mg/ ml 25 ml
mg/ml
Ferrous gluconate 300 mg 37 mg 5 tablets

Ferrous fumarate 200 mg 67 mg 3 tablets


300 mg 100 mg 2 tablets
Indications for Parenteral
Iron
 Unable to tolerate iron compounds orally
 Poor compliance
 Persistent loss of blood or iron at a rate too
rapid for oral intake to compensate for the loss
 Disorder of GI tract e.g. ulcerative colitis
 Malabsorption of iron
 Inability of maintain iron balance during
treatment with hemodialysis
 Donating large amounts of blood for
autotransfusion
Computing for the dose of
parenteral iron

= Body weight (kg) x 2.3 x (15 –


patient’s Hgb, g/dL) + 500 or 1000
mg (for stores)
Case 1-02-01
 75 year old female consulted because of progressive
weakness and loss of balance
 numbness and tingling sensation in all extremities
 no gastrointestinal complaints
 hypertensive on Felodipine 5 mg per day, but not a diabetic
 Diet consists of vegetables and fish because of poor dentition
 P.E. Vital signs: BP: 150/90, PR: 80/min, regular, RR:
21/min., regular, Temp: 35.5’C
 pale, has slightly icteric sclerae

 smooth, red tongue

 no lymph nodes, nor anterior neck mass.

 regular rate and rhythm, no murmurs

 Lung examination is normal

 no abdominal masses palpated

 some problems with gait but has an otherwise normal


neurologic examination
Case 1-02-01
1. What other questions should you
ask of this patient who presents
with pallor?
2. What other findings should you
look for in the physical
examination?
Case 1-02
 CBC:
Hb: 80 g/L Hct:
.26
MCV: 102fL MCH:
36 pg MCHC: 38%
WBC: 9 x 109/L
seg: 74%
lymph: 20%
eos: 2%
mono: 4%
platelets:
adequate
Case 1-02-01
3. What laboratory examinations
would you request in this case?
4. What other
differential diagnoses should be
considered?
> 36 32-36 < 32
macrocytes normochromic hypoochromic
normocytic microcytic
Reticulocyte count

Increased
INCREASED Normal/Decreased
NORMAL/DECREASED

bone marrow
• prior hemolysis megaloblasti
• prior hemorrhage YES c NO
• treated disease • deficiency of Vit. • hypothyroidism
• deficiency of B12, Folate
- Vit. B12
• hypoplastic
• disorders of DNA
- Folate marrow and misc.
synthesis
- drug-induced
- inherited Back to Questions
Diagnostic Tests: Megaloblastic
Anemia
 Reticulocyte index
 Unconjugated bilirubin may be increased
 LDH may be increased
 Serum levels of
 Cobalamin (Vitamin B12) (NV: 300 – 900

pg/mL)
 Folate (6 – 20 mg/mL)

 Red cell folate levels


 not subject to fluctuations in folate intake

 better indication of folate stores


Bone marrow findings:
Megaloblastic anemia
 Hypercellular
 Decreased
myeloid/erythroid ratio
 Abundant stainable iron
 RBC precursors
abnormally large, nuclei
less mature (nuclear-
cytoplasmic asynchrony)
 Nuclear chromatin more
disperse and condenses
in a fenestrated pattern
 Abnormal mitosis
 Granulocyte precursor
larger than normal with
giant bands and metas
 Megakaryocytes
Back to discussion decreased, abnormal
Interpretation?
 MCV high (macrocytic)
 MCH high (hyperchromic)
 PS: macrocytic red cells, some
hyperchromic red cells,
hypersegmented neutrophils

 Macrocytic anemia, probably


megaloblastic anemia
Megaloblastic anemia
 disorder caused by impaired DNA
synthesis
 Cells primarily affected: blood
cells, GI epithelial cells
 slowed nuclear cell division with
normal progression of cytoplasmic
maturation
megaloblastosis in bone marrow
Causes of Megaloblastic anemia
 Cobalamin deficiency
 Inadequate intake (vegans)

 Malabsorption

 Gastric achlorydia, partial gastrectomy,

drugs that block acid secretion


 Pernicious anemia, total gastrectomy

 Terminal ileal disease: sprue, enteritis,

resection, tumors
 Competition of cobalamin: fish

tapeworm, “blind loop” syndrome


Causes of megaloblastic anemia
 Folic acid deficiency
 Inadequate intake: unbalanced diet (alcoholics,
teenagers, some infants)
 Increased requirements
 Pregnancy
 Infancy
 Malignancy
 Increased hematopoiesis (chronic hemolytic
anemias)
 Chronic exfoliative skin disorders
 Hemodialysis
 Malabsorption
 Impaired metabolism
Other causes of megaloblastic
anemia
 Drugs that impair DNA metabolism
 Purine antagonists: 6 mercaptopurine,
azthioprine
 Pyrimidine antagonists: 5FU, cytosine
arabinoside, others
 Others: procarbazine, hydroxyurea,
zidovudine
 Metabolic disorders (rare)
 Hereditary orotic aciduria
 Lesch Nyhan syndrome
 Megaloblastic anemia of unknown etiiology
 Refractory megaloblastic anemia
 DiGuglielmo’s syndrome
 Congenital dyserythropoietic anemia
Treatment of Megaloblastic
anemia
 Treat the cause
 Cobalamin deficiency
 IM cyanocobalamin: 1000 mcg

per week for 8 weeks then


monthly
 Oral cobalamin: 2 mg crystalline

B12 per day


 Folic acid: 1 mg/day po
Case 1-03-01
 50 year old female was referred for evaluation of
anemia
 easy fatigability about 5 weeks
 cough and fever and was diagnosed to have pneumonia.
She was given antibiotics which included Cefuroxime
500 mg BID
 other symptoms
 passage of highly colored urine

 weight loss of about 5 lbs in the last 2 months

 P.E. Vital signs: BP: 120/70, PR: 110/min, regular, RR:


23/min, regular, Temp: 37’C
 pale palpebral conjunctivae, icteric sclerae, small
cervical lymph nodes on both sides,
 no hepatomegaly and slight splenomegaly
Case 1-03
 CBC:
Hb: 70 g/L Hct: .21
MCV: 98fL MCH:
35pg
MCHC: 36%

WBC: 13x 109/L


seg: 80% lymph:
20%
platelets: adequate
 Reticulocyte count:
80 x 10-3/L
Case 1-03-01
1. What other questions should you
ask of this patient who presents
with pallor?
2. What other findings should you
look for in the physical
examination?
Case 1-03-01
3. What is the most likely problem
in this patient?
4. What diagnostic tests are
important in this patient?
Diagnostic tests for
hemolytic anemia
 Peripheral smear
 Direct Coomb’s test (antiglobulin test)
 Clue to immune (antibody-mediated)

hemolysis of RBC
 Ham’s test (acid hemolysis); sucrose
hemolysis test screens for paroxysmal
nocturnal hemoglobinuria
 Flow cytometry diagnostic

 Osmotic fragility test


 Hemoglobin electrophoresis for
hemoglobinopathies (e.g. thalassemia)
Morphology in hemolytic
anemias

Spherocytes: hereditary spherocytosis


Autoimmune hemolytic anemia

Schistocytes: microagiopathic hemolytic


Target cells: thalassemias Anemia, intravascular prostheses
Causes of Hemolysis
Abnormalities of RBC interior
Enzyme defects HEREDITARY
Hemoglobinopathies
INTRACORPUSCULAR RBC membrane abnormalities
Hereditary spherocytosis, etc
Paroxysmal nocturnal
hemoglobinuria
Spur cell anemia
Extrinsic factors
Hypersplenism ACQUIRED
EXTRACORPUSCULAR Antibody: immune hemolysis
Microangiopathic hemolysis
Infections, toxins, etc.

Back to Questions
HEMOLYTIC ANEMIA

COOMB’S TEST

NEGATIVE POSITIVE

EXTRACORPUSCULAR

AUTOIMMUNE HEMOLYTIC ANEMIA


Primary
Secondary (CT disease, drugs)
Isoimmune Hemolytic Disease
Rh,ABO, mismatched transfusion
HEMOLYTIC ANEMIA

COOMB’S TEST

NEGATIVE POSITIVE

CORPUSCULAR EXTRACORPUSCULAR

Hemoglobinopathies Idiopathic
Enzymopathies Secondary
Membrane Defects Drugs
Morphology Infection
Autohemolysis Microangiopathic
Osmotic Fragility
Immune-mediated
hemolysis
 Usually due to IgG or IgM antibodies
with specificity to antigens on red cell
membrane(autoantibodies) or with
alloantigens on transfused RBC
(alloantibodies)
 Diagnostic tool: Coomb’s antiglobulin
test
 Direct: ability of anti-IgG or anti-C3

sera to agglutinate patient’s RBC


 Indirect: serum of patient incubated

with normal RBC & antibody is


detected with anti-IgG
Hemolysis due to
Antibodies
 Warm-Antibody  Cold-Antibody
Immunohemolytic Immunohemolytic
anemia Anemia
 Idiopathic
 Cold-agglutinin
 Lymphomas
disease
 SLE & other collagen
 Acute:
vascular disease
Mycoplasma,
 Drugs
infectious
 Alpha methyl dopa
mononucleosis
 Penicillin
 Chronic:
 Quinidine
idiopathic,
 Postviral infections
lymphoma
 Other tumors
 Paroxysmal cold

hemoglobinuria
Treatment: Autoimmune
hemolytic anemia
 Glucocorticoids: Prednisone
 Splenectomy
 Immunosuppressive drugs
 Blood transfusion for severe
anemia
Case 1-04-01
 48 year old male farmer with
progressive weakness and pallor
 no jaundice nor
hepatosplenomegaly
petechiae noted on both L.E.’s
Case 1-04
 CBC:
Hb:7 gm/dl Hct:
21
WBC: 3,000
lymph: 48%
segs:
52%
Platelet count:
80,000
 Reticulocyte
Count:5 x 10-3
Interpretation?
 Pancytopenia (anemia, leukopenia,
thrombocytopenia)
 Reticulocyte index low
 Peripheral smear: normocytic,
slightly hypochromic RBC,
leukopenia, platelets nil

 Bone marrow failure


Back to algorithm
Case 1-04-01
 What examination will establish
the diagnosis in this case?
Diagnosis of hypoproliferative anemias
Tests Iron Inflammatio Renal Hypometaboli
deficiency n disease c states
anemia Mild- mild Mild- mild
severe severe
MCV (fl) 70-90 80-90 90 90
morpholog Normo- normo normo normo
y micro
Serum Iron <30 <50 normal normal
TIBC >360 <300 normal normal
Saturation <10 10-20 normal normal
%
Serum <15 30-200 115-150 normal
ferritin
Iron stores 0 2-4+ 1-4+ normal

Adamson, J in Harrison’s Principles of Internal Medicine, 15


th
ed., 2001
Back to Case 1-04-01
Bone marrow examination

 Bone marrow
aspiration
 Smear for

morphology
 Flow cytometry

 Cytogenetics

 Bone marrow
biopsy
 cellularity
Normal bone marrow

Fatty marrow: Aplastic anemia


Classification of Aplastic Anemia
 Acquired  Inherited
 Secondary  Fanconi’s anemia

 Radiation  Dyskeratosis congenita

 Drugs/chemicals  Shwachman-Diamond

 Viruses syndrome
 Reticular dysgenesis
• EBV
 Amegakaryocytic
• Hepatitis (non-A,
non-B, non-C) thrombocytopenia
 Familial aplastic
• Parvovirus B19
• HIV1 anemias
 Immune diseases

• Eosinophilic
fascitis
• Hypoimmunoglob
ulinemia
• Thymoma/thymic
ca
• GVHD
 PNH

 Pregnancy

 Idiopathic
Treatment: Aplastic
Anemia
 Treatment of identifiable cause
 Supportive care
 Blood component therapy

 Treatment of infections

 Severe acquired AA:


 Stem cell transplantation

 Immunosuppression

 ALG or ATG + cyclosporine

 Moderate
 Androgens
Summary
 History and Physical examination are essential in the
assessment of a patient who may have anemia
 CBC, done and reported correctly is an important tool in
anemia
 Confirms presence of anemia

 Clues to the type and possible etiology of anemia

 Additional tests indicated depending on type of anemia


 Bone marrow examination

 Iron studies

 Hemoglobin electrophoresis

 Blood chemistries

 Vitamin levels: B12, folic acid

 Coomb’s test

 Others

 Treatment depends on the cause


Acknowledgements:
This presentation has been the
collective effort of the following
members of the staff of the
Section:
 Gina V. Panuncialman, MD
 Priscilla B. Caguioa, MD
 Irene D. Castillo, MD