ANEMIA – term used to denote conditions
associated with DECREASED RED CELLS
Can be the result of:
 Absolute BM failure
 Prematurely destroyed (hemolysis)
Polycythemia Vera & Erythrocytosis – Increased
RBC in the circulation
4 GROUPS OF ANEMIA
a. Hypoproliferative – decreased marrow
stimulation
b. Maturation disorders – abnormal nuclear
development
c. Hemolytic disorder
d. Blood loss
3 CLASSIFICATIONS OF ANEMIA
1. Etiological classification - focuses on the
principal underlying pathophysiologic
mechanism; most difficult means to
classify anemia because of associations
with multiple factors causing the
pathology.
2. Morphologic classification- classification
based on the BLOOD CELL INDICES (MCV,
MCH, MCHC) & RDW; e.g. N/N, M/H,
Macro/Hypochromic
NORMOCYTIC – Normal MCV
 Acute Post Hemorrhagic Anemia
 Hemolytic Anemia
 Aplastic Anemia
MICROCYTIC – MCV <80 fL
- Shortage in hemoglobin
 Anemia of Chronic disease
 Thalassemia (Normal RDW)
 Iron deficiency anemia (Inc RDW)
MACROCYTIC – MVC >100 fL
- Shortage in DNA precursor
 Megaloblastic anemia – Vit. B12
(Cobalamin deficiency) & Folic acid
deficiency
RDW
Red Cell Distribution width provides a
measure of red cell size variation it is an
index of red cell population heterogeneity
and can reflect anisocytosis of PBS.
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 HYPOPROLIFERATIVE
I. APLASTIC ANEMIA
- PANCYTOPENIA (decreased in ALL
CELL CONSTITUENTS)
- BM is severely hypoplastic/aplastic
- No IMMATURE MYELOID cells in the
peripheral blood (wherein
hematopoietic cells are replaced by
fat) and lack of splenomegaly---- helps
differentiate aplastic anemia from a
number of pancytopenic conditions.
- Lack of SPLENOMEGALY
- Incidence rate: 50 y/o and above
i. PRIMARY APLASTIC ANEMIA
a. CONGENITAL APLASTIC ANEMIA
(FANCONI’S ANEMIA)
- It is a rare, inherited form of aplastic
anemia first reported from three
brothers by Fanconi.
- It is defined as a PANCYTOPENIC
disorder with HYPOPLASTIC TO
APLASTIC BM.
CLINICAL PRESENTATION
1. Microencephaly (ABNORMALLY SMALL
BRAIN)
2. Brown skin pigmentation
3. Short stature
4. Malformations of thumb
5. Internal strabismus (CROSSED EYES)
6. Malformation of the kidneys
7. Genital hypoplasia
8. Mental retardation
LABORATORY FINDINGS
 Increased RDW – Marked anisocytosis and
poikilocytosis
 Marked increased HbF
 Marked decreased HbA
 Increased OFT – test for the membrane of
RBC
 Increased ESR – based on the shape and
size of RBC; Abormal RBC = inc.
sedimentation rate
TREATMENT
o Use of ANDROGENS accompanied with
CORTICOSTEROIDS--- this helps stimulate
erythropoiesis and maintains reasonable
level of hemoglobin.
 o Bone marrow transplant--- possible II. PURE RED CELL APLASIA
treatment but makes patient vulnerable - Decrease production of ERYTHROID CELLS
to malignant diseases. ONLY
b. DYSKERATOSIS CONGENITA a. ACQUIRED PRCA
- A rare, inherited BM failure syndrome i) PRIMARY – Idiopathic or Immune
- Characterized by mucocutaneous, ii) SECONDARY
abnormalities (albinism), bone b. DIAMOND-BLACKFAN ANEMIA
marrow failure (hypoplasia and - Aka CONGENITAL HYPOLASTIC
pancytopenia ANEMIA or CONGENITAL PRCA
- Erythroid cells are unresponsive to
ii. SECONDARY APLASTIC ANEMIA EPO
- Due to drugs, chemicals , radiation, - Caused by sensitized lymphocytes
immune mechanism (autoantibody) that are capable of
producing abnormal antibodies
DRUGS CHEMICALS CLINICAL PRESENTATION:
Chloramphenicol Chlordane
1. Retarded growth
Benzene Chlorophenotane
2. Bone age retardation
Benzene derivatives Gamma benzene
Osteoporosis
Sulfonamides hexachloride
3. Failure of second sexual maturation
(Lindane)
4. Hemosiderosis – accumulation of iron in
Gold preparation BLOOD &TISSUES
Chloramphenicol
**PALLOR may be evident at birth and is almost
- is a classic drug associated with marrow always evident at the age of 1
aplasia.
LAB FINDINGS:
- BM of patients who were overexposed
 N/N
with this drug presents vacuolated cells in
 Leukocyte & PC ct are NORMAL
the BM particularly the cells of the
 RETIC CT & RPI EXTREMELY LOW –
erythroid series.
indicating poor erythropoietic response to
LAB FINDINGS: the anemia
PBS  Inc EPO
 Inc HbF
 Normocytic, normochromic – normal MCV  Dec Hb
 Leukopenia
 Thrombocytopenia TREATMENT

BM o PRBC transfusion every 3-6 weeks

o BM transplantation – is seen as only a
 Hypoplastic/aplastic – more of yellow POTENTIAL CURATIVE THERAPY. But
marrow patients who undergone this treatment
 Inc. fat content progress to complications secondary to
 Dec hematopoietic count hemosiderosis
Special Hematology
 RETIC CT and RPI DECREASED
 Inc HbF
 Inc LAP score
 Inc Serum Fe
 + Ham acid serum test – also OFT

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 FANCONI’S DIAMOND IV. ANEMIA OF SYSTEMIC DISORDER OR
ANEMIA BLACKFAN DECREASED MARROW STIMULATION
Classification Aplastic Pure red cell - Systemic disorders that can be associated
anemia aplasia with anemia wherein all of these are
Brown skin Common Uncommon effect of insufficient EPO for the
pigmentation stimulation of RBC production
Thumb Common Uncommon
abnormalities a. ANEMIA OF CHRONIC RENAL FAILURE
Renal Common Uncommon - Related to accumulation of metabolic
abnormalities wastes and decreased EPO
Onset 5-10yo <1 yo LAB FINDINGS:
BM biopsy Hypoplastic- Cellular
 Dec EPO
Aplastic
 Dec Serum Fe and Dec TIBC
BM aspirate Pancytopenia Marked dec in
 Dec HCT
erythroid cells
 Inc serum BUN
Peripheral Pancytopenia Dec RBC, Norm
 Inc CREATININE levels
Blood WBC&PC
 SOME acanthocytes/spurr cells
 + echinocytes/burr cells
III. MYELOPHTHISIC ANEMIA  N/N
- Refers to invasion of abnormal cells  NORMAL RETIC
- Common in patients with metastatic TREATMENT:
carcinoma
- Considered as chronic form wherein the o Dialysis to improve erythropoiesis
BM of the patient is replaced by o Renal transplant
abnormal/malignant cells o Recombinant Human Erythropoietin (r-
- Anemia that is associated with BM HuEPO) administration
infiltration & hypoproliferation by non-
erythroid cells b. ANEMIA OF ENDOCRINE DISORDER
- Interchangeable with i) HYPOTHYROIDISM
LEUKOERYTHROBLASTIC REACTION – - Body’s metabolic rate is decreased thus
presence of NRBC and immature there is decreased oxygen demand
leukocytes in the peripheral blood but LAB FINDINGS:
patient does not present anemia; poor
 Presence of MACROCYTES
prognosis
 Presence of ACANTHOCYTES/SPURR CELLS
CAUSE OF MA:  No shift to the right
 Metastatic carcinoma ii) HYPOPITUITARISM
- Patients have decreased metabolic
 Multiple myeloma
demands
 Leukemia
- N/N
 Lymphoma
iii) ADRENAL DISORDER
 Lipidoses of storage disease
- As seen in Addison’s disease
iv) HYPOGONADISM
LAB FINDINGS: - Decreased androgen that will stimulate
erythropoiesis
 Inc NRBC c. ANEMIA OF PREGNANCY
 Granulocytic shift to the left – most of the - Most often a result of IDA due to
premature cells present are BANDS, increased iron demand
METAMYLOCYTES AND MYELOCYTES - It is not a systemic disorder but is a
systemic condition

3
  MATURATION DISORDER
- Abnormal nuclear development
- Characteristic pf changes in overall cell
size, shape, color and presence of
chromatin clumping – DNA & RNA
remnants
I. MEGALOBLASTIC ANEMIA
- Caused by Vit b12 or Folate deficiency –
essential in maturation of RBC
- Accompanied with NEUTROPENIA and/or
THROBOCYTOPENIA
- Dyserythropoiesis (abnormal RBC prod)
and Pancytopenia
LAB FINDINGS:
 MACROOVALOCYTES – narrow oval
cells with normal central pallor
 BASOPHILIC STIPPLING
 HOWELL-JOLLY BODIES – RNA
remnants found in severe hemolysis,
leukemia,Hgbnopathies splenectomy;
presence may indicate RAPID BLOOD
REGENERATION
 MACROPOLOCYTES – hypersegmented
neutrophils
 CABOT RINGS (rare)
a. VITAMIN B12/COBALAMIN
DEFICIENCY
VITAMIN B12
- It is the only vitamins that can be
DIAGNOSIS OF COBALAMIN DEFICIENCY:
synthesized by microorganisms and is
found practically in all animal tissues.
- Sources: MEAT, EGG, FISH, MILK
- It is related to DNA synthesis since it is a
cofactor needed in the conversion of
methyl tetrahydrofolate to
tetrahydrofolate.
- It is an important substrate needed for
the synthesis of thymidine which is a DNA
base
- Normal serum value: 200-900 ng/Dl
- If vitamin B12 intake stopped, total body
stores may last for several years (10-20
years) before megaloblastic anemia could
occur.
4
CAUSES OF VIT. B12 DEF:
1. Inadequate intake- seen in patients who
completely abstain from animal food
including milks and eggs; seen in patients
who are strict vegetarians
2. Defective Production of IF- this is the
most common cause cobalamin def. IF is
released by the parietal cells of the
stomach. It binds/protect vit b12 that has
been released from the food intake so
that it will be absorbed in the ileum.
TRANSCOBALAMIN II- transport protein of
cobalamin
3. Pernicious Anemia- a hereditary condition
wherein the stomach lining becomes
atrophied resulting to inability to secrete
IF; common in person older than 40 y/o;
beefy red tongue
4. Gastrectomy- surgical removal of
stomach, removes the source of IF
5. Intestinal Malabsorption or defective
absorption of cobalamin seen the
following cases:
 Crohn’s Disease- disease that affects
the ileum; also known as the regional
enteritis
 Fish tapeworm Infection-
Diphyllobothrium latum infection; D.
latum competes with the absorption of vit
B12
 Imerslund Grasbeck Syndrome- defective
ileal receptors
1. Therapeutic trial- parenteral
administration of a physiologic dose of
cobalamin to patient
2. Serum Cobalamin Assay- mirobiological
assay (reference method) that employs
Euglena gracilis or Lactobacillus
leichmanni
3. Methymalonic and Homocysteine Acid
Excretion test – urine sample; product of
propionate catabolism inhibited in the
presence of cyanocobalamin
4. Deoxyuridine Suppression Test –
measures the degree to which the
patient’s plasma suppresses uptake of
radioactive thymidine into the DNA and
 BM cells in the culture; (+) DNA takes up
excess radioactive thymidine
5. Radioimmunoassay- most sensitive
method; uses cobalt 57 labeled
cobalamin; specimen can be serum or
EDTA blood
6. Schilling test – measures the body’s ability
to secrete viable intrinsic factor and
absorb orally administered Cobalt 57
labelled vit b12 in the ileum; 24hr urine
sample
b. FOLATE/ FOLIC ACID DEFICIENCY
FOLIC ACID aka Pteroyl Monoglutamic Acid
contains 3 parts: PTERIDINE, P-
AMINOBENZOATE, L- GLUTAMIC ACID
- Sources are: leafy vegetables
- Minimum daily requirement has been set
at 50 mg and the body’s reserve can last
only up to 3 months.
- Storage Site: LIVER- main site for folic acid
- Normal serum values: 5-21 ug/L and RBC
folate: 150-600 ug/L
- Clinical symptoms from inadequate
dietary folate can occur within weeks as
compared with years for vitamin b12
deficiency.
CAUSES OF FOLIC ACID DEFICIENCY
• Dietary/nutritional deficiency- as seen in
malnutrition, meat diet and chronic
alcoholism
• Defective absorption of folate in SI- as
seen in celial disease, non-tropical sprue
and intestinal blind loop syndrome
 Blind loop syndrome- in which bacteria
preferentially utilize folate.
• Increased requirement for folate- as seen
in multiple pregnancy, chronic hemolytic
anemia, malignancy
• Deficiency due to drugs- drugs that
blocks folic acid metabolism like
METHOTREXATE
5
DIAGNOSIS OF FOLIC ACID DEFICIENCY
1. Serum and red cell folate determination-
thru microbiological assay using
Lactobacillus casei
2. Urinary formimino glutamic level
determination
3. Therapeutic trial
4. Deoxyuridine suppression Test
5. Plasma homocysteine Assay
6. Radioimmunoassay- uses Iodine 125
labeled Folate; Specimen: HEMOLYZED
EDTA BLOOD; fasting is required for
folate determination
II. CONGENITAL DYSERYTHROPOIETIC
ANEMIA
- In these types of anemias, normoblast in
the BM shows karyohexis (fragmentation
of the nucleus) and bizarre malformations
due to dyserythropoiesis and
hyperbilirubinemia.
- In these types of anemias, there is
asynchrony of nuclear and cytoplasmic
maturation that results to abnormal or
atypical cell production of RBC
- Bizarre nuclear changes
- WBC and platelets NOT affected
3 TYPES OF CDA
A. TYPE I CDA
- Rare & inherited
- Mildly macrocytic
- Marked anisocytosis and poikilocytosis
- Presence of cabot rings and basophilic
stippling
CABOT RING
- Cytoplasmic inclusion that may appear
looped or assume as a figure of 8
- Indicates abnormal RBC production which
can also be found in pernicious anemia
and lead poisoning
B. TYPE II CDA (Hereditary Erythroblastic
Multinuclearity with Positive Acidified
Serum Test)
- Most common
- Normocytic anemia
- BM shows multinuclearity of normoblast
with no megaloblastic change
- RBC shows hemolysis on acid serum test
- RBC’s contain the blood group antigen “I”
C. TYPE III
- Rare and inherited
- Normocytic to slightly macrocytic anemia
- BM shows as many as 30& multinucleated
RBC
ANEMIA OF ABNORMAL IRON METABOLISM
I. IRON DEFICIENCY ANEMIA
- Iron and its metabolism are important to
the body because a hemoglobin molecule
is non-functional without iron and 2/3 or
more of the total body iron is in the RBCs
and their precursors.
FACTS:
1. 1 ml of RBC contains 1 mg of iron
2. Storage iron is present in macrophage and
normoblast in two forms (ferritin and
hemosiderin)
3. Majority of iron used in hemoglobin
synthesis is from iron released and
recycled by Hb that is degraded in
macrophages and transported to
normoblast by plasma ”transferrin”
4. 0.9-1.3 mg of iron is lost from the body
per day
5. Small amount of iron is lost from the body
per day and is maintained by dietary
absorption
6. Dietary iron is digested in the ferric form
but is reduced by HCl and food in the
stomach into the ferrous form
7. Once in the mucosal cells of the
duodenum, ferrous is oxidized again into
ferric state and binds with protein
apoferritin to form Ferritin. The serum
Ferritin concentration is 15-200 ng/mL
while normal TIBC of ferritin id 250-400
mg/dL
THE DEVELOPMENT OF IDA OCCURS IN 3
STAGES:
1. Iron depletion stage- the beginning of iron
deficiency, when iron loss exceeds
absoprtion, when iron is utilized by RBC at
a faster rate (as seen during infancy or
bleeding), when dietary absorption is not
sufficient to keep up to the increased
demand.
2. Iron deficient erythropoiesis stage- occurs
when tissue iron stores are depleted.
Utilization of stored iron, anemia is not
6
yet present, anemia at this stage is still
N/N
3. IDA stage- when the deficiency becomes
critically detectable.
IDA OCCURS WHEN:
1. There is an excessive loss of blood thereby
reducing the body’s reserves of iron GI or
uterine hemorrhage
 Hookworm infection
 Excessive menstruation
 Multiple pregnancy
2. There is an increase need for iron Growth
in infancy, childhood, adolescence
Women of childbearing age
** Note that adult male has no increase
demand for iron and could live without
dietary iron for approx. 3-4 years before IDA
could manifest. When IDA is found in men, it
is an indication that IDA is due to chronic
blood loss.
3. Inadequate iron intake Milk fed infants
4. There is a decreased iron absorption
Gastric, celiac or Crohn’s disease*
*CROHN’S DISEASE- it is an inflammatory
bowel disease.
CLINICAL MANIFESTATIONS:
1. Parasthesias (numbness, tingling)
2. Atrophy of the epithelium of the tongue
with soreness
3. Angular cheilosis (cracks or ulcers at the
corner of the mouth)
4. PICA (abnormal craving for unusual
substances like ice)
5. Concave or spoon shaped nails
6. Difficulty in swallowing
7. Chronic gastritis
LAB FINDINGS
 Microcytic/Hypochromic
 Marked anisocytosis and poikilocytosis
 DEC: MCV, HGB, HCT, RBC CT
 DEC OFT
 DEC SERUM FE, INC TIBC
II. SIDEROBLASTIC ANEMIA
- Disorder of iron excess DUE TO A DEFECT
IN HEME SYNTHESIS
- Now classified as one of the 5 MDS
(Myelodysplastic syndrome)
- May be inherited or acquired
- The defect in heme synthesis may occur
as a result of decreased activity of the
enzyme ALA SYNTHETASE
TYPES OF SIDEROBLASTIC ANEMIA
A. HEREDITARY SIDEROBLASTIC ANEMIA
- Inherited type THAT OCCURS PRIMARY IN
MALE POPULATION
- Usually manifests during adolescence
- Anemia is usually severe with very low Hct
level
- Dimorphic RBC population- HAS N/N AND
MICROCYTIC HYPOCHROMIC
MORPHOLOGICAL CHARACTERISTIC
- Moderate aniso and poikilocytosis
- Target cells and basophillic stippling is
usually present
- TARGET CELLS- leptocytes, mexican hat
cell, RBCs with bull’s eye appearance
- Seen in Chronic liver disease, thalassemia,
post splenectomy, Hgb C and E disease
- BASOPHILIC STIPPLING- probably remnant
of RNA, RBC inclusions
- appearing as fine-coarse gray-black
granules seen in conditions with:
- Accelerated erythropoiesis, toxic anemia,
hemolytic anemia, leukemina,
thalassemia, Pb poisoning, other
congenital forms of anemia.
- WBC and PC are normal
- BM iron stores and serum ferritin:
MARKEDLY INCREASED
B. PRIMARY IDIOPATHIC SIDEROBLASTIC
ANEMIA
- More common than HAS, AN ACQUIRED
DISEASE FOUND IN ADULTS OVER 50 Y/O
- Moderate anemia with Hct of 25-30%
- 10% of patient may develop acute
leukemia TREATMENT: transfusion ONLY
IF ANEMIA IS Severe
7
LAB FINDINGS:
 Not dimorphic- RBCs are usually
NORMOCYTIC to SLIGHTLY MACROCYTIC
although you may also observe some
micro/hypo rbc
 WBC AND PC are normal
 BM: erythroid hyperplasia with large
number of ringed SIDEROBLAST
** SIDEROCYTE: Non-nucleated rbc with small
blue dots in the cytoplasm
** SIDEROBLAST: NUCLEATED RBC with small
blue dots in the cytoplasm
** RINGED SIDEROBLAST: NUCLEATED RBC with
blue dots ringing the nucleus
C. SECONDARY SIDEROBLASTIC ANEMIA
- Caused by agents that can inhibit or
interfere with heme synthesis.
- May be found in alcoholism, Pb poisoning,
TB therapy and intake or Chloramphenicol
in large dose
- Reversible, withdrawal of drug results in
correction of the anemia.
III. HEMOCHROMATOSIS
- Rare and inherited disease caused by a
disorder in iron absorption wherein excess
iron which was not reabsorbed by the
body are deposited in the tissues of
pancreas, liver and spleen
Hemochromatosis- accumulation of iron in
parenchymal liver cells
HEMOSIDEROSIS- accumulation of iron in
BLOOD & TISSUES
CLINICAL MANIFESTATIONS
1. PATIENTS SHOW Hepatolomegaly
2. Bronze color skin pigmentation - FROM
MELANIN DEPOSITS IN SKIN WHICH HAS
BEEN EXPOSED TO SUNLIGHT
3. About 50% of cases are DM patients,
THAT’SWHY IT IS ALSO REFERRED TO AS
“BRONZE DIABETES”
4. Cardiac abnormalities
LAB FINDINGS:
 Inc serum Fe
 Slightly dec serum transferrin
 NORMAL HB HCT and PBS

** SIDEROBLASTIC ANEMIAS and

HEMOCHROMATOSIS are types of anemia
resulting to iron overload
NOTE:
Other causes of iron overload:
1. Increased number of transfusion
2. Association of chronic anemias like
thalassemia major

IV. ANEMIA OF CHRONIC DISEASE

- Chronic infections, inflammatory,
malignant disorders
- DECREASED Fe release from storage in
macrophages
- DECREASED BM survival - hypoplastic
- DECREASED RBC survival
LAB FINDINGS:
 Can be N/N or MICRO/HYPO
 DEC RPI, TIBC, Fe
 NORMAL/dec Transferrin saturation
 INC ferritin