ERYTHROCYTE DISORDERS

MORPHOLOGIC CLASSIFICATION OF ANEMIA

I.

NORMOCYTIC, NORMOCHROMIC
1. Aplastic Anemia
- Classification:
a. Primary
- Fanconi Anemia
Microencephaly, brown skin pigmentation, short stature, malformations of the thumbs, crossed eyes,
malformations of the kidney, genital hypoplasia and mental retardation
Anisocytosis and poikilocytosis (Target cells with nRBC and immature WBC)
Marked increase in Hb F and a decrease in Hb A
Increased OFT and ESR
a.
b. Secondary
o Drugs and Chemicals
- Chloramphenicol: classic drug associated with aplastic anemia
- Benzene and its derivatives, hydantoins, sulfonamides and gold preparations
- Insecticides (chlordane, chlorophenothane and Lindane)
o Radiation
- Individuals exposed to long-term, low-dose radiation
- Radiation may damage the stem cells or hematopoietic microenvironment
o Others
- Viral infections
- Non-A, non-B hepatitis
- Miliary tuberculosis
- Brucellosis
- Parasites
- Paroxysmal nocturnal hemoglobinuria (PNH)
b.
o Clinical Presentation
- Related to pancytopenia
- If anemia is severe: pallor, weakness and easy fatigability
- Decreased neutrophils due to increased incidence of bacterial infections
- Hemorrhage due to thrombocytopenia
c.
o Laboratory Findings
- BONE MARROW: <25% of normal or 50% of normal cellularity with <30% hematopoietic cells
- PERIPHERAL BLOOD
Granulocytes
<0.5x109/L
Platelets
<20x109/L
Anemia with
<1% reticulocytes
- Bleeding time and CRT: abnormal
- SPECIAL TEST
Hb F is elevated in some patients
LAP scores are increased
Ham acid-serum test may be positive
- CHEMISTRY
Serum iron is elevated and iron binding protein is saturated
Erythropoietin is normal or elevated
d.
o Treatment:
RBC transfusions to maintain a minimum hemoglobin level
Platelet transfusion if necessary

2.

Pure Red Cell Aplasia

o Congenital Hypoplastic Anemia/ Diamond-Blackfan Syndrome
- Seen during the first 2-3 months of life (pallor, hepatomegaly and splenomegaly)
- Hb: 2-10 g/dL
- Reticulocytes are decreased to absent
- Corticosteroid therapy
-

Acute Acquired Erythropoietic Hypoplasia

Erythroblasts in the bone marrow will disappear and anemia will develop if this condition persists for a long time

Chronic Acquired Erythrocytic Aplasia

Reticulocytes are decreased to absent
Serum iron level is increased
Iron binding capacity is saturated

o
o

3.

CONGENITAL DYSERYTHROPOIETIC ANEMIAS

- Types:
a. Type I
- Mildly macrocytic anemia with marked anisocytosis and poikilocytosis
- Cabot rings and basophilic stippling are present
- Splenomegaly is present
b. Type II
- HEMPAS
- Hepatosplenomegaly is generally present; jaundice may or may not occur
- Normocytic anemia with anisocytosis, poikilocytosis and basophilic stippling
- RBC display hemolysis in the acid serum test
- Cells contain blood group antigen I
c. Type III: normocytic to slightly macrocytic anemia

Hemolytic Anemia
o Enzyme Deficiency
a. G-6-PD Deficiency
- Lab:
Acute hemolysis is followed by a sudden decrease in Hb concentration (3-4g/dL below the reference range)
Bite cells are seen
Increased plasma hemoglobin and serum bilirubin levels, decreased serum haptoglobin level, hemoglobinuria,
hemosiderinuria, increased urinary and fecal urobilinogen
b. PK Deficiency
- Most common cause of nonspherocytic hemolytic anemia
- Decreased lifespan of RBC due to lack of ATP
- Red cells are removed from the circulation extravascularly by the spleen and liver
c. Pyrimidine-5-Nucleotidase (PN) Deficiency
- Accumulation of pyrimidine nucleotides degraded from RNA in the reticulocyte
d. Glucose-Phosphate Isomerase Deficiency
- Abnormality in the anaerobic glycolysis
- Third most common RBC enzyme deficiency
o

Membrane Defect
a. Hereditary Spherocytosis
- Characterized by numerous microspherocytic erythrocytes on blood film
- Defect in the red cell membrane protein involving spectrin
- MCHC is >36%; MCV 77-87 fL
- Hb above 10g/dL (adults); 8-11g/dL (infants and young children)
- Lab:
CBC with MCH
PBS
OFT
Reticulocyte count
Occasionally required: Autohemolysis test, DAT, Serum bilirubin, serum haptoglobin
Rarely required: BM exam

b. Hereditary Elliptocytosis
- Hb: >12g/dL
- Reticulocyte count <4%
- Types:
Common HE
- Most prevalent form
- Typical HE red cell morphology
- Hemolysis ranges from nonexistent to moderate
Spherocytic HE
- 10-20% cases
- Significant amount of rounded elliptocytes and spherocytes
Stomatocytic HE
- Rare
c.
-

Hereditary Pyropoikilocytosis
Fragments, spherocytes, elliptocytes and other bizarre-shaped cells
MCV between 25 to 55 fL
Hb is decreased in proportion to the degree of hemolysis
Reticulocyte count is elevated, RPI depends on the ability of the patients BM to respond to anemia
Increased OFT and markedly elevated autohemolysis test result

d. Hereditary Stomatocytosis
- Hb rarely not less than 8 to 10 g/dL
- Reticulocytosis is moderate (10-20%)
- MCV increased in both conditions
- MCHC decreased in stomatocytosis and increased in xerocytosis
- 10-50% circulate as stomatocytes
- Target cells predominate in hereditary xerocytosis
- OFT is increased when stomatocytes persist
- OFT is decreased when target cells of xerocytosis predominate
- Autohemolysis is increased
- Tx: splenectomy except for hereditary xerocytosis
e.
-

Abetalipoproteinemia (Basse-Kornsweig Syndrome)

Decreased cholesterol level
Acanthocytes of the red cells, retinitis pigmentosa and neurologic damage
OFT is normal or slightly decreased and autohemolysis is increased

Lecithin-Cholesterol Acyltransferase Deficiency

Prominent target cell formation results from increased red cell membrane cholesterol
Hemolysis and decreased erythropoiesis

f.

Antibody Mediated
a. Autoimmune Hemolytic Anemia
Warm-Antibody Autoimmune Hemolytic Anemia
- Weakness, acute fever, pain, hemoglobinuria, mild jaundice, splenomegaly, hepatomegaly and lymphadenopathy
- Blood smear shows anisocytosis , polychromatophilia, spherocytosis, some macrocytosis and nucleated red cells
- Reticulocytosis is evident
- DAT is positive (confirming the presence of IgG antibodies)
- Autohemolysis is increased and OFT will be increased
-

Cold-Antibody Autoimmune Hemolytic Anemia

May occur in association with infection, lymphoproliferative disorders, malignancy or autoimmune disorders
Complication of Mycoplasma pneumoniae infection and infectious mononucleosis
Blood film shows polychromatophilia, spherocytosis, and agglutination of red cells

Drug-Induced
Penicillin, stibophen, quinidine, sulfonamides, cephalosporin and alpha-methyldopa

b. Paroxysmal Cold Hemoglobinuria

- After cold exposure, the patient may present with headache, vomiting, pain in the abdomen and extremities,
severe chills, fever and hemoglobinuria
- Mild jaundice, splenomegaly and hepatomegaly may be seen
- Decreased Hb
- Spherocytes, fragmented RBC and polychromasia
- Reticulocyte count is increased
Warm AIHA
37OC

Cold AIHA
0-4OC

20-37 OC
IgG

0-32 OC
IgM

Antibody type
Mechanism of Ab prod

Incomplete
Immune response

Complement activation
Protein structure
Blood group specificity
1O mechanism of RBC
destruction
Severity of disease
Treatment

May bind C`
Polyclonal
Rh, Kell
Extravascular (splenic)

Agglutinin
Naturally occurring and
immune response
Binds C`
Monoclonal/polyclonal
Ii
Extravascular (hepatic)

Optimal reaction
temperature
Thermal amplitude
Immunoglobulin type

Transfusion requirements
c.

Severe
Steroids, splenectomy,
immunosuppressants
Contraindicated

PCH
0-4OC (Ab binds to cell)
37OC (hemolysis takes place)
<15 OC
IgG (Donath-Landsteiner
Autoantibody)
Hemolysin
Immune response
Binds C`
Polyclonal
Pp
Intravascular

Mild
Avoid cold

Distinct episodes of severity

Avoid cold

Rarely needed

Could be required

Microangiopathic/Traumatic Hemolytic Anemia (MAHA)

Associated with TTP, HUS, DIC, abnormalities of blood vessel structure like hemangioma and abnormalities of
blood vessels secondary to hypertension
- Peripheral blood smear shows a large number of schistocytes, irregular contraction of red cells and decreased to low
normal platelet count
-

d. Paroxysmal Nocturnal Hemoglobinuria (PNH)

- Abnormality in the erythrocyte membrane
- Platelet and WBC counts usually decreased; reticulocyte count is elevated
- Diagnosis is confirmed by acid serum test and sugar water test
- No specific treatment
e.
f.
g.

Hemolytic Disease of the New Born

Anemia caused by destruction of the infants red cells when a maternal antibody that is specific to an antigen on the
infants red cell crosses the placenta
Hemolytic Transfusion Reaction
Results from the transfusion of red cells with antigens that are foreign to the recipients immune system
Lead Poisoning - Occupational in adults and due to pica (eating inedible materials)

h. Parasitic Infections - Malarial infections and Babesia

i. Hypersplenism

II.

MICROCYTIC, HYPOCHROMIC
1.

Iron-Deficiency Anemia
o Causes:
a. Increased physiologic demand
b. Inadequate intake
c. Chronic blood loss
- Characterized by microcytosis, hypochromia and poikilocytosis
- FEP is increased
- Physical findings:
o Stomatitis
o Glossitis
o Gastritis
- Hematologic findings:
o RPI: below 2.0
o WBC and Reticulocyte count: Normal
o PC: Low, normal or high
o MCV is decreased, RDW is increased
o MCH and MCHC values are decreased
- Treatment: Iron supplements, controlling bleeding or both

2.
3.

Anemia of Chronic Disease

Chronic infections, inflammatory processes and malignant neoplasms
Basic defect is in the iron utilization for erythropoiesis
Anemia is mild to moderate
Tx: Directed at the primary disease

Sideroblastic Anemia
o Types:
a. Hereditary Sideroblastic Anemia
- Sex-linked recessive trait primarily occurring in males
- Laboratory:
Anemia is severe with Hb of 6.0g/dL
Basophilic stippling is observed
Microcytic, hypochromic cells and normocytic, normochromic cells
WBC and PC: normal
BM: erythroid hyperplasia with inadequate or defective hemoglobin synthesis
Ferritin levels, serum iron and transferrin saturation: High
TIBC is normal
- Tx: Pyridoxine, removal of excess iron
b. Primary Idiopathic Sideroblastic Anemia
- Acquired disease found in adults older than 50
- Characterized by abnormal erythropoietic maturation and abnormal iron utilization
- Laboratory:
Moderate anemia (Hb 7-10g/dL; mean Hct: 0.27 L/L)
Dimorphism is evident in PBS
Target cells, schistocytes
10% of patients develop acute leukemia
BM: erythroid hyperplasia; M:E ratio is 1:1 (Normal 3:1 or 4:1)
c.
-

Secondary Sideroblastic Anemia

Caused by toxins, drugs or agents that interfere with heme synthesis
Found in alcoholism, lead poisoning, TB therapy and intake of large amount of chloramphenicol
Laboratory:
Anemia is moderate to severe (Hb: 6-10gdL in alcoholics)
PBS: dimorphic population of RBC

4.

MCV normal or slightly increased

MCHC normal or slightly reduced
Tx: Pyridoxine

Thalassemia
o Beta-Thalassemia
a. Thalassemia Major or Cooleys Anemia
- May be expressed as:
oo Beta chain synthesis is absent
++ Beta chain synthesis is reduced
- Alpha chain production is normal
- Retarded growth with mongoloid appearance
- Microcytic, hypochromic anemia with poikilocytosis and anisocytosis
- Basophilic stippling, increased polychromatophilia, target cells, Howell-Jolly bodies, and siderocytes are common
- Reticulocyte count is increased
- OFT is decreased
b. Thalassemia Minor or Cooleys Trait
- Slight splenomegaly and mild anemia
- Target cells, increased polychromatophilia, basophilic stippling and occasional nRBC
c.
o
-

Thalassemia Intermedia
Mildest form of homozygous beta thalassemia

Alpha Thalassemia
Reduced or abnormal alpha chain synthesis
Accumulation of excess gamma chains in fetal life to form hemoglobin Barts and excess beta chains to form
hemoglobin H

III. MACROCYTIC, NORMOCHROMIC

Megaloblastic Anemia
o CAUSES:
1. Vitamin B12 Deficiency
- Dietary sources: animal protein
- Transport: mediated by three different binding proteins that are capable of binding the vitamin at its required
physiological concentrations:
a. Intrinsic Factor (IF)/ Castles Factor
b. Transcobalamin II (TC II)
c. R Proteins
- Deficiency:
a. Increased utilization of vitamin B12
b. Malabsorption syndrome
c. Nutritional deficiency or diminished supply of vitamin B12
d. Medications
e. Impaired utilization
f. Increased demand
g. Pernicious anemia
e.
PERNICIOUS ANEMIA
- Most common in patients above 60 years
- Megaloblastic madness: hallucinations, maniacal outbursts, paranoia and schizophrenia
- Lab:
MCV is over 100 fL
Pancytopenia
Basophilic stippling, Howell-Jolly bodies and nucleated rbc exhibiting karyorrhexis
Hypersegmented of neutrophils
BM: hypercellular with erythroid hyperplasia; M:E ratio 1:1 to 1:3
Schilling Test

2.
-

3.

Provides a measure of the bodys ability to secret viable IF and absorb orally administered radioactive
vitamin B12 (radioactive Cobalt tag)

Other conditions due to vitamin B12 deficiency:

Blind Loop Syndrome
- Disease of the small intestines
Imerslunds Syndrome
- Inherited autosomal recessive trait
- Manifested during the first 2 years of life
- Inability in absorbing vitamin B12
Zollinger-Ellison Syndrome
- Impaired vitamin B12 absorption without megaloblastic anemia
- Hypersecretion of the gastric juice resulting to low pH
Crohns Disease
- Regional enteritis or inflammatory bowel disease
- Affects lower ileum producing vitamin B12 malabsorption and megaloblastic anemia

Folic Acid Deficiency

Causes:
a. Dietary deficiency
b. Alcoholic cirrhosis
c. Pregnancy
d. Infant malnutrition
e. Folate antagonists

Conditions that cause both B12 and Folate deficiency

Tropical Sprue and gluten-sensitive enteropathy
- Weight loss, steatorrhea, weakness
- Tropical Sprue
Affects the entire small intestine
Caused by some infectious agents
- Gluten-sensitive Enteropathy
Childhood celiac disease: anemia is due to IDA
Adult nontropical sprue: folate malabsorption and deficiency