ANEMIAS

and LEUKEMIAS 1

ANEMIA

MICROCYTIC, HYPOCHROMIC ANEMIA

Hypochromic Anemia
Causes
o Disorders of iron metabolism and utilization

1. Iron deficiency
- Indices and features:
o Clinical
Onset of IDA is insidious occurring over a period of months to years
Early stages show no clinical manifestation but as anemia develops, clinical symptoms appear
Koilonychia (concavity of the nails)
Glossitis
Pharyngeal webs
Muscle dysfunction
Inability to regulate body temperature when cold or stressed
Gastritis
Pica (unusual craving for ingesting unnatural items)
o Morphological
Hypochromic, microcytic RBC
Mild to moderate anisopoikilocytosis (target cells, elliptocytes, dacryocytes)
Decreased storage iron
Decreased sideroblasts
Absent ringed sideroblasts
o Laboratory
Decreased serum iron
Decreased serum ferritin
Decreased % transferrin saturation
Increased TIBC
Increased FEP
Increased serum soluble transferrin receptor levels

2. Chronic disease states

- Indices and features
o Clinical
Anemia is present for several months following development of a chronic disease state
o Morphological
Usually normocytic RBCs (normal MCV)
Maybe hypochromic or normochromic
Normal number of bone marrow erythrocytic precursors
Increase storage iron
Decreased sideroblasts
Rare to absent ringed sideroblasts
o Laboratory
Decreased serum iron
Decreased TIBC
Decreased % transferrin saturation
Normal to increased serum ferritin levels
Normal serum soluble transferrin receptor levels
 ANEMIAS and LEUKEMIAS 2

o Disorders of heme synthesis
Sideroblastic anemia

1. Hereditary sideroblastic anemia

- Most common form of hereditary SA is sex linked and due to an abnormal delta aminolevulinic acid synthase
(ALAS)
- Anemia appear early, usually within the first few months or years of life
- PBS: Microcytic, hypochromic RBC; dimorphic populations RBCs are seen with prominent
anisopoikilocytosis
- Serum iron, ferritin, transferrin saturation and FEP are increased
- TIBC may be normal or decreased
- Serum soluble transferrin receptor levels are normal or decreased
- Increased storage iron and ringed sideroblasts are seen within the bone marrow after Prussian blue staining
- Treatment: Pyridoxine therapy; rarely bone marrow transplantation

2. Acquired sideroblastic anemia

- Categorized as:
a. Refractory anemia with ringed sideroblasts (RARS)/ Idiopathic acquired sideroblastic anemia
(IASA)
- Affected individuals are usually older than 50 years of age
- Weakness, pallor fatigue associated with anemia
- Morphological:
Dimorphic RBC population with prominent hypochromic component
Anisopoikilocytosis of RBC, associated with basophilic stippling
Hypercellular bone marrow with erythroid hyperplasia
More than 15% ringed sideroblasts

b. Secondary to drugs or toxins: Toxins including lead, alcohol and drugs

- Anemia is moderate to severe
- Dimorphic population of RBC
- Tx: Pyridoxine

Porphyrias

MACROCYTIC, NORMOCHROMIC ANEMIA

Megaloblastic Anemia
- Clinical features:
o Bone marrow:
Hypercellular
Low M:E ratio
Megaloblasts
Giant bands and metamyelocytes
o Peripheral blood:
Pancytopenia
Macro-ovalocytes
Hypersegmented neutrophils
o Biochemical changes:
Elevated LDH
Elevated indirect bilirubin
Increased serum iron and ferritin
Increased erythropoietin
 ANEMIAS and LEUKEMIAS 3

Etiology
1. Vitamin B12 Deficiency
- Sources: Produced by microorganisms and fungi; present in foods of animal origin such as liver, fish, poultry,
meat, eggs, and dairy products; Liver
- Causes of Vitamin B12 Deficiency
o Dietary: Strict vegans
o Malabsorption: major cause of vitamin B12 deficiency
Pernicious anemia
- Most common cause of vitamin B12 deficiency
- Chronic disease caused by a deficiency in the IF due to gastric parietal atrophy (associated with a decrease
in other gastric juices)
- Achlorhydria: reduction of HCl due to gastric atrophy
- More common after the age of 50/60
- Clinical manifestations:
o Fever, loss of appetite
o Glossitis
o Weakness
o BM: Megaloblastic, PBS: macro-ovalocytes
o Megaloblastic madness: hallucinations, maniacal outbursts, paranoia, schizophrenia

Gastrectomy (total or partial): IF-producing cells are removed

Blind loop syndrome: overgrowth of bacteria in the small bowel (bacteria take up vitamin B12 and make it
unavailable for absorption by the ileum)
Fish tapeworm (D. latum): Parasite that competes for vitamin B12 by splitting B12 from IF
Diseases of ileum
Chronic pancreatic disease
o Other disorders
Hemodialysis
HIV infection
AIDS
o Drugs
Alcohol
Nitrous oxide
Para-aminosalicylic acid

2. Folic Acid Deficiency

- Clinical manifestations are the same as vitamin B12 deficiency
- Causes of deficiency:
o Dietary deficiency
- Due to poverty, old age, alcoholism, pregnancy and chronic diseases

o Malabsorption
Tropical Sprue
- An infection that causes intestinal atrophy
- Weakness, weight loss and steatorrhea
- Affects the entire intestine and causes other nutritional deficiencies, including vitamin B12
Gluten-sensitive enteropathy
- Same clinical manifestations as those mentioned in tropical sprue
- Includes both nontropical sprue and childhood celiac disease
- Affected individuals cannot digest gluten, a protein found in wheat and other grains
- Lesions are most severe in the proximal intestine

o Drug-induced folate deficiency

 ANEMIAS and LEUKEMIAS 4

LABORATORY DIAGNOSIS OF MEGALOBLASTIC ANEMIA
Differential diagnosis of vitamin deficiency:
Serum B12 Serum folate Red cell folate
Vitamin B12 deficiency Decreased Increased-normal Decreased-normal
Folate deficiency Normal Decreased Decreased
Vit. B12 and folate Decreased Decreased Decreased
deficiencies

Schilling test
- Definitive test useful in distinguishing cobalamin deficiency due to malabsorption, dietary deficiency or absence of
IF

Corrected by Intrinsic Factor in Part II Not Corrected by Intrinsic Factor in Part II

Pernicious anemia Crohns disease
Abnormal intrinsic factor molecule Tropical sprue
Hereditary intrinsic factor deficiency Celiac disease
Gastrectomy Surgical resection of the ileum
Imerslund-Grsbeck disease
Pancreatic insufficiency
Drugs
Blind loop syndrome
Diverticulitis
D. latum
Transcobalamin deficiency

v Points to consider when interpreting Schilling test

1. Test results are not valid with the presence of renal disease
2. Incomplete collection of urine invalidates the results

NORMOCYTIC, NORMOCHROMIC ANEMIA

APLASTIC ANEMIA
- Classification
a. Primary
- Congenital with no known cause
- Fanconi Anemia
Rare, inherited form of aplastic 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
b. Secondary

- Clinical presentation
o Pancytopenia
o If anemia is severe: pallor, weakness and easy fatigability
o Decreased neutrophils due to increased incidence of bacterial infections
o Hemorrhage due to thrombocytopenia
 ANEMIAS and LEUKEMIAS 5

- Laboratory Findings:
o Hematocrit: 20-25% o Total WBC count: 1.5x109/L
o Hemoglobin: 70g/L o Absolute neutrophil count: 0.5x109/L
o Absolute reticulocyte count: 25x109/L o Platelet count: 20-60x109/L
o CRC: < 1%

- Treatment:
o Removal of causative agent
o RBC transfusions to maintain a minimum hemoglobin level
o Platelet transfusion if necessary
o Antibiotics to prevent infection

PURE RED CELL APLASIA

o Congenital Hypoplastic Anemia/ Diamond-Blackfan Syndrome
- Rare congenital progressive erythrocyte aplasia that occurs in very young children

o Acquired Acute PRCA

- Occurs for a short period during hemolytic anemia, infections, malnutrition or drug therapy
- Erythroblasts in the bone marrow will disappear and anemia will develop if this condition persists for a long
time

o Chronic Acquired PRCA

- Patients with thymoma (thymic tumor), autoimmune HA, SLE, RA or hematologic neoplasms
- Reticulocytes are decreased to absent
- Serum iron level is increased
- Iron binding capacity is saturated

HEMOLYTIC ANEMIA
o Enzyme Deficiency
a. G-6-PD Deficiency
- Inheritance of any one of the abnormal genes that code for G6PD enzyme
- Sex-linked
- 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
- Red cell autohemolysis is increased and only poorly corrected with glucose

d. Glucose-Phosphate Isomerase Deficiency

- Abnormality in the anaerobic glycolysis
- Third most common RBC enzyme deficiency
 ANEMIAS and LEUKEMIAS 6

o 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

- Caused by pathologic antibodies that react most effectively at cold temperatures in vivo and in vitro
- Blood film shows polychromatophilia, spherocytosis, and agglutination of red cells

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

b. Paroxysmal Cold Hemoglobinuria

- Autoimmune disease similar to cold-antibody AIHA
- 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
- Donath-Landsteiner test is positive
- Reticulocyte count is increased

Warm AIHA Cold AIHA PCH

Optimal reaction 37OC 0-4OC 0-4OC (Ab binds to cell)
temperature 37OC (hemolysis takes place)
Thermal amplitude 20-37 OC 0-32 OC <15 OC
Immunoglobulin type IgG IgM IgG (Donath-Landsteiner
Autoantibody)
Antibody type Incomplete Agglutinin Hemolysin
Mechanism of Ab prod Immune response Naturally occurring and Immune response
immune response
Complement activation May bind C` Binds C` Binds C`
Protein structure Polyclonal Monoclonal/polyclonal Polyclonal
Blood group specificity Rh, Kell Ii Pp
1O mechanism of RBC Extravascular (splenic) Extravascular (hepatic) Intravascular
destruction
Severity of disease Severe Mild Distinct episodes of severity
Treatment Steroids, splenectomy, Avoid cold Avoid cold
immunosuppressants
Transfusion requirements Contraindicated Rarely needed Could be required

c. Microangiopathic/Traumatic Hemolytic Anemia (MAHA)

- Complication of one of several conditions in which there is a disturbance of the microvascular environment
- A result of fibrin deposits within small vessels
- Peripheral blood smear shows a large number of schistocytes, irregular contraction of red cells and decreased to
low normal platelet count
 ANEMIAS and LEUKEMIAS 7

d. Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Rare acquired defect that arises in the bone marrow stem cells
- Acquired intrinsic defect in RBC that makes the cells more sensitive to lysis by complement

e. 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

f. Hemolytic Transfusion Reaction

- Results from the transfusion of red cells with antigens that are foreign to the recipients immune system