HAEMATOLOGY Pathology:

ANAEMIA - B12 FOLATE DEFICIENCY

MACROCYTIC (MEGALOBLASTIC) ANAEMIA VitB12/Folate Deficiency:

- (Including PERNICIOUS ANAEMIA)
- (2nd most common type of anaemia)
- Megalobla s = large, Erythroblasts with Immature Nuclei - seen in the Marrow)
- Aetiology:
o Vitamin B12/Folic Acid Deficiency (Deficiency of either Megaloblastic Anaemia)
**Malnutrition
**Alcoholism (or Liver Disease)
**Pernicious Anaemia ( Parietal Cells Intrinsic Factor B12 Malabsorption)
Intrinsic Factor Deficiency
Cytotoxic Chemo Drugs
Malabsorption Syndrome (Coeliac, IBD, Gastrectomy, Ileal Resection)
Old Age
- Pathogenesis:
o VitB12/Folate are Necessary for Nuclear DNA Synthesis :. Bottlenecks RBC Production
- Morphology:
o Marrow Biopsy:
Megaloblasts in Bone Marrow (large, Erythroblasts with Immature Nuclei)
o Blood Film:
*Normochromic
*Oval Macrocytes (Large, Oval RBCs)
*Hypersegmented Neutrophils (Some with >6 Lobes in Nucleus)
*Pancytopenia (Reduction in Number or ALL Cells RBCs/WBCs/Platelets)
A emp ed E h opoie i
Re ic loc e
Some Pol ch oma ophil (Biger, Blueish RBCs)
Some Nucleated RBCs
+ An-Isocytosis (variations in size)
+ Poikilocytosis (Variations in shape)

- Clinical Features:
o General Anaemia Symptoms & Signs:
o Signs & Symptoms Specific to Megaloblastic Anaemia:
Glossitis (Red Sore Tongue)
Angular Stomatitis/Cheilitis
Peripheral Neuropathy (Paresthesia Vib a ion Proprioception, Weakness & Ataxia)
- Investigations:
o Blood Film (Oval Macrocytes, Hypersegmented Neutrophils, Pancytopenia)
o FBC MCV Panc o enia
o Bone Marrow Biopsy (Shows Megaloblasts) Rarely Required
o Serum B12/Folate if B /Folate Deficiency)
- Treatment:
o Oral B12
o Oral Folate
o Corticosteroids + B12 Supplements (If Pernicious Anaemia)

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 HEMOGLOBIN AND HEMOGLOBINOPATHIES . . . CONT.

❏ hydroxyurea to enhance production of HbF

• causes depression of the gene for HbF or by initiating differentiation of stem cells in which this gene
is active; presence of HbF in the SS cells decreases polymerization and precipitation of HbS
• Note: hydroxyurea is cytotoxic and may cause bone marrow suppression

Table 5. Organs Affected by Vaso-Occlusive Crisis

Organ Problem

brain seizures, hemiplegia

eye hemorrhage, blindness
liver infarcts, RUQ syndrome
lung chest syndrome
gall bladder stones
heart hyperdynamic flow murmurs
spleen enlarged (child); atrophic (adult)
kidney hematuria; loss of renal concentrating ability
intestines acute abdomen
placenta stillbirths
penis priapism
digits dactylitis
femoral head aseptic necrosis
bone infarction, infection
ankle leg ulcers

Treatment of Vaso-Occlusive Crisis

❏ oxygen
❏ hydration (reduces viscosity)
❏ antimicrobials
❏ correct acidosis
❏ analgesics/narcotics (give enough)
❏ magnesium (inhibits potassium and water efflux from RBCs thereby preventing dehydration)
❏ exchange transfusion for CNS crisis
❏ experimental anti-sickling agents

MEGALOBLASTIC ANEMIA
❏ failure of DNA synthesis resulting in asynchronous maturation of RBC nucleus and cytoplasm
❏ non-megaloblastic anemia reflects membrane abnormality with abnormal cholesterol metabolism
❏ megaloblast = large, nucleated RBC precursor; macrocyte = large RBC
Causes of Megaloblastosis
❏ folate deficiency (seen after 4 months of decreased intake)
❏ B12 deficiency (seen after 10-15 years decreased intake)
❏ antimetabolite drugs
• methotrexate
• folate analogues (sulpha drugs)
• purine/pyrimidine analogues (6-MP, 5-FU)
❏ nitrous oxide
❏ myelodysplasia/some cases of AML

B12 DEFICIENCY
Etiology
❏ if intake stops abruptly body stores last 3-4 years
❏ diet
• strict vegetarian (rare)
❏ gastric
• mucosal atrophy of pernicious anemia
• post-gastrectomy
❏ intestinal absorption
• malabsorption (e.g. Crohn’s, celiac sprue, pancreatic disease)
• stagnant bowel (e.g. blind loop, stricture)
• fish tapeworm
• resection of ileum as in Crohn’s and celiac sprue
❏ rare genetic causes
H10 – Hematology MCCQE 2002 Review Notes

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 HEMOGLOBIN AND HEMOGLOBINOPATHIES . . . CONT.

Pernicious Anemia
❏ auto-antibodies produced against gastric parietal cells leading to
achlorhydria and no intrinsic factor secretion
• intrinsic factor is required to stabilize B12 as it passes through the bowel
• decreased intrinsic factor leads to decreased ileal absorption of B12
❏ female:male = 1.6:1
❏ may be associated with other autoimmune disorders e.g. thyroid and adrenal deficiency
❏ often > 60 years old
Neurological Lesions in B12 Deficiency
❏ cerebral (common; reversible with B12 therapy)
• confusion
• delirium
• dementia
❏ cranial nerves
• optic atrophy (rare)
❏ cord (irreversible damage)
• subacute combined degeneration
• posterior columns - paresthesias, disturbed vibration, decreased proprioception
• pyramidal tracts - spastic weakness, hyperactive reflexes
❏ peripheral neuropathy (variable reversibility)
• usually symmetrical
• affecting lower limbs more than upper limbs
Diagnosis
❏ serum
• anemia often severe +/– neutropenia +/– thrombocytopenia
• MCV > 120
• low reticulocyte count relative to the degree of anemia
❏ serum B12 and RBC folate
• caution: low serum B12 leads to low RBC folate because of failure of
folate polyglutamate synthesis in the absence of B12
❏ blood film
• oval macrocytes (see Colour Atlas H2A)
• hypersegmented neutrophils (see Colour Atlas H2B)
❏ bone marrow
• differentiates between megaloblastic and myelodysplastic anemias
• hypercellularity
• failure of nuclear maturation
• elevated unconjugated bilirubin and LDH due to marrow cell breakdown
❏ Schilling test to distinguish pernicious anemia from other causes
• Schilling test: part 1
• tracer dose (1g µg) of labelled B12 (cobalamin (Co*)), PO
• flushing dose (1mg) of cold B12, IM to saturate tissue binders
of B12 thus allowing radioactive B12 to be excreted in urine
• 24 hour urine Co* measured
• normal ––> 5% excretion
• Schilling test: part 2
• tracer dose B12 (Co*) plus intrinsic factor, PO
• flushing dose of cold B12, injected IM
• 24 hour urine Co* measured
• normal test result (> 5% excretion) = pernicious anemia
• abnormal test result (< 5% excretion) = intestinal causes (malabsorption)
Management
❏ B12 100 µg IM monthly for life or oral B12
❏ watch for hypokalemia (due to return of potassium to intracellular sites) and thrombocythemia

FOLATE DEFICIENCY
❏ more common than B12 deficiency because folate stores are depleted in 3-6 months
❏ folate complexes with gastric R binder
❏ R binder is replaced by intrinsic factor in the duodenum
❏ this complex is absorbed in the jejunum
Etiology
❏ diet (folate is present in leafy green vegetables)
• most common cause
• e.g. infancy, poverty, alcoholism
❏ intestinal
• malabsorption

MCCQE 2002 Review Notes Hematology – H11

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 HEMOGLOBIN AND HEMOGLOBINOPATHIES . . . CONT.

❏ drugs/chemicals
• alcohol
• anticonvulsants
• antifolates (MTX)
• birth control pills
❏ increased demand
• pregnancy
• prematurity
• hemolysis
• hemodialysis
• psoriasis, exfoliative dermatitis
Clinical Presentation
❏ mildly jaundiced due to hemolysis of RBC secondary to ineffective hemoglobin synthesis
❏ glossitis and angular stomatitis
❏ rare
• melanin pigmentation
• purpura secondary to thrombocytopenia
❏ folate deficiency at time of conception and early pregnancy has been
linked to neural tube defects
Management
❏ never give folate alone to individual with megaloblastic anemia because it
will mask B12 deficiency and neurological degeneration will continue
❏ folic acid 15 mg PO/day x 3 months; then 5 mg PO/day maintenance if cause not reversible
❏ folic acid supplementation 1 mg PO/day will protect against elevated homocysteine levels
(risk factor for CAD)
HEMOLYTIC ANEMIAS (HA) (see Colour Atlas H4)
Classification
❏ hereditary causes (intrinsic)
• abnormal membrane (spherocytosis, elliptocytosis)
• abnormal enzymes (pyruvate kinase deficiency, G6PD deficiency)
• abnormal hemoglobin synthesis (thalassemias, hemoglobinopathies)
❏ acquired causes (extrinsic)
• immune
• hemolytic transfusion reaction
• idiopathic immune HA
• drugs
• cold agglutinins
• secondary autoimmune HA
• non-immune
• RBC fragmentation syndromes
• paroxysmal nocturnal hemoglobinuria
• liver disease
• hypersplenism
• march hemoglobinuria
Clinical Presentation
❏ jaundice
❏ cholelithiasis
❏ splenomegaly
❏ skeletal abnormalities
❏ leg ulcers
❏ regenerative crisis
❏ folic acid deficiency
❏ iron overload with extravascular hemolysis
❏ iron deficiency with intravascular hemolysis
Diagnosis
❏ indirect - not specific to hemolytic anemias
• increased reticulocyte count
• reduced haptoglobin
• increased unconjugated bilirubin
• increased urine bilinogen
• increased LDH
❏ tests exclusive for intravascular hemolysis
• serum free hemoglobin present
• methemalbuminemia (heme + albumin)
• hemoglobinuria (immediate)
• hemosiderinuria (delayed)
H12 – Hematology MCCQE 2002 Review Notes

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