Megaloblastic Anemia
Answer. Megaloblastic anaemias are characterized by macrocytic blood picture (MCV > 100 fl and megaloblastic bone marrow.
Causes of Megaloblastic Anemia
1. Due to Vitamin B12 defiiency
1. Inadequate intake: In strict vegetarians, poor quality diet,in elderly
2. Impaired absorption
Gastric
- Pernicious anaemia
- Congenital intrinsic factor defiiency
- Gastrectomy
Small intestinal disease
- Bacterial overgrowth
- Crohn’s disease and resection of terminal ileum
- Tropical sprue and nontropical sprue
- Selective ileal malabsorption of B12 .
- Fish tapeworm disease
- Coeliac disease (folic defiiency more common)
Miscellaneous — HIV infection, severe pancreatic disease, drugs
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3. Increased requirement: In pregnancy and disseminated cancer
2. Due to folic acid defiiency
- Inadequate intake: In malnutrition, Old age, Poverty,Alcoholism, Goat‘s milk, Kwashiorkor
- Impaired absorption: Coeliac disease, Dermatitis
herpetiformis, Tropical sprue, Congenital folate malabsorption and Oral contraceptives - Increased requirement: Infancy, pregnancy and hyperplastic marrow due to haemolytic anaemia
- Impaired utilization: Folic acid antagonists, methotrexate,pyrimethamine, trimethoprim, anticonvulsant drugs
- Increased loss (combined folic acid and vitamin B12 deficiency): Tropical sprue, Non—tropical sprue and haemodialysis
Megaloblastic Anemia Clinical Features
1. Due to anaemia: Shortness of breath, dyspnoea, pallor and in older subjects angina or cardiac failure.
2. Gastrointestinal: Diarrhoea, loss of appetite and weight.
Sore tongue due to glossitis and angular cheilosis. Mild jaundice may give the patient a lemon yellow tint.
3. Neurological
- Vitamin B12 neuropathy: Due to symmetrical damage to peripheral nerves and posterior and lateral columns of spinal cord, the legs being more affcted than arms.
Psychiatric abnormalities and visual disturbances may occur (from folate defiiency). - Neural tube defects: Folic acid supplements during pregnancy have been shown to reduce incidence of spina bifia, encephalocele and anencephaly in the foetus.
4. CVS disease — Raised serum homocysteine concentrations have been associated with arterial obstruction and venous thrombosis.
5. Gonadal dysfunction — Deficiency of either B12 or folic acid may cause sterility, which is reversible with appropriate vitamin supplements.
6. Knuckle pigmentation
Megaloblastic Anemia Laboratory diagnosis
1. Blood Film
1. Macrocytosis: Hemoglobin content in red cells is proportionately increased hence normal MCHC.
2. Peripheral smear: It shows
- Oval macrocytes
- Anisopoikilocytosis.
- Few tear drop cells and normocytes.
- Few nucleated RBCs.
- Macrocytes without central pallor.
- Evidence of dyserythropoiesis: basophilic stippling, Cabot ring and
3. HowellJolly bodies.
4. Haemoglobin is decreased.
5. Hypersegmented neutrophils may be the first evidence of megaloblastic anaemia.
6. Iron ferritin level increases.
2. Bone marrow
- Hypercellularity with marked erythroid hyperplasia.
- Megaloblasts are larger than normoblasts and have sieve like nuclear chromatin. Evidence of dyserythropoiesis.
- Myelopoiesis — Giant metamyelocytes and giant band forms with abnormal nuclear shapes.
- Megakaryocytes with hyperlobulation and immature nucleus.
- Dimorphic anaemia — Macrocytes and hypochromic microcytes in cases of combined B12/Folate and iron defiiency.
3. Biochemical estimations
- Serum folate levels: Decrease determined by isotope dilution method, microbiologic assay.
- Serum vitamin B12 levels — Decrease determined by isotope dilution technique or microbiological assay
- Increased levels of methylmalonic acid in serum and urine in B12 defiiency.
- FIGLU excretion in urine in excess in folic acid defiiency.
- Deoxyuridine suppression test for defiiency of both vitamin B12 and folate.
- Schillings test of vitamin B12 absorption. Radioactive vitamin B12 is used to assess intrinsic factor and
Vitamin B12 to distinguish megaloblastic anaemia due to intrinsic factor defiiency (pernicious anaemia) from other causes of B12 defiiency. - Serum homocysteine levels increased in folateand B12 defiiency.
Diagnosis Of Megaloblastic Anaemia
- Oval macrocytes in peripheral smear.
- Hypersegmented neutrophils.
- Megaloblastic erythropoiesis in bone marrow.
- Response to B12/Folate therapy.
Megaloblastic Anemia Treatment
1. Vitamin B12 defiiency
- Initially: Hydroxycobalamin 1000 µg IM, 6 injections in 2-3 weeks.
- Maintenance dose is 5001000 mcg IM every three months for life.
- For patients sensitive to B12 injections or those who refuse injections, oral B12 (cyanocobalamin) in large daily doses (100 µg or more).
2. Folate defiiency
- Initially folic acid 5 mg daily orally for at least 4 months. Folic acid in such big doses should not be given until B12 defiiency has been excluded, since folic acid may precipitate B12 neuropathy in a severely defiient B12 patient.
- Maintenance: Need depends on whether the underlying cause can be reversed, e.g. glutenfree diet in coeliac disease.
Mechanism of coagulation
Blood coagulation occurs in three major stages:
- Stage 1: Activation of StuartPrower factor (formation of prothrombin activator)
- Stage 2: Formation of thrombin from prothrombin
- Stage 3: Formation of firin from firinogen
Activation Of Stuart-Prower Factor (Factor X)
Activation of StuartPrower factor or factor X is the key to blood coagulation. Factor Xa is called prothrombin activator as it activates prothrombin to form thrombin. Therefore, this process is also called prothrombin activation.
This is achieved by two pathways: the intrinsic pathway and the extrinsic pathway.
Intrinsic Pathway
Intrinsic mechanism of prothrombin activation occurs in four steps:
step 1 (activation of factor XII)
Activation of intrinsic pathway starts with contact of Hageman factor with a negatively charged surface or exposed collagen of the injured vessel wall.
1. High molecular weight kininogen and kallikerin act as cofactors to facilitate the activation of factor XII
2. Exposed collagen stimulates platelet adhesion and aggregation before initiating blood coagulation.
step 2 (activation of factor XI)
Activated factor XII (XIIa) converts factor XI to its active form (XIa). This step is accelerated in the presence of high molecular
weight kininogen.
step 3 (activation of factor IX )
Factor XIa then converts factor IX to IXa, which is accentuated by factor VIIa. Calcium accelerates this process.
step 4 (activation of factor X)
Final step in activation of prothrombin activator is activation of factor X. Factor IXa causes activation of factor X to Xa, the activated Stuart prower factor. The membrane phospolipid, calcium and activated factor VIII act as cofactors for the activation of Stuart prower factor is crucial in Stage 1.
Formation of factor VIIIa is the key to the process of activation of factor X
Extrinsic Pathway
Extrinsic pathway of blood coagulation occurs in three steps:
step 1 (release of tissue thromboplastin)
Key to the clotting mechanism is the release of tissue thromboplastin from the injured tissue. As tissue thromboplastin is the tissue factor which is viewed as extrinsic to circulating blood, this system of blood coagulation is called extrinsic system of clottng.
step 2 (activation of vII)
Tissue thromboplastin converts factor VII to its active form (VIIa). This is the key step in extrinsic mechanism. Factor VIIa directly activates not only factor X, but also factor IX. Thus it also inflences intrinsic mechanism of activation of factor X.
step 3 (activation of X)
Factor VIIa converts X to Xa. This process is accelerated in the presence of calcium, platelet phospholipid and tissue thromboplastin.
Pathogenesis of hemophilia
- Haemophilia is caused by quantitative reduction of factor VIII in 90% of cases, while 10% cases have normal or increased level of factor VIII with reduced activity.
- Factor VIII is synthesized in hepatic parenchymal cells and regulates the activation of factor X in intrinsic coagulation pathway.
- Factor VIII circulates in blood complexed to another larger protein, von Willebrand’s factor (vWF), which comprises 99% of the factor VIII— vWF complex.
- Normal haemostasis requires 25% factor VIII activity.
Though occasional patients with 25% factor VIII level may develop bleeding, most symptomatic haemophilic patients have factor VIII levels below 5%.
Coagulation Clinical Features
- At birth: Newborn with hemophilia is usually healthy,though bleeding from cord and cephalohematoma may occur.
- In infant: Hemophilia is asymptomatic till 6 to 12 months,when bruising becomes more obvious. Bleeding from the mouth is common.
- During childhood: In severly affected individuals,spontaneous bleeding may occur in joint and muscles,including psosas muscle.
- In adults: Frequency of spontaneous bleeding decreases,but joints may already have been damaged. Intracranial hemorrhage is a lifethreatening complication. Spontaneous bleeds are common in mildly affcted individuals, but after injury bleeding occurs till appropriate therapy has begun.
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