• Definition of anemia, according to World Health Organization criteria 
    1. Adult men : Blood hemoglobin concentration < 13 g/dL or Hematocrit < 39% 
    2. Adult women : Blood hemoglobin concentration < 12 g/dL or Hematocrit < 37% 
  1. Marrow production defects: Hypoproliferation 
    • Reflects absolute or relative marrow failure in which the erythroid marrow has not proliferated appropriately for the degree of anemia 
    • Can result from marrow damage, iron deficiency, or inadequate erythropoietin stimulation ( insufficient production or ineffective action ) 
  2. Erythrocyte maturation defects: ineffective erythropoiesis 
    • Nuclear maturation defects associated with macrocytosis and abnormal marrow development 
    • Cytoplasm maturation defects associated with microcytosis and hypochromia, usually from defects in hemoglobin synthesis 
  3. Decreased erythrocyte survival: blood loss or hemolysis 
Symptoms & Signs 
  • Acute anemia (nearly always due to blood loss or hemolysis) 
    • Losses of 10–15% of total blood volume : Hypotension and decreased organ perfusion 
    • Loss of > 30% of blood volume :Postural hypotension and Tachycardia 
    • Loss of > 40% of blood volume :Hypovolemic shock 
  • Chronic or progressive anemia 
    • Fatigue 
    • Loss of stamina 
    • Breathlessness 
    • Pale skin and mucous membranes 
    • Palmar creases are lighter in color than the surrounding skin with the fingers extended . 
    • Tachycardia (particularly with physical exertion) 
    • Forceful heartbeat 
    • Strong peripheral pulses 
    • Systolic flow murmur 
  • In patients with coronary artery disease , anginal episodes may appear or increase in frequency and severity. 
  • In patients with carotid artery disease , lightheadedness or dizziness may develop. 
Differential Diagnosis 
  1. Hypoproliferative anemias ( reticulocyte index < 2.5, and normocytic, normochromic anemia ) 
    • Marrow damage: Infiltration/fibrosis , Aplasia 
    • Iron deficiency
    • Decreased stimulation due to low erythropoietin: Inflammation , Metabolic defect / hypometabolic states, Hypothyroidism and CKD
  2. Maturation disorder ( reticulocyte index < 2.5, and microcytic or macrocytic anemia ) 
    • Cytoplasmic defects: Iron deficiency , Thalassemia and Sideroblastic anemia
    • Nuclear defects : Folate deficiency , Vitamin B12 deficiency , drug toxicity,  alcohol and myelodysplasia 
  3. Hemolysis/hemorrhage (  reticulocyte index > 2 ) 
    • Blood loss 
    • Intra cellular defects like enzyme deficiencies ( G6PD), hemoglobinopathies, sickle cell disease 
    • Intravascular hemolysis 
    • Metabolic defect 
    • Membrane abnormality 
    • Hemoglobinopathy 
    • Autoimmune defect 
    • Fragmentation hemolysis 
Laboratory Tests 
  • CBC 
  • Reticulocyte count 
  • Erythrocyte indices ( MCV, MCH, MCHC, RDW )
  • Vitamin B12 
  • Folate (particularly red blood cell folate levels) 
  • Iron supply studies ( Serum iron , Total iron-binding capacity (TIBC),Serum ferritin, marrow iron stain).
  • Hemoglobin electrophoresis 
  • Serum erythropoietin levels (implies a marrow defect if elevated) 
  • Thyroid function tests (anemia of hypothyroidism) 
  • Urine or serum levels of homocysteine and methylmalonic acid (folate and B12 deficiency); B12 deficiency produces an increase in homocysteine and methylmalonic acid.  
  • Cell morphology on peripheral blood smear 
  • Anemia of chronic disease shows Low serum iron , Normal or low TIBC , Low percent transferrin saturation and Normal or high serum ferritin.  
  • Iron deficiency anemia shows Low serum iron level , High TIBC , Low percent transferrin saturation and low serum ferritin level  
  • Lactate dehydrogenase (elevated in hemolytic states) and low haptoglobin in hemolysis. 
  • Classification according to functional defect in erythrocyte production 
    • Marrow production defects: hypoproliferation 
    • Erythrocyte maturation defects: ineffective erythropoiesis 
    • Decreased erythrocyte survival: blood loss/hemolysis 
  • Classification by MCV 
    • Microcytic: MCV < 80 fL 
    • Normocytic: MCV 80–100 fL 
    • Macrocytic: MCV > 100 fL 
Iron-Deficiency Anemia 
  • Increased demand for iron :  Rapid growth in adolescence , Pregnancy and Erythropoietin therapy 
  • Increased iron loss :  Menses, blood donation, phlebotomy , chronic occult GI bleed
  • Decreased dietary iron intake or absorption : celiac sprue, Crohn's disease, post gastrectomy 
Clinical Features
  • Fatigue, Pallor, Shortness of breath, Decreased exercise tolerance 
  • Glossitis, Cheilosis (fissures at corners of mouth) and Koilonychia (spooning of fingernails) 
Laboratory Tests 
  • MCH< 80 pg, MCHC< 30 g/dL, microcytosis, and hypochromia on blood smear with anisocytosis; poikilocytosis appears when anemia is severe 
  • Serum ferritin measurement :  Although levels can be elevated in setting of chronic inflammatory states, even when iron deficiency is present, a ferritin level > 10 μg/dL essentially rules out iron deficiency. 
  • Serum iron content (amount of circulating iron bound to transferrin) : Not as specific as serum ferritin measurement 
  • TIBC is an indirect measure of circulating transferrin. TIBC is elevated in iron deficiency.  
  • Transferrin saturation< 18% in iron deficiency 
  • Erythrocyte protoporphyrin levels : Protoporphyrin accumulates in cells with impaired heme synthesis. Levels > 100 mg/dL indicate iron deficiency (can also indicate lead poisoning). 
  • Oral iron therapy : Ferrous sulfate 325-mg tablet PO TID . Should be taken on an empty stomach. 
  • Parenteral iron therapy :  Use in patients who cannot tolerate oral iron and have acute needs and/or need iron on an ongoing basis (e.g., because of persistent GI blood loss). Iron dextran may cause anaphylaxis, especially in patients with a history of multiple allergies or prior allergic reaction to dextran. A 25-mg test dose is recommended. 
  • Red blood cell transfusion if Hb < 7
B12 Deficiency Anemia; Pernicious Anemia 
  • The only dietary sources of B12 are animal products (meat and dairy). 
  • Most common cause of B12 deficiency is Pernicious anemia 
  • Inadequate intake of B12 :  Strict vegetarians (vegans) and their breast-fed infants.  B12 deficiency often coexists with folate deficiency due to inadequate intake (e.g., chronic alcoholism).  
  • Malabsorption : Drugs that block acid secretion ( PPI, H2 blockers) and bacterial overgrowth
  • Inadequate production of IF 
  • Pernicious anemia (autoimmune mediated destruction of parietal cells) 
  • Total gastrectomy 
  • Drugs 
  • Increased requirements: hyperthyroidism 
Symptoms & Signs 
  • Cobalamin deficiency can affect the hematologic, neurologic, and GI systems. 
  • Neurologic symptoms include Peripheral neuropathy, degeneration (demyelination) of the posterior and pyramidal tracts (Sub acute combined degeneration of spinal cord), optic atrophy, diminished position and vibration sense, ataxia and positive romberg sign. 
Laboratory Tests 
  • Macrocytic anemia (mean corpuscular volume >100) 
  • Best indicators of tissue cobalamin deficiency are the serum methylmalonic acid and homocysteine levels, both of which should be elevated. 
  • Peripheral blood smear shows marked anisocytosis (varying cell sizes) , poikilocytosis (abnormal variation in shape) and macroovalocytes: large, oval, fully hemoglobinized erythrocytes typical of megaloblastic anemias 
  • Neutrophils show nuclear hypersegmentation (6 or more lobes)—characteristic finding 
  • low vitamin B12 levels 
  • Homocysteine and methylmalonic acid (MMA) levels are both elevated. Only homocysteine is elevated in folic acid deficiency 
  • Folate and B12 levels may both be low. Folate supplementation can correct the hematologic effects of B12 deficiency but not the neurological effects. 
  • Patients with pernicious anemia have antiparietal cell antibody (sensitive) but not specific for pernicious anemia 
  • B12 replacement : Intramuscular cyanocobalamin 1000 μg given at 3- to 7-day intervals . Maintenance therapy 1000 μg IM every month for the rest of the patient’s life 
  • Oral replacement therapy : Vitamin B12 must be given in high doses. In theory, high doses result in IF-independent, ileum-independent diffusion of adequate levels to compensate. 2 mg crystalline B12 per day 
  • B12 malabsorption due to bacterial overgrowth can frequently be corrected by administration of antibiotics (e.g., metronidazole 250 mg bid). 
  • Watch out for hypokalemia from the rapid generation of new cells with B12 therapy.
Folate Deficiency Anemia 
  • Inadequate intake 
  • Malabsorption : Tropical sprue, gluten-induced enteropathy, small bowel resection, Crohn’s disease, partial gastrectomy (including bariatric surgery), Whipple’s disease, scleroderma, amyloid, diabetic enteropathy, systemic bacterial infection, lymphoma, sulphasalazine 
  • Excess utilization or loss : Pregnancy and lactation ,  chronic hemolytic anemias, lymphoma and leukemia
  • Antifolate drugs: methotrexate, pyrimethamine, trimethoprim , phenytoin, primidone, barbiturates, sulphasalazine, nitrofurantoin, tetracycline
  • Mixed causes like liver disease and alcoholism
Symptoms & Signs 
  • Unlike vitamin B12 deficiency, folate deficiency does not lead to neurologic disease. 
Laboratory Tests 
  • Macrocytic anemia (mean corpuscular volume > 100 fL) 
  • Leukopenia 
  • Thrombocytopenia 
  • Peripheral blood smear show marked anisocytosis, poikilocytosis and macro-ovalocytes 
  • Neutrophils show hypersegmentation of the nucleus. 
  • Serum folic acid levels are low. However, erythrocyte folate levela are more diagnostic than serum levels 
  • Severe cobalamin deficiency because of the block in conversion of methyl tetrahydrofolate to tetrahydrofolate inside cells 
  • Normal Methylmalonic acid levels 
  • Homocysteine is raised in both early cobalamin and folate deficiency. 
  • Replacement therapy: Folic acid 5–15 mg/d PO daily. 
  • It is customary to continue therapy for about 4 months, when all folate-deficient red cells will have been eliminated and replaced by new folate-replete populations. 
  • To counteract the effects of folate antagonists (e.g., methotrexate,  pentamidine, trimethoprim, triamterene) , Folinic acid100–200 mg/d is used
  • Folate and folinic acid must be used cautiously in the setting of cancer, as they may accelerate the cancer’s growth. 
  • When vitamin B12 deficiency occurs together with iron deficiency (which occurs in up to 20–25% of patients), MCV may not be elevated. 
  • A clue to the correct diagnosis will be the presence of neutrophil hypersegmentation. 
  • Iron deficiency often means occult blood loss. 
  • A single guaiac-negative stool is insufficient to rule out GI blood loss because colorectal cancer may bleed only intermittently. 
  • 3–6 stool samples should be examined over 2–3 weeks to assure the absence of stool occult blood. 
  • In a person with iron deficiency in whom a source for blood loss cannot be defined, don’t forget to ask about blood donation. 
  • Donation of 3 or 4 units per year can result in the loss of a gram of iron. 
  • Three methods are used to diagnosis neutrophil hypersegmentation. They are found in both B12 and folate deficiency. 
  • Count the lobes of 100 cells and divide by 100. 
  • A level >3.5 is abnormal. 
  • The rule of 5’s: finding 5% of the cells with 5 lobes 
  • Finding a single cell with 6 or more lobes 
  • Incidence of spina bifida has decreased dramatically since the institution of food folate supplementation. 

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