ANAEMIAS Background: Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying etiology Anemia is strictly defined as a decrease in red blood cell (RBC) mass. In practice however; anemia is usually discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and hematocrit (Hct).In kenya defined as Hb below 10g/dl.WHO definition Hb below 12g/dl. Changes in plasma volume. eg, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass. Pathophysiology: Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes. -Reticulocytes remain in the circulation for approx. 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. -The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system. -Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy -Basically, only 3 causes of anemia exist: 1)       Blood loss 2)       Increased RBC destruction (hemolysis) 3)       Decreased production of RBCs. -Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy. -Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC and produces pan-hemolysis of RBCs of all ages. Prevalance Although geographic diseases, such as §  sickle cell anemia §  Thalassemia §  malaria §  Hookworm §  Chronic infections, are responsible for a portion of the increase - nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia because heme iron is better absorbed from food than inorganic iron History: Primary symptoms result from tissue hypoxia and might include the following: -          Fatigue, weakness, irritability -          Headache, Dizziness, especially postural -          Vertigo ,Tinnitus ,Syncope -          Dyspnea, especially with increased physical activity (exercise intolerance) -          Chest pain, palpitations -          Difficulty sleeping or concentrating -          Thirst ,Anorexia, Decreased urine output/bowel irregularity -          Decreased libido or impotence -History of prescription of hematinics provides clues that anemia was detected previously. -Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs-sickle cell disease and thalasaemia. -Patient's occupation -Drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents.  many drugs and toxins can cause anemia (eg, alcohol, isoniazid, lead) -Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried. -Blood loss §  Obs/gy-pregnancies,Abortions,menstrual loss §  Peptic ulcer disease §  Hematochizia and melena stool Changes in bowel habits can be useful in uncovering neoplasms of the colon. §  Hematuria ,hemopytisis,haematemesis §  Any other bleeding disorder-epistaxis, echymoes, bleeding from the gums. -Dietary history-A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient both eats and avoids as well as an estimate of their quantity. Taking tea after meal impair iron absorption -Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin. -Nutritional deficiencies may be associated with unusual symptoms. §  Iron deficiencies frequently eat soil(soil), dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs. §  In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common. Sometimes no anemia is present despite overt neuro psychiatric disease caused by administration of folic acid to patients with cobalamin deficiency. This partially corrects the anemia, but not the neuropathy. §  Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia -A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia. -The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. -The heart enlargement may provide evidence of the duration and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.or haemic murmurs. Etiology First decision whether anemia is due to §  A decreased production of RBCs §  Increased destruction RBC or loss of blood The reticulocyte count is the most valuable test in answering this question. If the reticulocyte count is low, a failure in RBC production is indicated. If it is high, hemolysis is suggested. a)Hypochromic microcytic anemia-cause 1)       Iron deficiency 2)       Thalassemia 3)       Sideroblastic anaemia 4)       Lead poisoning. b) Macrocytic anemia/ Megaloblastic anaemia Causes of Megaloblastic anaemia 1.Vitamin B-12 deficiency §  Nutritional deficiency:-vegetarian diets without milk, cheese, and eggs over a number of years because depletion of cobalamin reserves stored in the liver takes years. §  Pernicious anemia (PA) In most cases, the loss of functional IF is caused by the autoimmune destruction of gastric parietal cells. However, some cases of PA can be traced to a hereditary lack of production of IF. §  Gastrectomy: Patients develop PA following gastrectomy because of the lack of a source of IF. Development of overt megaloblastosis requires approximately 3-5 years following total gastrectomy and approximately 12 years following partial gastrectomy. The lag is because of the time required to deplete cobalamin stores. §  Zollinger-Ellison syndrome:, the persistent acidity inactivates pancreatic proteases in the duodenum and prevents transfer of cobalamin from r-factor to IF. This factor (r-factor) is a cobalamin binder secreted by salivary glands. §  Severe abnormalities in the terminal ileum due to ileal resection, regional ileitis, lymphoma, TB, Crohns disease .The terminal ileum is the site of uptake of cobalamin-IF complexes; therefore, these disorders can lead to cobalamin deficiencies §  Diphyllobothrium latum (ie, fish tapeworm): When the tapeworm is entrenched in the small intestine, it competes with the host for ingested cobalamin. The organism is most often found in Canada, Alaska, and the Baltic Sea 4.Non –megaloblastic Macrocytic anemia ü  Liver disease ü  Hypothyroidism ü  Chronic alcoholism ü  Other inborn errors ü  Accelerated erythropoiesis (reticulocytes) ü  Hypoplastic and aplastic anemia ü  Infiltrated bone marrow c)Normocytic anaemia-2 main groups i)Primary bone marrow involvement -Aplastic anemia -Myelophthisic anemia: accumulation of malignant or reactive cells or cell products. Immature myeloid cells and nucleated RBCs in the peripheral blood. The 3 major classes of disorders that can produce myelophthisic anemia are intrinsic bone marrow malignancies (eg, leukemia, lymphoma, myeloma), metastatic tumors (eg, neuroblastoma, melanoma, cancers that are more prone to bone marrow metastasis (eg, prostate, breast, lung, stomach, renal carcinomas), and granulomatous disease (eg, tuberculosis, sarcoidosis). -Myelofibrois is known as agnogenic myeloid metaplasia and involves gradual bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly with no known underlying systemic disorder. ii)Anemia chronic  illness: Most cases of anemia in the world are secondary to an underlying disease. This type of anemia includes ü  Liver cirrhosis ü  Uremia ü  chronic inflammation ü  Hypoendocrine conditions (eg, thyroid, adrenal, pituitary disorders). iii)Hemolytic anemias Congenital and Acquired Congenital cause a)Erythrocyte membrane abnormalities ü  Congenital spherocytosis ü  Stomatocytosis ü  hereditary elliptocytosis ü  Paroxysmal nocturnal hemoglobulinaemia b) Enzymatic defects ü  G6 Phosphate DH deficincey ü  Pyruvate kinase deficinecy c)Hemoglobin abnormalities ü  Sickle cell anemia ü  Thalasaemia Investigations I Confirm diagnosis of anaemia FBC-RBC count(4.6-5.4 x1012/L and Hb        -WBC and differentials                Neutrophils 60-75%,               Lymphocytes 20-45%                     Monocytes 1-10%                     Eosinophils1-6%                     Basophils 0.4-1%-infections        -Platelets-purpura or bleeding problem II Tests to establish the type of anaemia  1.RBC indices MCV-Normal  79-96fl MCH-27-32 picogram MCHC-32-36% RDW (red cell distribution width)-upto 9. It is measure anisocytosis. ESR- Male: 1 - 13 mm/hr Female: 1 - 20 mm/hr  2.Reticulocyte count, erythroblasts and polychromasia  3. PBF evaluation -Size-Macro or micro, anisocytosis-size variation -Shape-poikilocytosis-shape variation          -Sickle cells-SCD          -Target cells-IDA,SCD,Thalasaemia,Liver disease          -Ovalocytes-Macrocytic anaemia          -Tear drop-most anaemias          -Spherocytes,elliptocytes          -Acanthocytes(burr cells)-Hemolytic anaemia,           Pyruvate kinase deficiency, Abetalipoproteinaemia -Colour-Hypochromic-IDA, Thalasaemia,Sideroblastic             -Polychromasia-variation in colour-hemolytic ,pts              On hematinics -Inclusions Basophilic stippling-Lead posisoning Parasites-malaria,babesia,trypanosomes  III Tests for etiology of Anaemia-Dependent on the tests II above: 1.Hypochromic anaemia -Iron studies. -serum ferritin, TIBC, total iron, and percent saturation. Iron stores stain BM aspirate with Prussian blue. -Blood loss-Stool for Ova and cyst.Stool for occult blood                  -Urinalysis-hematuria                  -Upper GI endoscopy or lower GI endoscopy -Hb electrophoresis-thalasaemia 2.Hemolytic picture-ie -Reticulocytosis -PBF §  Sickle cells-SCD §  polychromasia- indicating RBC immaturity §  Ovalocytes-membranopathy §  Spherocytes §  Acanthocytes. §  Schistocytes (fragmented RBCs), suggesting TTP, HUS, or mechanical damage §  hematological malignancy associated with hemolysis (ie, CLL) -A 3rd  phase can be performed in which the patient is treated with antibiotics prior to administering radioactive cyanocobalamin. If antibiotics restore cobalamin absorption from the GI tract, the patient most likely has a blind loop syndrome. NB.The results of the Schilling test may indicate cobalamin malabsorption in patients who have severe and long-standing folate deficiencies. This is because of the effect of severe folate deficiency on the ileal mucosa that leads to a decrease in cobalamin uptake in the terminal ileum. iii) Methylmalonic aciduria. Urinary excretion is a reliable index of cobalamin deficiency, provided the patient does not have renal failure. Serum methylmalonic acid and homocysteine test results are elevated in more than 90% of patients with cobalamin deficiencies. iv) Antiparietal cell antibodies .Of patients with PA, 90% are positive for these antibodies. However, antiparietal cell antibodies are also present in patients with thyroid disease and other autoimmune disorders. Anti-IF antibodies (type I and II) are highly specific for PA. Evaluation of Folate deficiency i)Serum  folate levels, and the red cell folate level are Folate levels respond rapidly to changes in dietary folate. A low folate level reflects dietary intake during the previous 2-3 days. Conversely, a single meal with normal folate content can restore serum folate levels to normal. Other Tests: -Cobalamin deficiency – Tests for autoimmune disorders, regional ileitis, fish tapeworm infection, Zollinger-Ellison syndrome, pancreatitis, and myeloproliferative disorders -Folate deficiency - Detect and evaluate pregnancy; malnutrition; and other complications of sprue, chronic hemolysis, and exfoliative dermatitis Other causes of macrocytosis i)Liver Function test ii) Thyroid function studies-hypothyroidism Confirmation of diagnosis megaloblastosis -Bone marrow aspiration and biopsy results are useful to confirm the diagnosis, to rule out myelodysplasia, and to assess the iron stores. -Marrow is cellular with erythroid hyperplasia. Megaloblastic RBC precursors are abundant, and giant metamyelocytes are present. - Megakaryocytes may be large and hyperlobulated. Iron stores vary from being increased before therapy to decreased if iron is consumed during therapy Surgical Care: -Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the gastrointestinal tract, the uterus, or the bladder. Patients should be hemodynamically stable before and during surgery. A blood transfusion may be needed. -Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary hemolytic disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvic kinase deficiency). Improvement in survival rates has been reported in patients with aplastic anemia, but splenectomy is not the preferential therapy. Leg ulcers have shown improvement in some patients with thalassemia. Prior to splenectomy, patients should be immunized with polyvalent pneumococcal vaccine. Preferably, this should be administered more than 1 week prior to surgery. -Bone marrow and stem cell transplantation have been used in patients with leukemia, lymphoma, Hodgkin disease, multiple myeloma, myelofibrosis, and aplastic disease.. Allogeneic bone marrow transplantation successfully corrected phenotypic expression of sickle cell disease and thalassemia and provided enhanced survival in patients who survive transplantation. Specific Treatment. VIT.B12 and Folate deficinecy In either of the deficiency both cobalamin and folate therapy is admin. Transfusion therapy should be restricted to patients with severe, uncompensated, and life-threatening anemia. Because megaloblastic anemia usually develop gradually, most patients have adjusted to low Hgb levels and do not require transfusions. -Cobalamin (1000 mcg) should be given parenterally daily for 2 weeks, then weekly until the hematocrit value is normal, and then monthly for life. This dose is large, but it may be required in some patients. Patients with neurological complications should receive cobalamin at 1000 mcg (more in some cases) every day for 2 weeks, then every 2 weeks for 6 months, and monthly for life -Folate (1-5 mg) should be administered orally. - Prophylactic folate therapy (1 mg/d) should be administered during ü  Pregnancy and the perinatal period to meet the increased demand for folate by the fetus and during lactation. ü   Folate should also be given daily to patients with chronic hemolysis. ü  Folate therapy is currently recommended for individuals with high levels of homocysteine who have a propensity for thromboembolic disease to prevent this complication ü  Multivitamins that contain folate have been recommended for elderly persons.

Mortality/Morbidity: -The morbidity and mortality of anemias vary greatly depending on the etiology. -Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approximately 1% with benign peptic ulcers). -Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy. -Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle cell disease may remain relatively asymptomatic with a nearly normal lifespan. -Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo bone marrow transplantation. -Hereditary spherocytosis either may present with a severe hemolytic anemia or may be asymptomatic with compensated hemolysis. -Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or exist without anemia until the patient receives an oxidant medication. -The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy. -In addition, tolerance of anemia is proportional to the anemia's rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia. Sex: Overall, anemia is twice as prevalent in females as in males. -This difference is significantly greater during the childbearing years due to pregnancies and menses. -Approximately 65% of body iron is incorporated into circulating Hb. -Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias. Age: -Severe genetically acquired anemias (eg sickle cell disease, thalassemia, Fanconi syndrome) are more commonly found in children because they do not survive to adulthood. -During the childbearing years, women are more likely to become iron deficient. -Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. -Use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce gastrointestinal bleeding. -Folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea -Color, bulk, frequency, and odor of stools and whether the feces float -malabsorption. In steatorrhea whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush. -Fever because infections, neoplasm, and collagen vascular disease can cause anemia. -Occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding -Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias. -The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria. -Explore the presence or the absence of symptoms suggesting an underlying disease such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy. Physical: -General Appearance for underdevelopment, malnutrition, or chronic illness. -Eyes-Pale conjunctiva, Retinal hemorrhages -Cardiovascular-Tachycardia, Orthostatic hypotension -Pulmonary-Tachypnea,Rales -Abdomen-Hepatomegaly and/or splenomegaly, Ascites Masses, Positive result on Hemoccult test -The skin and mucous membranes ü  Pallor ü  abnormal pigmentation, prominent venous pattern on the abdominal wall-liver disease ü  icterus, spider nevi, palmar erythema-liver disease ü  Petechiae, purpura-bleeding tendency ü  Angiomas, ulcerations ü  Coarseness of hair ü  Puffiness of the face-Renal, hypothyroidism ü  Thinning of the lateral aspects of the eyebrows-hypothyroididm. ü  Nail defects-Iron deficiency anaemia -Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies. -Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. -Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated. -:Hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ. §  Blind loop syndrome: This syndrome involves bacterial colonization of intestines that are either deformed because of strictures, surgical blind loops, or anastomoses or abnormal because of scleroderma or amyloidosis. Bacteria compete with the host for cobalamin 2.Folate deficiency §  Dietary insufficiency, the destruction of folate by excessive heating of diluted foods, or consuming alternative diets that are low in folate §  Tropical sprue: Tropical sprue has a more severe effect on the distal ileum than nontropical sprue. Therefore, tropical sprue can lead to cobalamin deficiency and folate deficiencies. §  Others malabsorption causes regional enteritis, intestinal lymphoma, surgical intestinal resection, amyloidosis, Whipple disease, and scleroderma. §  Increased turnover or requirements: This can occur during pregnancy s and during lactation.. Patients with psoriasis and exfoliative dermatitis require additional folate because of the increased turnover of epidermal cells. §  Miscellaneous: Folate deficiency can occur during hyperalimentation and hemodialysis because folate is lost in dialysis fluid. Megaloblastosis in persons with alcoholism is often due to folate deficiency. 3.Drugs that can cause megaloblastic anemia §  Antifolates - Methotrexate, aminopterin §  Purine analogs - 6-Mercaptopurine, 6-thioguanine, acyclovir §  Pyrimidine analogs - 5-Fluorouracil, 5-azacitidine, zidovudine §  Ribonucleotide reductase inhibitors - Hydroxyurea, cytarabine arabinoside §  Anticonvulsants - Phenytoin, phenobarbital, primidone §  Other drugs that can depress folates - Oral contraceptives, glutethimide, cycloserine §  Drugs that affect cobalamin metabolism - p-Aminosalicylic acid, metformin, phenformin, colchicine, neomycin, biguanides Others -Hereditary orotic aciduria -Lesch-Nyhan syndrome -Thiamine-responsive megaloblastic anemia - This condition is an autosomal recessive disorder with features that include megaloblastic anemia, deafness, and diabetes mellitus. Thiamine uptake into cells is disturbed, and treatment with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus. -Neoplastic or viral infections (eg, myelodysplastic syndromes, other clonal neoplastic diseases) and HIV infections - Can directly affect bone marrow stem cells - Acquired hemolytic conditions a) Immune disorders ü  Autoimmune hemolytic anaemia-AIHA ü  Alloimmune hemolytic anemia-Blood transfusion ü  Hemolytic disease of newborn ü  Allograft-solid Transplant b) Toxic chemicals and drugs Drug-induced immune hemolysis is classified according to three mechanisms of action: ü  drug-absorption (hapten-induced) ü  Immune complex ü  Autoantibody- Production These IgG- and IgM-mediated disorders produce a positive DAT and are clinically and serologically indistinct from AIHA. Drug-absorption (hapten-induced) -Hemolysis resulting from high-dose penicillin therapy is an example of the drug-absorption mechanism, in which a medication attached to the red blood membrane stimulates IgG antibody production. When large amounts of drug coat the cell surface, the antibody binds the cell membrane and causes extravascular hemolysis. Others-Ampicillin Methicillin,Carbenicillin,Cephalothin (Keflin)* Cephaloridine (Loridine) Immune complex hemolysis -Quinine-induced hemolysis is the prototype of the immune complex mechanism, in which the drug induces IgM antibody production. The drug-antibody complex binds to the red blood cell membrane and initiates complement activation, resulting in intravascular hemolysis. Others-Phenacetin ,Hydrochlorothiazide, Rifampin ,Sulfonamides ,Isoniazid Autoantibody -Alpha-methyldopa is the classic example of anti-erythrocyte antibody induction. Although the exact mechanism is unknown, the drug (perhaps by altering a red blood cell membrane protein and rendering it antigenic13) induces the production of ant erythrocyte IgG antibodies and causes an extravascular hemolysis. Others Mefenamic acid (Ponstel),L-dopa,Procainamide Ibuprofen,Diclofenac),Interferon alfa c)Physical damage -MAHA-Microangiopathic anemia is found in patients with disseminated intravascular coagulation (DIC) or hemolytic uremic syndrome (HUS) and TTP. Fragmented erythrocytes (schistocytes) also occur with defective prosthetic cardiac valves -March hemoglobilunuria d)Infections -Protozoa-malaria,babesia -Bacteria-Clostridia welchi e)Hypersplenism f)Liver disease-defective fat metabolicm which affect the cell membrane. Other tests -LDH- Serum LDH is a criterion for hemolysis -Serum haptoglobin -A low serum haptoglobin is a criterion for moderate-to-severe hemolysis. -Indirect bilirubin -Unconjugated bilirubin is a criterion for hemolysis Specific hemolytic screen. i)Sickling test –with Na metabisulphite or Na dithionate ii)Hb Electrophoresis-HbSS, HbAS, HbSF, Thalasaemia iii) Osmotic fragility Test(Mean Corpuscular osmotic fragility)-For congenital spherocytosis. Cells more fragile with a tail of fragile cells. iv)G6 phosphate DH test(Dye Reduction Test)- v) Hams Test-For paroxysmal Nocturnal hemoglobinuria. vi) Coomb’s test-Immune hemolytic anaemia vi) MPS for malaria parasites vii)ABO and Rhesus grouping –Newborns 3.Macrocytic anemia Suggestive fingings CBC count-Pancytopenia may occur. RBC indices-Raised MCV>100fl. Reticulocyte count-Low (normal 0.2-2%) PBF-Hypersegmented neutrophils contain 5 or more lobes,          While normal neutrophils contain 3-4 lobes.         -Macro Ovalocytes-Macrocytes may contain nuclear         remnants         -Erythrocytes with megaloblastic nuclei. Other tests LDH and indirect bilirubin high because of intramedullary destruction of megaloblastic red cell precursors. The LDH level is often extremely high, and, following therapy, the fall in the LDH level is an excellent indication of response to or failure of therapy Specific tests Vit B12 i)Serum vitamin B-12 ii)A Schilling test is a radiometric test of cobalamin absorption. The test is given in 3 parts: -First part, radioactive cyanocobalamin is given orally. Meanwhile, unlabeled cyanocobalamin is given intramuscularly to inhibit the uptake of radioactive cobalamin by the liver. Urinary secretion of radioactive cobalamin is then  measured to estimate whether the orally administered cobalamin has been taken up. Low secretion suggests either PA or an abnormality in the terminal ileum that prevented the uptake of IF-cobalamin complexes. -The 2nd phase of the test is performed in the same manner, except that IF is given orally along with radioactive cyanocobalamin. If IF restores the uptake of ingested radioactive cyanocobalamin, the patient most likely has PA. However, if IF does not restore uptake, then an abnormality in the terminal ileum is most likely present. MANAGEMENT Medical Care: The purpose of establishing the etiology of an anemia is to permit selection of a specific and effective therapy. -Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia. Transfusion is only palliative. -In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or reducing transfusions of packed RBCs. -The appropriate treatment of anemia due to blood loss is correction of the underlying condition and oral administration of ferrous sulfate for up to 3months after the correction of anemia to replenish stores. -Relatively few indications exist for the use of parenteral iron therapy, and blood transfusions should be reserved for the treatment of shock or hypoxia. -Nutritional therapy is used to treat deficiency of iron, vitamin B-12, and folic acid. Pyridoxine may be useful in the treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder. -Corticosteroids are useful in the treatment of autoimmune hemolytic anemia. -Treatment of aplastic disorders includes removal of the offending agent whenever it can be identified, supportive therapy for the anemia and thrombocytopenia, and prompt treatment of infection. Avoid transfusion in patients with a potential bone marrow donor because transfusion worsens the probability of cure from transplantation. Certain patients seem to develop a salutary response with immunosuppressive therapy (ie, antithymocyte globulin, cyclosporin). Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic, marrow so that transfusion is not necessary, and platelet and granulocyte counts increase to less dangerous levels  -Therapy and medical care vary considerably in the group of hereditary disorders. Splenectomy has been advantageous in hereditary spherocytosis and hereditary elliptocytosis, in some of the unstable hemoglobinopathies, and in certain patients with pyruvic kinase deficiency. It has little value in most other hereditary hemolytic disorders - Drugs and chemicals capable of producing aplasia or a maturation arrest of erythroid precursors should be discontinued and avoided. Similarly, diseases known to be associated with anemia should be appropriately treated.