Approach to Anemia - Copy.pptx how to diagnose

Important topic for undergraduate students

1. General Approach to Anemia Presenter: Dr Afrah Malik Facilitator: Brig Tahir

2. Contents Definition Clinical Evaluation Laboratory Evaluation Classification of Anemia Treatment References

3. Definition Normal range of hemoglobin values for: Adult males: 13.5–17.5 g/dL (135–175 g/L) Adult females: 12–15 g/dL (120–150 g/L) WHO defines anemia as a hemoglobin level <13 g/dL (130 g/L) in men <12 g/dL (120 g/L) in women Hematocrit levels are less useful than hemoglobin levels in assessing anemia because they are calculated rather than measured directly.

4. Definition cont. These "normal" ranges may not apply to certain populations:   Athletes  – Athletes have been reported to have anemia from a number of causes :   Dilutional anemia from increased plasma volume   Exercise-induced acute phase response with production of inflammatory cytokines   Gastrointestinal bleeding and iron deficiency   Intravascular hemolysis from "march" hemoglobinuria   Note: Performance-enhancing agents including androgens and erythropoietin may cause polycythemia that could mask some of these causes of anemia Living at high altitude  – Patients living at high altitude have values higher than those living at sea level Smokers  – P atients who smoke or have significant exposure to secondary smoke or other sources of carbon monoxide may have HCT higher than normal, occasionally masking the presence of an underlying anemia African-Americans  – Values for hemoglobin in African-Americans of both sexes and all ages are 0.5 to 1.0 g/dL lower than values in comparable Caucasian populations . Some, but not all, of these differences may be attributable to co-existing iron deficiency anemia and/or alpha thalassemia.   Presence of chronic disease  – Normal values for a population with a high incidence of chronic disease may be skewed toward anemic levels. Thus, anemia may be difficult to define in countries in which malnutrition, infection (eg, tuberculosis, malaria), and/or congenital hematologic disorders (eg, thalassemia) are common. Older adults  

5. Clinical Evaluation of Anemia Detailed History Thorough Physical Examination

6. History Any recent history of loss of appetite, weight loss, fever, and/or night sweats , bleeding, fatigue, malaise  infection or malignancy? Is there a history of, or symptoms related to, a medical condition that is known to result in anemia (eg, tarry stools in a patient with ulcer-type pain, significant blood loss from other sites, rheumatoid arthritis, renal failure)? i s the anemia of recent origin, subacute, or lifelong? Recent anemia  an acquired disorder L ifelong anemia accompanied by a positive family history  inherited (eg, the hemoglobinopathies, thalassemia, hereditary spherocytosis). Nutritional history: An assessment of nutritional status is especially important in older adults and alcoholics. P ast history of blood transfusions, liver disease, treatment of the patient (or other family members) with iron or other hematinics, herbal preparations E xposure to toxic chemicals in the workplace or environment should also be obtained. Drugs: alcohol intake , aspirin, nonsteroidal anti inflammatory drugs ethnicity and country of origin  thalassemias and other hemoglobinopathies are particularly common in Middle East, sub-Saharan Africa, and Southeast Asia

7. Physical Examination The skin and mucous membranes may be pale if Hb <8–10 g/dL (80–100 g/L). Especially in areas where vessels are close to the surface such as the mucous membranes, nail beds, and palmar creases If palmar creases are lighter in color than surrounding skin when the hand is hyperextended, the Hb level is <8 g/dL (80 g/L). Clues to the mechanisms of anemia by findings of infection, blood in the stool, lymphadenopathy, splenomegaly, or petechiae. Hepatosplenomegaly and lymphadenopathy  underlying lymphoproliferative disease signs of other hematologic abnormalities Petechiae , purpura  platelet dysfunction signs and symptoms of recurrent infections  neutropenia or immune deficiency states A Palpable mass  underlying carcinoma

8. Physical Examination cont. GPE: the presence or absence of tachycardia, dyspnea, fever, or postural hypotension should be noted Jaundice — Hemolytic Anemia B one tenderness over sternum or anterior tibia Bone pain may signify expansion of the marrow space due to infiltrative disease, as in CML , or lytic lesions, as in multiple myeloma or metastatic cancer. CVS: forceful heartbeat, strong peripheral pulses, and a systolic “flow” murmur neurological signs, including peripheral neuropathy, dementia and signs of subacute combined degeneration of the cord  B12 deficiency Anemia may be multifactorial and the lack of specific symptoms and signs does not rule out silent pathology.

9. Laboratory Evaluation in Initial Workup of Anemia CBC Peripheral Blood Smear Reticulocyte count Tests for Iron supply and storage Bone Marrow Examination Other specialized tests

10. Complete Blood Count H emoglobin H ematocrit R ed cell indices : mean cell volume (MCV) in femtoliters mean cell hemoglobin (MCH) in picograms per cell mean concentration of hemoglobin per volume of red cells (MCHC) in grams per liter (non-SI: grams per deciliter) A number of physiologic factors affect the CBC, including age, sex, pregnancy, smoking, and altitude. Marked alterations in the red cell indices usually reflect disorders of maturation or iron deficiency. The components of the CBC also help in the classification of anemia. Microcytosis is reflected by a lower than normal MCV (<80) MCV >100 reflect macrocytosis The MCHC reflects defects in hemoglobin synthesis ( hypochromia )

11. Peripheral Blood Smear P rovides information about defects in red cell production R eveals variations in cell size ( anisocytosis ) and shape ( poikilocytosis ) RBC morphology RBC Inclusions Leukocyte inclusions and nuclear contour abnormalities Platelet abnormalities

12. Peripheral Blood Smear: RBC MORPHOLOGY Normal: 7.5 um diameter. Roughly the size of the nucleus of a small lymphocyte Anisocytosis : variation in RBC size; large cells imply delay in erythroid precursor DNA synthesis caused by folate or B12 deficiency or drug effect; small cells imply a defect in hemoglobin synthesis caused by iron deficiency or abnormal Hb genes. The automated red cell distribution width (RDW)is a measure of anisocytosis Poikilocytosis : abnormal RBC shapes; suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circulating red cells. RBC INCLUSIONS Howell Jolly bodies Basophilic stippling Heinz bodies Pappenheimer (iron) bodies: iron-containing granules usually composed of mitochondria and ribosomes resemble basophilic stippling but also stain with Prussian blue; lead poisoning, other sideroblastic anemias. Parasites: characteristic intracytoplasmic inclusions; e.g. Trophozoites in malaria

13. Peripheral Blood Smear: LEUKOCYTE INCLUSIONS AND NUCLEAR CONTOUR ABNORMALITIES Toxic granulations: dark cytoplasmic granules; bacterial infection Döhle bodies: 1- to 2-micrometers, blue, oval cytoplasmic inclusions; bacterial infection, Chédiak-Higashi anomaly Auer Rods Hypersegmentation PLATELET ABNORMALITIES Platelet clumping: in vitro artifact- readily detected on smear Giant platelets: very young platelet, increased platelet production or abnormal karyocyte maturation If platelets > 5-6 micrometers in diameter, may not be counted at platelets by electronic counters

14. Abnormality Associated condition(s) Appearance Target cells: central and outer rim staining with intervening ring of pallor Iron deficiency anemia Thalassemia Sickle cell anemia liver disease Teardrop cells: Myelofibrosis other infiltrative processes of marrow Spherocytes: small hyperchromic cell lacking normal central pallor hereditary spherocytosis autoimmune hemolytic anemia G6PD deficiency

15. Abnormality Associated condition(s) Appearance Basophilic stippling: multiple, punctate basophilic cytoplasmic inclusions composed of precipitated mitochondria and ribosomes Lead poisoning Thalassemia Sideroblastic anemia Myelodysplasia Howell-Jolly bodies : 1-um-diameter basophilic cytoplasmic inclusion that represents a residual nuclear fragment, usually single Asplenic patients Heinz Bodies: spherical inclusions of precipitated hemoglobin seen only with supravital stains, such as crystal violet G6PD deficiency Alpha Thalassemia

16. Abnormality Associated condition(s) Appearance Schistocytes ('helmet cells’): fragmented cells of varying sizes and shapes Intravascular haemolysis Mechanical heart valve Disseminated intravascular coagulation 'Pencil' poikilocytes : Iron deficiency anemia Burr cells (echinocytes): regularly shaped, uniformly distributed spiny projections Uraemia Pyruvate kinase deficiency

17. Abnormality Associated condition(s) Appearance Acanthocytes (spur cells): irregularly spiculated Abetalipoproteinemia severe liver disease anorexia nervosa Hypersegmented neutrophils : neutrophil nuclei contain > 2-4 lobes B12 deficiency Folate deficiency Drug effects Auer Rods: eosinophilic rodlike cytoplasmic inclusions AML

18. Reticulocyte Count An accurate reticulocyte count is key to the initial classification of anemia. R eticulocytes  red cells that are slightly larger than normal and grayish blue in color on the Wright-Giemsa stain ( polychromasia) Red cells released prematurely from the bone marrow and their color represents residual amounts of ribosomal RNA. This residual RNA is metabolized over the first 24–36 h of the reticulocyte’s life span in circulation . These cells appear in circulation in response to EPO stimulation or to architectural damage of the bone marrow (fibrosis, infiltration of the marrow by malignant cells, etc.) that results in their disordered release from the marrow. Normally, the reticulocyte count ranges from 1% to 2% R eflects the daily replacement of 0.8–1.0% of the circulating red cell population.

19. Reticulocyte Index- measure of RBC production Reticulocyte count is corrected for: Anemia Early release of marrow reticulocytes into the circulation  increase in lifespan of circulating reticulocytes beyond the usual 1 day The doubly corrected reticulocyte count is the reticulocyte production index RI = (% reticulocytes x patient’s HCT/45%) x (1 / shift correction factor) Shift correction factor varies with the Hct 1.5  Hct 35% 2  Hct 25% 2.5  Hct 15% RI < 2-2.5% - inadequate RBC production for the level of anemia RI > 2.5% - excessive RBC destruction or loss

20. Reticulocyte Count cont. In many hospital laboratories, the reticulocyte count is reported not only as a percentage but also in absolute numbers. If so, no correction is required. In severe chronic hemolytic anemia - red cell production increases six- to sevenfold. This measure alone confirms the fact that the patient has an appropriate EPO response, a normally functioning bone marrow, and sufficient iron available to meet the demands for new red cell formation. If RI <2 in the face of established anemia, a defect in erythroid marrow proliferation or maturation must be present  RBC morphology helps distinguish maturation disorder from hypoproliferative marrow states

21. Tests of Iron Supply and Storage S erum iron, the TIBC, and the percent transferrin saturation : reflect the availability of iron for Hb synthesis Transferrin Saturation % = (Serum Iron / TIBC) x 100 N ormal serum iron : 9 to 27 μmol/L (50–150 μg/dL) N ormal TIBC: 54–64 μmol/L (300–360 μg/dL) N ormal transferrin saturation : 25 to 50% A diurnal variation in the serum iron leads to a variation in the percent transferrin saturation. S erum ferritin : evaluate total body iron stores Adult males: average 100 μg/L, corresponding to iron stores of 1 g. Adult premenopausal females : average 30 μg/L, reflecting lower iron stores (300 mg) A serum ferritin level of 10–15 μg/L indicates depletion of body iron stores However, ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise several-fold above baseline levels. As a rule, a serum ferritin >200 μg/L means there is at least some iron in tissue stores.

22. Bone Marrow Examination A bone marrow aspirate and smear or a needle biopsy can be useful in the evaluation of some patients with anemia. Indications for bone marrow biopsy: When blood laboratory evaluation fails to reveal etiology Additional cytopenias are present Underlying primary or secondary bone marrow process is suspected such as myelofibrosis, a red cell maturation defect, or an infiltrative disease In patients with hypoproliferative anemia, normal renal function, and normal iron status, a bone marrow is indicated. Either the marrow smear or biopsy can be stained for the presence of iron stores or iron in developing red cells. The storage iron is in the form of ferritin or hemosiderin . On carefully prepared bone marrow smears, small ferritin granules can normally be seen under oil immersion in 20–40% of developing erythroblasts. Such cells are called sideroblasts .

23. Other laboratory measurements Additional laboratory tests may be of value in confirming specific diagnoses. E.g. Hb electrophoresis for Thalassemia

24. Classification of Anemia 1. According to mean corpuscular volume 2. Physiological Classification

25. Hypoproliferative Anemias 75% of all cases of anemia It reflects absolute or relative marrow failure in which the erythroid marrow has not proliferated appropriately for the degree of anemia CAUSES: Mild to moderate iron deficiency or inflammation (Majority of cases) Marrow damage Inadequate EPO stimulation  impaired renal function Suppression of EPO production by inflammatory cytokines eg. IL-1 Reduced tissue needs for O2 from metabolic disease such as hypothyroidism. With diabetes mellitus or myeloma, the EPO deficiency may be more marked than would be predicted by the degree of renal insufficiency Characterized by normocytic, normochromic red cells Microcytic, hypochromic cells with mild iron deficiency or long-standing chronic inflammatory disease. The key laboratory tests in distinguishing between the various forms of hypoproliferative anemia include: Iron studies Renal and thyroid function tests A marrow biopsy or aspirate to detect marrow damage or infiltrative disease An iron stain of the marrow will determine the pattern of iron distribution. In anemia of acute or chronic inflammation hepcidin , the iron regulatory hormone produced by the liver, increased in inflammation  binds iron and prevents its reutilization in Hb synthesis Marrow damage by drugs, infiltrative disease such as leukemia or lymphoma, or marrow aplasia is diagnosed from the peripheral blood and bone marrow morphology

26. Hypoproliferative Anemias

27. Maturation Disorders Anemia + inappropriately low reticulocyte production index +macro- or microcytosis on smear + abnormal red cell indices Maturation disorders are divided into two categories: 1. nuclear maturation defects , associated with macrocytosis 2. cytoplasmic maturation defects , associated with microcytosis and hypochromia usually from defects in hemoglobin synthesis. The inappropriately low reticulocyte production index is a reflection of the ineffective erythropoiesis that results from the destruction within the marrow of developing erythroblasts Bone marrow examination shows erythroid hyperplasia.

28. Maturation Disorders: Nuclear Maturation Defects result from: vitamin B12 or folic acid deficiency Drug damage : Drugs that interfere with cellular DNA synthesis, such as methotrexate or alkylating agents Myelodysplasia Alcohol , alone, is also capable of producing macrocytosis and a variable degree of anemia, but this is usually associated with folic acid deficiency.

29. Maturation Disorders: Cytogenetic Maturation Defects Result from severe iron deficiency or abnormalities in globin or heme synthesis Iron deficiency occupies an unusual position in the classification of anemia. Mild to moderate IDA : erythroid marrow proliferation is blunted and the anemia is classified as hypoproliferative. Severe and prolonged IDA : erythroid marrow will become hyperplastic despite the inadequate iron supply, and the anemia will be classified as ineffective erythropoiesis with a cytoplasmic maturation defect. In either case, an inappropriately low reticulocyte production index, microcytosis, and a classic pattern of iron values make the diagnosis clear and easily distinguish iron deficiency from other cytoplasmic maturation defects such as the thalassemias. Defects in heme synthesis, in contrast to globin synthesis, are less common and may be acquired or inherited Acquired abnormalities usually associated with myelodysplasia, may lead to either a macro- or microcytic anemia, and are frequently associated with mitochondrial iron loading. In these cases, iron is taken up by the mitochondria of the developing erythroid cell but not incorporated into heme. The iron-encrusted mitochondria surround the nucleus of the erythroid cell, forming a ring. Based on the distinctive finding of so-called ringed sideroblasts on the marrow iron stain, patients are diagnosed as having a sideroblastic anemia—almost always reflecting myelodysplasia

30. Blood Loss Anemia Trauma, GI hemorrhage, GU sources, internal bleeding Acute blood loss is not associated with an increased reticulocyte production index because of the time required to increase EPO production and, subsequently, marrow proliferation  Manifestations of h ypovolemia Subacute blood loss  modest reticulocytosis, macrocytosis Anemia from chronic blood loss  iron deficiency, hypochromasia, microcytosis

31. Hemolytic Anemia Hemolysis is associated with red cell production indices ≥2.5 times normal. The stimulated erythropoiesis is reflected in the blood smear by the appearance of increased numbers of polychromatophilic macrocytes. A marrow examination is rarely indicated if the reticulocyte production index is increased appropriately. The red cell indices are typically normocytic or slightly macrocytic, reflecting the increased number of reticulocytes. Hemolytic disease: least common forms of anemia. The ability to sustain a high reticulocyte production index reflects the ability of the erythroid marrow to compensate for hemolysis and, in the case of extravascular hemolysis, the efficient recycling of iron from the destroyed red cells to support red cell production. With intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria, the loss of iron may limit the marrow response. The level of response depends on the severity of the anemia and the nature of the underlying disease process. Hemoglobinopathies, such as sickle cell disease and the thalassemias, present a mixed picture  The reticulocyte index may be high but is inappropriately low for the degree of marrow erythroid hyperplasia

32. Hemolytic Anemias cont. Hemolytic anemias present in different ways. Some appear suddenly as an acute, self-limited episode of intravascular or extravascular hemolysis, a presentation pattern often seen in patients with autoimmune hemolysis or with inherited defects of the Embden-Meyerhof pathway or the glutathione reductase pathway. Patients with inherited disorders of the hemoglobin molecule or red cell membrane generally have a lifelong clinical history typical of the disease process. Those with chronic hemolytic disease, such as hereditary spherocytosis, may actually present not with anemia but with a complication stemming from the prolonged increase in red cell destruction such as symptomatic bilirubin gallstones or splenomegaly. Patients with chronic hemolysis are also susceptible to aplastic crises if an infectious process interrupts red cell production.

33. Hemolytic Anemias cont. Precise diagnosis may require more specialized laboratory tests: hemoglobin electrophoresis screen for red cell enzymes Acquired defects in red cell survival- immunologically mediated and require a direct or indirect antiglobulin test or a cold agglutinin titer to detect the presence of hemolytic antibodies or complement-mediated red cell destruction

34. Treatment An overriding principle is to initiate treatment of mild to moderate anemia only when a specific diagnosis is made. Rarely, in the acute setting, anemia may be so severe that red cell transfusions are required before a specific diagnosis is available. Whether the anemia is of acute or gradual onset, the selection of the appropriate treatment is determined by the documented cause(s) of the anemia. Often, the cause of the anemia is multifactorial. For example, a patient with severe rheumatoid arthritis who has been taking anti-inflammatory drugs may have a hypoproliferative anemia associated with chronic inflammation as well as chronic blood loss associated with intermittent gastrointestinal bleeding. In every circumstance, it is important to evaluate the patient’s iron status fully before and during the treatment of any anemia. Therapeutic options for the treatment of anemias have expanded dramatically during the past 30 years. Blood component therapy is available and safe. Recombinant EPO as an adjunct to anemia management in patients with chronic renal failure on dialysis and reduced transfusion needs of anemic cancer patients receiving chemotherapy. Eventually, patients with inherited disorders of globin synthesis or mutations in the globin gene, such as sickle cell disease, may benefit from the successful introduction of targeted genetic therapy.

35. References Harrisons CMDT Davidson UpToDate

36. Thank you