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APPROACH TO A PATIENT WITH ANEMIA Acibadem University Acibadem Medical Faculty Department of Pediatrics Cengiz Canpolat M.D. Professor of Pediatrics Division of pediatric Hematology-Oncology Objectives • Review basic science of the RBC • Define Anemia • Review key aspects of history, physical and laboratory evaluation • Review a systematic approach to the differential diagnosis • http://www.anemia.org/professionals/ • http://www.anemia.org/patients/bonemarrow-basics/ Bone Marrow Definitions • Anemia is defined as the values of hemoglobin, hematocrit which are more than 2 standard deviations below the mean • RBC counts and RBC indices helps us in differential diagnosis RBC-The important players • Hemoglobin – reversibly binds and transports oxygen from lungs to tissues – 4 globin chains & iron RBC-The important players (2) • Iron – key element in the production of hemoglobin – absorption is poor • Vitamin B12 • Folic acid • Zinc General Principles • • • • Anemia is a sign, not a disease. Anemias are a dynamic process. Its never normal to be anemic. The diagnosis of iron deficiency anemia mandates further work-up. Differential Diagnosis • Classification by Pathophysiology – Blood Loss – Decreased Production – Increased Destruction Blood Loss • Acute – Traumatic – Variety of sources • Melena, hematemesis, menometrorrhagia • Chronic – Occult bleeding • • • • Fissura Hemorrhoids Polyps menstruation Decreased Production • • • • • Infectious Neoplastic Endocrine Nutritional Deficiency Anemia of Chronic Disease Decreased Production INFECTIOUS • Bacterial – Tuberculosis • Viral – HIV – Parvovirus – CMV Decreased Production NEOPLASTIC • • • • Leukemia Lymphoma/solid tm mets Myeloproliferative Syndromes Myelodysplasia Decreased Production ENDOCRINE • Thyroid Dysfunction – Hypothyroidism • Erythropoietin Deficiency – Renal Failure Decreased Production NUTRITIONAL DEFICIENCY • Iron • B12 • Folate Anemia of chronic disease * Infections: TB, SBE, osteomyelitis, chronic UTI or pyelonephritis, fungal infections * Chronic inflammatory disorders: JRA, SLE, Sarcoidosis, Collagen Vascular Disease, * Malignancy: Metastasis, Leukemia, Lymphoma, INCREASED DESTRUCTION Hemolytic Anemias • Immune Mediated • Non-immune Mediated Evaluation of the Patient • HISTORY – Is the patient bleeding? • Actively? In past? – Is there evidence for increased RBC destruction? – Is the bone marrow suppressed? – Is the patient nutritionally deficient? Pica? Evaluation of the Patient (2) REVIEW OF SYMPTOMS CNS Fatique, Depression, Impaired cognitive function GIS Anorexia, Neausia CVS Lower skin temperature, Pallor of skin mucous membranes and conjuctivae CRS Dyspnea, Tachycardia, Palpitations, Cardiac enlargement/hypertophy, increased pulse pressure, Systolic ejection murmur, Risk of cardiac failure IS Impaired T-cell and Macrophage function GUS Menstrual Problems Evaluation of the Patient (3) PHYSICAL EXAM •Stable or Unstable? -ABCs -Vitals •Pallor •Jaundice / hemolysis •Lymphadenopathy •Hepatosplenomegally •Bony Pain •Petechiae •Rectal-? Occult blood Red Cell Indices • • • • • • • RBC Hb Hct MCV MCH MCHC RDW Red Blood Cell Hemoglobin Hematocrit Mean Corpuscular Volume Mean Corpuscular Hemoglobin MCH concentration Red Cell Distribution Width Red blood cell indices (RBC), MCH, MCHC, MCV, RDW – Use of volume-sensitive automated blood cell counters, such as the Coulter counter. The red cells pass through a small aperture and generate a signal directly proportional to their volume. – Other automated counters measure red blood cell volume by means of techniques that measure refracted, diffracted, or scattered light Red blood cell indices • • • • • • Automated RBC measurement: –RBC, Hb, MCV Derived RBC indices: –Hct = MCVx RBC x 0.1 –MCH = Hb/RBC x 1 000 000 –MCHC = Hb/Hct x 0.1 Laboratory Evaluation • Initial Testing – CBC w/ differential (includes RBC indices) – Reticulocyte count – Peripheral blood smear Erythrocyte Development Reticulocytes Reticulocytes Reticulocyte count • • • • Retic count = % immature RBC Normal 0.5-1.5% (for non-anemic) <1% Inadequate production >=2% Increased production (? adequacy) Laboratory Evaluation (2) • Bleeding – Serial HCT or HGB • Iron Deficiency – Iron Studies • Hemolysis – Serum LDH, indirect bilirubin, haptoglobin, coombs, coagulation studies • Bone Marrow Examination • Others-directed by clinical indication – hemoglobin electrophoresis – B12/folate levels Differential Diagnosis No 2 • Classification by Morphology – Normocytic – Microcytic – Macrocytic Microcytic Anemia • MCV <70 • Reduced iron availability • Reduced heme synthesis • Reduced globin production Iron deficiency is a common form of malnutrition that affects more than 2 billion people globally. - Project IDEA (Iron Deficiency Elimination Action)®, CDC Iron defficiency Microcytic Anemia REDUCED IRON AVAILABILTY • Iron Deficiency – – – – Deficient Diet/Absorption Increased Requirements Blood Loss Iron Sequestration • Anemia of Chronic Disease – Low serum iron, low TIBC, normal serum ferritin – MANY!! • Chronic infection, inflammation, cancer, liver disease Iron absorbtion (2) • • The body absorbs iron best from ingestion of meat (heme-iron pathway) • • Absorption of iron can be increased by adjunct ingestion of the following: – Absorption of iron can be enhanced by foods high in vitamin C _ Iron absorption can be blocked by coffee, tea, egg yolk, milk, fiber and spinach Microcytic Anemia REDUCED HEME SYNTHESIS • Lead poisoning • Acquired or congenital sideroblastic anemia Characteristic smear finding ``Basophylic stippling`` Sideroblastic Anemias • Heterogenous grouping of anemias defined by presence of ringed sideroblasts in the BM • Etiologies: – Hereditary (rare), type of porphyria – Myelodysplasia – EtOH – Drugs (INH, Chloramphenicol) • Tx: – Trial of pyridoxine for hereditary or INH induced SA Sideroblastic anemia • Accumulation of mitochondrial iron in erythroblasts • Hereditary • Drugs - INH, lead, zinc, alcohol, chloramphenicol, cycloserine, plavix • Hypothermia • Confirm w/ BM Bx Microcytic Anemia REDUCED GLOBIN PRODUCTION • Thalassemias • Smear Characteristics – – – – Hypochromia Microcytosis Target Cells Tear Drops Thalassemias • Genetic defect in hemoglobin synthesis – synthesis of one of the 2 globin chains ( or ) – Imbalance of globin chain synthesis leads to depression of hemoglobin production and precipitation of excess globin (toxic) – “Ineffective erythropoiesis” – Ranges in severity from asymptomatic to incompatible with life (hydrops fetalis) – Found in people of African, Asian, and Mediterranean heritage Macrocytic anemia Macro RPI >= 2 RPI < 2 Check Occult Blood Loss Check B12 and folate No Coombs’ test Yes Macrocytic Anemia • MCV > 100 • Megaloblastic Abnormalities in nucleic acid metabolism – B12, Folate • Non-megaloblastic: Abnormal RBC maturation – Myelodysplasia • Alcohol, liver disease, hypothryroidism, GIS Ca, chemotherapy/drugs Macrocytic: RPI < 2 B12/Folate B12 Low Normal Folate Low MMA High MMA Homocysteine Normal Homocysteine High Consider Liver, Renal, Thyroid, Alcohol, Chronic dis. Consider Bone Marrow Bx Macrocytic: RPI < 2 Megaloblastic Anemia B12 • Inadequate absorption • Synthesized by bacteria • Meat, fish, dairy (strict vegans) • Absorbed as B12-IF complex in ileum (gastrectomy) • Ca++ and pH dependant (PPI) Folate • Inadequate intake • Synthesized by plants and microorganism • Green leafy vege’s • Fruits • Absorbed in jejunum Macrocytic: RPI < 2 Megaloblastic Anemia Smear • Macro-ovalocytic • Polychromasia • Hypersegmented neutrophil Other Labs • Homocysteine – Folate def. • Methylmalonic A – B12 def. • Intrinsic Factor Ab test – very specific for pernicious anemia but only 50%sensitve • Parietal cell AB test – quite sensitive (90%) but not Spesific • Schilling test Macrocytic: RPI < 2 Non-megaloblastic • Consider Liver, Renal, Endocrine (thyroid), alcohol, drugs • Consider anemia of chronic disease • Myelodysplastic • Myeloproliferative Leukemia, Lymphoma, Multiple Myeloma • Get Bone Marrow Biopsy Macrocytic: RPI < 2 continues Aplastic Anemia • Fanconi anemia – congenital • Direct stem cell destruction – external radiation • Drugs - chloramphenicol, gold, sulfonamides, felbamate • Other Toxins - Solvents, degreasing agents, pesticides • Viral infection - parvovirus B19, HIV, other • Idiopathic Macrocytic: RPI >= 2 Occult Blood Loss? Yes Investigate source No Check for Hemolysis Peripheral smear Coombs’ (DAT) Macrocytic: RPI >= 2 Hemolytic Anemia Other Lab Characteristics • • • • • • RBC morphology Serum haptoglobin Serum LDH Unconjugated bilirubin Hemoglobinuria Hemosiderinuria Macrocytic: RPI >= 2 Hemolytic Anemia Coombs’ (DAT) Positive Immune Hemolysis Drug related Hemolysis Transfusion, Infection, Cancer Negative Hemoglobinopathy, G6PD, PK, Spherocytosis, Eliptocytosis, PNH, TTP, DIC Normocytic Anemia Hyperproliferative (RPI >= 2) • Use same flow chart as macrocytic hyperproliferative Occult Blood Loss? Yes Investigate source No Check for Hemolysis Peripheral smear Coombs’ (DAT) Normocytic Anemia Hypoproliferative (RPI < 2) 1. Get iron panel (ferritin)/B12/folate - some clue from RBC indices to check early disease, high RDW, peripheral smear. 2. Consider liver, renal, drugs, toxin, endocrine (thyroid), and anemia of chronic disease. 3. Get BM bx - Leukopenia, thrombocytopenia, CRI < 0.1 - Aplastic anemia/pancytopenia - Abnormal (immature) cells on smear Elliptocytes/ovalocytes • Abnormal cytoskeletal proteins • Hereditary elliptocytosis Howell Jolly body Nuclear remnant - DNA • hemolytic anemia • absent or hypofunction spleen Schistocyte/helmet cells • Fragmented (mechanical or phagocytosis) • DIC • TTP • HUS • Vasculitis • prosthetic heart valve • severe burns Sickle cells • Molecular aggregation of Hgb-S • SS, SC, S-thallassemia • Rarely S-trait Spherocyte • There is an absent central pallor, red cells look smaller Hereditary spherocytosis Stomatocyte Mouth like membrane defects • Smear artifact • Hereditary stomatocytosis • Liver disease TTP-HUS / DIC Target cells • Hemoglobinopathies • Thalassemia • Liver disease Tear drop cells • Smear artifact • Myelofibrosis • Promyeloblastic leukemia • Space occupying lesions of marrow