Diagnostic Approach to Anemia Prof. Dr. Teoman SOYSAL Definition of anemia ◼ Anemia: A reduction in – red cell mass – ◼ O2-carrying capacity of blood It is expressed in terms of reduction in the concentration of Hb (or RBC or Hct%) compared to values obtained from a reference population. (2 SD below normal) Reference values (adults) (I) Parameter ◼ ◼ ◼ Female Male RBC (x1012/L) 4.8+0.6 5.4+0.9 Hb (g/dL) 14+2 16+2 Htc (%) 42+5 47+5 Definition of anemia ◼ ◼ Hb level of a patient which is below the normal ranges of that age and sex. For adults: WHO criteria define anemia as – hemoglobin ◼ ◼ ◼ But: <12 g/dL in women and <13 g/dL in men The reference values for red cells ,Hb or Hct may difer according to – – – – – sex/age Race Altitude Socioeconomical changes Study/reference etc BEUTLER andWAALEN BLOOD, 1 MARCH 2006 VOLUME 107, NUMBER 5 Age and blood count changes Neutrophyls Eos. Baso Lenfo Mono Hb 12 mo 6-17.5 1.5-8.5 0.05-0.7 0-0.20 4-10.5 0.05-1.1 11.1-14.1 4y 5.5-15 1.5-8.5 0.020.65 0-0.20 2-8 0-0.8 11.2-14.3 6y 5-14.5 1.5-8 0-0.65 0-0.20 1.5-7 0-0.8 11.4-14.5 10 y 4.5-13 1.8-8 0-0.60 0-0.20 1.5-6.5 0-0.8 11.8-15 21 y 4.5-11 1.8-7.7 0-0.45 0-0.20 1-4.8 0-0.8 E: 16 K: 14 age WBC WBC: x10E3/mm3 Hb:g/dL Reference values (II) ◼ Ret (% / n) 0.5-2.5 / 50-100x109/L ◼ MCV (fl) 90+7 ◼ MCH (pg) 29+2 ◼ MCHc (g/dL) 34+2 ◼ RDW (%) 11.5-14.5 RBC % 50 100 200 fl RBC RDW: Red cell distribution width % 50 100 200 fl RBC % 50 100 200 fl Reticulocyte Normal Ranges ◼ Male: % 0.8 - 2.5 ◼ Female: % 0.8 - 4.1 Increased counts •Hemolysis •Acute bleeding •Response to treatment Corrected Rtc: Patient Hb/Normal Hb x Rtc % Reticulocytosis: > 100.000 /mm3 Diagnosis and investigation: ◼ ◼ ◼ Is the patient anemic? What is the type of anemia? What is the cause of anemia? Classification of anemia ◼ Morphologic – Normocytic: MCV= 80-100fL – Macrocytic: MCV > 100 fL – Microcytic : MCV < 80 fL ◼ Pathogenic (underlying mechanism) – Blood loss (bleeding) – Decreased RBC production – Increased RBC destruction/pooling !!!!! ◼ Plasma volume changes have to be considered before determining a diagnosis of anemia . – Volume contraction:Underestimation of anemia – Volume overload: Underestimation of Hb level Volume changes/acute bleeding and anemia 1 normal Hct:Normal 2 Increased plasma volume Hct: Low 3 Dehydration Hct:Increased 4 5 Acute blood loss(early) Hct:unchanged Chronic anemia Hct: Low !!!!! ◼ A normal Hb in a patient in whom an elevated Hb level is expected may represent anemia .(eg:COPD + Hb:N) !!!!!! ◼ ◼ Different red cell measures of a patient may give discordant values in special conditions. eg:Thalassemia trait Low Hb, high RBC, low MCV,normal RDW Hb: 10 g/dL (anemia) RBC: 6.5 million/mm3 (erythrocytosis) MVC : 65 fL RDW: Normal !!!! ◼ ◼ ◼ Anemia is rarely a disease by itself, It is mostly a manifestation or consequence of an underlying (genetic or acquired) disease. The finding of anemia has to start attempts to disclose an underlying disease . – What is the cause of anemia ? Normocytic Anemias ◼ ◼ ◼ ◼ ◼ Acute posthemorrhagic anemia Hemolytic anemia (except thalassemia and some other Hb disorders) Aplastic anemia Pure red cell aplasia Bone marrow infiltration ◼ ◼ ◼ ◼ ◼ ◼ Endocrin diseases Renal failure Liver disease Chronic disease anemia Protein malnutrition Hypovitaminosis C Microcytic anemias ◼ ◼ ◼ ◼ ◼ Iron deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning Anemia of chronic diseases (some cases) Macrocytic anemias ◼ Megaloblastic – Oval macrocytes ◼ Non-megaloblastic Megaloblastic Macrocytic Anemias ◼ ◼ ◼ Vit B12 deficiency Folic acid deficiency Other. Non-megaloblastic Macrocytic Anemias Anemia of acute bleeding ◼ Hemolytic anemias ◼ Leukemias (esp: acute) ◼ Myelodysplastic syndromes ◼ Liver disease ◼ ◼ ◼ ◼ ◼ ◼ Aplastic anemia Diseases infiltrative to the bone marrow Alcoholism Hypothyroidism Scurvy Pathogenic classification (Causes of anemia) ◼ ◼ ◼ Relative (increased plasma volume) Decreased RBC production Blood loss – Anemia due to acute bleeding ◼ Increased RBC destruction Pathogenic classification (Causes of anemia) ◼ Decreased RBC production – Decreased Hb production – Defective DNA synthesis – Stem cell defects ◼ ◼ Pluripotent stem cell Erythroid stem cell(progenitors) – Other less defined reasons ◼ Blood loss – Anemia due to acute bleeding ◼ ◼ Increased RBC destruction Relative(increased plasma volume) Decreased Hb production ◼ ◼ ◼ ◼ Iron deficiency anemia Thalassemia Sideroblastic anemia Lead poisoning Defective DNA synthesis ◼ ◼ ◼ Vit B12 deficiency Folic acid deficiency Other. Pluripotent stem cell defects ◼ ◼ Aplastic anemia Leukemia or myelodysplastic syndromes Defective erythroid stem cell ◼ ◼ ◼ ◼ Pure red cell aplasia Anemia of chronic renal failure Endocrin disease anemia Congenital dyserythropoetic anemias Decreased RBC production due to multipl or undefined mechanisms ◼ ◼ ◼ Anemia of chronic diseases Bone marrow infiltration Anemia due to nutritional defects Anemias caused by increased RBC destruction (hemolytic anemias) Can be classified as; ◼ Hemolysis due to intracorpuscular defects ◼ Hemolysis due to extracorpuscular defects Or ◼ Hereditary hemolytic diseases ◼ Acquired hem. diseases Or ◼ Intravascular hemolysis ◼ Extravascular hemolysis etc. A Very Simple Classification of Hemolytic Anemias 1- Abnormalities of RBC interior a. Enzyme defects b. Hemoglobinopathies & Thalassemia M Hereditary 2-RBC membrane abnormalities a. Hereditary spherocytosis, elliptocytosis etc b. Paroxysmal nocturnal hemoglobinuria c. Spur cell anemia 3- Extrinsic factors a. Hypersplenism b. Antibody : immune hemolysis c. Traumatic & Microangiopathic hemolysis d. Infections , toxins , etc Acquired Is the patient anemic ? ◼ ◼ ◼ ◼ RBC count HB level Hct level Volume status What is the type of anemia? ◼ ◼ ◼ ◼ ◼ History and physical exam. RBC,HB,Hct , MCV, MCH,RDW Red cell morphology ( peripheral smear) Reticulocyte count – Incresed ? ◼ Other Lab. investigations Lab. investigation of anemia(1) ◼ ◼ ◼ ◼ ◼ WBC count and differential Platelet count and morphology ESR Biochemistry, special tests and others Bone marrow exam.(only when indicated) Lab. investigation of anemia(2) ◼ Serum values of – Iron – TIBC – Ferritin – Bilirubins – Proteins / electrophoresis – LDH – Vit B12 and /or Folic acid (None of these tests are routine screening tests) Lab. Investigation of Anemia(3) ◼ ◼ Liver, renal, endocrin functional tests Urinalysis – Hemosiderin ◼ Occult GIS bleeding / parasites etc (tests should be chosen individually-do not order routinly ) ◼ Tests to diagnose the type of hemolytic anemia – If hemolytic anemia is considered Normocytic anemia Retic. count normal/low Secondary anemia Renal, Hepatic, Endocrin , Chronic disease Retic. count increased • No sign of secondary anemia • Other signs of bone marrow disease may be + Response to treatment Hemolytic anemia (Normal marrow) Hypoplastic Marrow AA, pure red cell aplasia Bone marrow infiltrative diseases Leukemia , Myelofibrosis Metastatic disease Dysplastic marrow: MDS Acute bleeding Microcytic anemia Serum iron high Serum iron normal /high Serum iron decreased Bone marrow iron content and sideroblasts Hemoglobin studies Ferritin low Ferritin: Normal or increased Sideroblastic anemia Thalassemia , HbC , others Iron deficiency Anemia of chronic diseases Macrocytic anemia Peripheral smear Retic. count Retic. count Normal/ decreased Retic. count Increased Hemolysis Megaloblastic Acute bleeding Deficiencies of VitB12 ,Folic acid or other causes Non-Megaloblastic Liver diseases Myelodysplastic syndrome Bone marrow infiltration Acute leukemia Aplastic Anemia, Alcoholism Hypothyoidism etc Case I ◼ ◼ 38 years old, ♀ Tiredness, hair loss, nail changes Microcytic anemia Serum iron high Serum iron normal /high Serum iron decreased Bone marrow iron content and sideroblasts Hemoglobin studies Ferritin low Ferritin: Normal or increased Sideroblastic anemia Thalassemia , HbC , others Iron deficiency Anemia of chronic diseases Microcytic anemias Diagnosis (type of anemia) MCV RDW Serum Iron Iron binding capacity Iron deficiency Thalassemia Chronic disease anemia N N RBC count: Thalassemia minor >Iron deficiency N Ferritin ESR/acute phase signs Hemogl. changes May change None Normal May be diagnostic Elevated None Case I ◼ ◼ 38 years old, ♀ Tiredness, hair loss, nail changes What is your diagnosis? ◼ What is the next step? – Prove iron deficiency ◼ Serum iron, TIBC, Ferritin – Find out the cause of iron deficiency ◼ Chronic blood loss / excessive need-inadequate intake – Menstruel bleeding, Pregnancy – GI bleeding – Inadequate intake or malabsorbtion etc – Treat both iron deficiency and the cause Case II 26 y o Slight symptoms •Decreased excercise tolerence •Paleness •Long history of being anemic on routine CBC’s ,non responsive to iron RBC:5.500.000/mm3 Hb: 10 g/dL MCV: 60 fL RDW: 14.3 Retic: %2 WBC: 5000/mm3 Plt: 200.000/mm3 Name the blood picture. Further questions to ask to the patient? Further tests to do ? Ferritin : slightly elevated HbA2: slightly elevated, Hb F: normal Final Diagnosis ? Case III • 70 y o, male •Fatigue, weakness •Sore tongue, poor taste sensation •Papill. atrophy-beefy tongue •Paresthesias •Loss of position sense, ataxia •Decreased deepWBC: tendon reflexes Hgb: 2.300/µl 11 g/dL 3 units of red cellHct: transfusion %33 made before admission MCV: 122 fL MCH: 39pg MCHC: %34 RDW: 30.5 Plt: 100.000/µl Retic: 1% Macrocytosis Anisocytosis, neutrophyl hypersegmentation, oval macrocytes Macrocytic anemia Peripheral smear Retic. count Retic. count Normal/ decreased Retic. count Increased Hemolysis Acute bleeding Megaloblastic Non-Megaloblastic Liver diseases Deficiencies of Myelodysplastic syndrome VitB12 ,Folic acid Acute leukemia or other causes Bone marrow infiltration Aplastic Anemia, Alcoholism Hypothyoidism etc What is the blood picture ? (The type of the disorder) ◼ What is your diagnosis? – Why? Normocytic anemia Retic. count normal/low Secondary anemia Renal, Hepatic, Endocrin , Chronic disease Retic. count increased • No sign of secondary anemia • Other signs of bone marrow disease may be + Response to treatment Hemolytic anemia (Normal marrow) Hypoplastic Marrow AA, pure red cell aplasia Bone marrow infiltrative diseases Leukemia , Myelofibrosis Metastatic disease Dysplastic marrow: MDS Acute bleeding 60 y o Normocytic anemia Reticulocytes: 1% Pale, pruritus, hypertension Urea + creatinin elevated ? Hoarse voice Lethargy Hair loss Dry skin Weight gain Poor memory Bradycardia ? Symmetric polyarthritis Morning stiffness Sc nodules ? Case IV • 65 y o , male •One month history of fever, cough and hemoptysis • ESR: 80mm/h; high CRP •Sputum + for TBC bacteria; chest x-ray shows right apical infiltrate Normocytic anemia, MCV normal, RDW ↑, What is the type of anemia? What is the diagnosis? •This case could also present as a microcytic anemia .What would you expect from the iron studies in that Retic.: 2% situation? Low iron, Low TIBC, High Ferritin Normocytic anemia Retic. count normal/low Secondary anemia Renal, Hepatic, Endocrin , Chronic disease Retic. count increased • No sign of secondary anemia • Other signs of bone marrow disease Response to treatment Hemolytic anemia Acute bleeding (Normal marrow) Hypoplastic Marrow AA, pure red cell aplasia Bone marrow infiltrative diseases Leukemia , Myelofibrosis Metastatic disease How to decide the next step? Dysplastic marrow: MDS History PE Smear Other tests Case IX 67 y o, male •Anemia symptoms •Severe bone pain CBC •Normocytic anemia What is your possible diagnosis? What is the next step? •ESR:>100mm/h •Hypercalcemia •Hyperglobulinemia •Renal failure Morphologic abnormalities in hemolytic anemias • Sickle cell: Sickle cell anemia • Target cels: Thalassemia, HbC disease, liver disease, splenectomy • Schistocytes: Microangiopathic hem anemia, uremia, DIC, malignant hypertesion, eclampsia, disseminated vasculitis or malignancy, • Agglutination: Cold agglutinin disease • Heinz bodies: Unstable Hb, G6PD deficiency and oxidant stress Special Lab. Examinations ◼ ◼ ◼ ◼ ◼ ◼ ◼ Coombs antiglobulin test - immune hemolysis Osmotic fragility test - spherocytosis Autohemolysis- G6PD,PK, spherocytosis Red cell enzyme assays- RBC enzyme defects Membrane protein analysis- membrane defects Red cell sickling, HbS- sickle cell anemia Hemoglobin electrophoresis and HbA2, Hb F , HHb,etc - Hemoglobinopathies and thalassemias ◼ ◼ HAM and sucrose lysis tests and GPI-linked protein analysis by flow cytometry- PNH Oxygen dissociation curve- High oxygen affinity Hb Case V 18 y o , male Weakness, paleness, slight icterus, splenomegaly, bile stones Family history + WBC: 5600/µl Hgb: 9,6 g/dL MCHC: %37 Plt: 300.000/µl Retic: %9 ? Ind Bil: slightly elevated LDH: elevated Haptoglobin : low Red cell osmotic fragility increased Normal RBC spherocyte ? Case VI 38 y o Cough , fever WBC: 12.000/µl Hgb: 11 g/dL Hct: 22 % MCV: 130 MCH: 40 MCHC: 36 RDW:28 Plt: 160.000/µl Case VII 34 y o, male 2-3 weeks history of •Decreased exercise capacity •Paleness •Headache, sore throat 2 days history of •Cough and fever •Red spots on the skin CBC WBC: 33.000/mm3 Hb: 7 g/dL Retic: 1% Plt: 12.000/mm3 Case IX 60 y o, female Sudden onset Pallor, palpitation Slight scleral icterus splenomegaly CBC Hb: 8 g/dL WBC: 10.000/mm3 Plt: 450.000/mm3 Retic: 10% What is your diagnosis? What is your next step? Indirect bilirubin: high LDH: high Haptoglobin: low D/I: Coombs + Case X 70 y o , male •Under examination for prostat enlargement +One month history of •Bone pain •Symptoms of anemia WBC: 8000/mm3 Hb: 8 g/dL MCV: 88 fL RDW: 14 Retic: 2% Plt: 220.000/mm3 Morphologic abnormalities in hemolytic anemias ◼ Polychromasia: Reticulocytes ◼ Spherocyte : Hereditary spherocytosis, immune hem. anemia, burns, chemical injury to RBC ◼ Elliptocytes: Hereditary ovalocytosis, ◼ Stomatocytes: Hereditary stomatocytosis, alcoholism ◼ Acanthocytes: Spur cell anemia with liver disease, abetalipoproteinemia ◼ Echinocytes: Pyruvate kinase deficiency, uremia
