ANAEMIA- BASIC ASPECTS H.A. MWAKYOMA, MD

Objectives Review basic science of the RBC Define Anemia Review key aspects of history, physical and lab evaluation Review a systematic approach to the differential diagnosis Case-based application of clinical concepts

RBC-The important players Hemoglobin reversibly binds and transports 02 from lungs to tissues 4 globin chains & iron

RBC-The important players (2) Iron key element in the production of hemoglobin absorption is poor Transferrin iron transporter Ferritin iron binder, measure of iron stores, *also acute phase reactant*

Definitions Anemia-values of hemoglobin, hematocrit or RBC counts which are more than 2 standard deviations below the mean HGB<13.5 g/dL (men) <12 (women) HCT<41% (men) <36 (women) Limitations-1. Given that these ranges include 95% of the normal population, the 2.5% of normal subject with values which fall below the normal range will be arbitrarily depicted as being anemic 2. The normal range for HGB and HCT is so wide that, for example a male patient with a baseline HCT of 49% may lose up to 15% of his RBC mass through hemolysis or blood loss and still have a HCT within the normal range

Definition of anemia 1. Reduction in the hemoglobin concentration in blood 2. Decreased total circulating red cell mass

Normal values for peripheral blood Female Male Erythrocytes (per µl) 4.8±0.6x106 5.4±0.8x106 Hemoglobin (g/dl) 14 ±2 16 ±2 Hematocrit (%) 42 ±5 47 ±5 Reticulocytes (%) 1 1 ___________________________________________ Mean corpuscular volume (MCV; µm3) 82-92 Mean corpuscular hemoglobin (MCH; pg) 27-32 Mean corpuscular hemoglobin concentration (MCHC; %) 32-36

Etiologic classification of anemias Impaired red cell production A. Disturbance of proliferation and differentiation of stem cells B. Disurbance of proliferation and maturation of erythrocytes II. Increased rate of destruction (hemolytic anemias) A. Intrinsic abnormalities B. Extrinsic abnormalities

Etiologic classification of anemias (1) I. Impaired red cell production A. Disturbance of proliferation and differentiation of stem cells ( aplastic anemia, pure red cell aplasia) B. Disurbance of proliferation and maturation of erythrocytes: 1.Defective DNA synthesis (megaloblastic anemias) 2.Defective Hb synthesis: a/. Deficient heme synthesis (iron deficiency) b/. .Deficient globin synthesis (thalassemia) 3. Unknown or multiple mechanisms (anemia of chronic disease, anemia of marrow replacement)

Etiologic classification of anemias (2) II. Increased rate of destruction (hemolytic anemias) A. Intrinsic abnormalities Hereditary 1. Red cell membrane defects (hereditary spherocytosis, hereditary eliptocytosis) 2. Red cell enzyme deficiencies a/. Glycolytic enzymes: pyruvate kinase, hexokinase b/. Enzymes of hexose monophosphate shunt: G-6PD, glutathione synthetase 3. Disorders of globin synthesis a/. Deficient globin synthesis (thalassemia) b/. Structurally abnormal globin synthesis (sickle cell anemia, unstable hemoglobins) Acquired 1. Membrane defect: paroxysmal nocturnal hemoglobinuria

Etiologic classification of anemias (3) B. Extrinsic abnormalities 1. Antibody mediated a/. Autoantibodies (idiopathic, drug-associated, SLE, malignancies) b/. Isohemagglutinins (transfusion reactions, erythroblastosis fetalis) 2. Mechanical trauma of RBC a/. Microangiopathic hemolytic anemias (thrombotic thrombocytopenic purpura, DIC) b/. Cardiac traumatic hemolytic anemia 3. Chemicals and microorganisms 4. Sequestration in mononuclear phagocytic system - hypersplenism

Classification of anemias (simplified) 1. Deficiency anemias 2. Aplastic anemia 3. Hemolytic anemias 4. Secondary anemias

Morphologic classification of anemias Type MCV MCHC Common cause ________________________________________________________ Macrocytic anemia increased normal Vitamin B12 deficiency Folic acid deficiency Microcytic anemia - hypochromic decreased decreased Iron deficiency Thalassemia - normochromic decreased normal Spherocytosis or normal Normocytic anemia normal normal Aplastic anemia - normochromic Chronic renal failure Some hemolytic anemia

Stem cell disorder 2. Pure red cell aplasia B. Acquired 1. Aplastic anemia 2. Pure red cell aplasia A. Congenital B. Acquired

CASE ML is a 64-year old male who has not had any primary care for several years. When he tried to give blood last week, he was told that he was anemic. He presents to your clinic for evaluation. What would you do??

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? PMH including medication review, toxin exposure

Evaluation of the Patient (2) REVIW OF SYMPTOMS Decreased oxygen delivery to tissues Exertional dyspnea Dyspnea at rest Fatigue Signs and symptoms of hyperdynamic state Bounding pulses Palpitations Life threatening: heart failure, angina, myocardial infarction Hypovolemia Fatiguablitiy, postural dizziness, lethargy, hypotension, shock and death

Evaluation of the Patient (3) PHYSICAL EXAM •Stable or Unstable? -ABCs -Vitals •Pallor •Jaundice -hemolysis •Lymphadenopathy •Hepatosplenomegally •Bony Pain •Petechiae •Rectal-? Occult blood

Laboratory Evaluation Initial Testing CBC w/ differential (includes RBC indices) Reticulocyte count Peripheral blood smear CBC-red cell indices-size-micro,macro, normo, color(chromasia) WBC-leukopenia should alert to bone marrow suppression Differential-immature forms Retic count-high-indicates increased response to continued hemolysis or blood loss stable anemia w/ low retic is strong evidence for deficient production of RBCs (reduced marrow response) Smear-as above, nuceated RBCs hematologic dz(sickle, thal,hemolytic anemia), things missed by automated counters: schistocytes, RBC parasits, evidence for hemolysis

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 Classification by Pathophysiology Blood Loss Decreased Production Increased Destruction Classification by Morphology Normocytic Microcytic Macrocytic

Blood Loss Acute Chronic Traumatic Variety of sources Occult bleeding Melena, hematemesis, menometrorrhagia Chronic Occult bleeding Colonic polyp/carcinonma

Decreased Production Infectious Neoplastic Endocrine Nutritional Deficiency Anemia of Chronic Disease

Decreased Production INFECTIOUS Bacterial Tuberculosis MAI Viral HIV Parvovirus

Decreased Production NEOPLASTIC Leukemia Lymphoma/Myeloma Myeloproliferative Syndromes Myelodysplasia Primary Bone Marrow involvement Marrow dysfunction vs. Marrow infiltration

Decreased Production ENDOCRINE Thyroid Dysfunction Hypothyroidism Erythropoietin Deficiency Renal Failure

Decreased Production NUTRITIONAL DEFICIENCY Iron B12 Folate

Macrocytic Anemia MCV > 100 Megaloblastic:Abnormalities in nucleic acid metabolism B12, Folate Non-megaloblastic:Abnormal RBC maturation Myelodysplasia ETOH, liver dz, hypothryroidism, chemotherapy/drugs Note hypersegmented polys – B12 & folate deficiency

Microcytic Anemia MCV <80 Reduced iron availability Reduced heme synthesis Reduced globin production

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

Microcytic Anemia REDUCED HEME SYNTHESIS Lead poisoning Acquired or congenital sideroblastic anemia Characteristic smear finding: Basophylic stippling

Microcytic Anemia REDUCED GLOBIN PRODUCTION Thalassemias Smear Characteristics Hypochromia Microcytosis Target Cells Tear Drops

Differential Diagnosis-Revisited Classification by Pathophysiology Blood Loss Decreased Production Increased Destruction

INCREASED DESTRUCTION Immune Mediated Non-immune Mediated AKA: hemolytic anemias

Increased Destruction IMMUNE MEDIATED Cold Agglutinin Paroxysmal nocturnal hemoglobinuria Post mycoplasmal hemolytic anemia Warm Agglutinin Drug induced Autoimmune hemolytic anemia Transfusion reaction

Increased Destruction NON-IMMUNE MEDIATED Extra-corpuscular Macro-circulatory Hypersplenism Extracorporeal circulation Micro-circulatory DIC Intra-corpuscular RBC Wall (membrane or enzyme defects) Heme or globin abnormalities (HbS, C)

A haemolytic state exists when the in vivo survival of the RBC is shortened. Anaemia occurs if the onset of haemolysis is sudden with no time for marrow compensation or in severe chronic haemolysis when the mean red cell life is very short.