Causes Anemia Workup - Exaggerated

Anemia - Definition Update on (Approach to) Anemia • Decrease in the number of circulating red blood cells How to efficiently and accurately • Most common hematologic disorder by far work up the anemic patient • Almost always a secondary disorder • As such, critical for internist to know how David L. Diuguid, MD Associate Professor of Clinical Medicine to evaluate/determine cause College of Physicians & Surgeons of Columbia University

Anemia - Causes Anemia Workup - Exaggerated

• Iron/TIBC/Ferritin •Acid hemolysis • Folate/B • Blood loss 12 • Osmotic fragility • LDH/Bilirubin • Rx iron/folate/B • Decreased production of red blood cells 12 • Haptoglobin/Urine for •Type & Cross (Marrow failure) hemosiderin • Transfuse 2-4 units • Increased destruction of red blood cells • Coombs Test – Direct & indirect • GI Consult –Hemolysis • Hemoglobin • Hematology Consult – electrophoresis Bone Marrow

ANEMIA

ANEMIA Decreased Production Increased Destruction

1 Anemia Anemia Workup - 1st Test

• History and Exam • Reticulocyte count RETICULOCYTE • Blood film COUNT •MCV • Ferritin • WBC, diff, platelets

Reticulocyte Count - Absolute Value

• = Retic % x RBC Count – eg 0.01 x 5,000,000 = 50,000 • Normal up to 120,000/µl • More accurate way to assess body’s response to anemia

Anemia - Peripheral Blood Smear Anemia Workup Findings

• If retic count is elevated, following • Look for size and shape of RBC’s - esp for tests not needed: variability in sizes & shapes – Iron/Iron Binding Capacity/Ferritin • Is there polychromasia present? (Often implies reticulocytosis) – Folate/Vitamin B12 • Is there a dimorphic population of RBCs? –Acid Hemolysis • Are there platelet and WBC abnormalities? – GI Consult – Bone Marrow

2 Mean Corpuscular Volume Anemia Workup - MCV

MCV Anemia

Macrocytic >100 fl Microcytic Normocytic Macrocytic

Normocytic 80-100 fl Iron Deficiency Anemia of chronic disease Megaloblastic anemias Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol Microcytic < 80 fl Thalassemias Hemoglobinopathies Hemoglobinopathies Hemoglobinopathies Primary marrow disorders Metabolic disorders

Sideroblastic Anemia Combined deficiencies Primary marrow disorders Increased destruction Increased destruction

Anemia – Normocytic (MCV 80-100) Anemia of Chronic Disease

•Common • Most commonly caused by anemia of chronic disease • Develops over 1 to 2 months • Early iron deficiency often causes • Non-progressive normocytic anemia as well • Usually mild to moderate • Anemia of chronic investigation – particular – but hematocrit < 0.20 occasionally hazard of ICU patients • 30% mildly microcytic • Combined deficiencies • WBC, platelets normal or increased

3 Anemia of Chronic Disease - Pathophysiology Effects of Interleukin-1 (IL-1)

Cytokine effects (eg, IL-1, TNF) Stimulates Inhibits DNA & RNA iron-response elements ↓ erythropoietin responsiveness (& production) fever erythropoiesis granulopoiesis ↓ transferrin synthesis thrombopoiesis ↓ Fe mobilization from macrophages synthesis of: ↓ Fe re-utilization in erythropoiesis ferritin synthesis of: ↓ serum Fe despite adequate stores Ig transferrin ↑ serum ferritin fibrinogen, VIII albumin Reticulocytopenia CRP Anemia IL-2, IL-6

Marrow Failure ANEMIA OF CHRONIC DISEASE - Causes Normocytic Anemia (MCV 80-100 fl)

• Thyroid disease Type of Marrow • Collagen Vascular Disease anemia Blood film Ferritin Fe TIBC Fe stores – Rheumatoid Arthritis – Systemic Lupus Erythematosus – Polymyositis Chronic Normochromic, Nl or ↑ ↓ ↓ Nl or ↑, – Polyarteritis Nodosa disease* normocytic • Inflammatory Bowel Disease clumped – Ulcerative Colitis – Crohn’s Disease • Malignancy Early Fe Mild anisocytosis, Nl or ↓ ↓ ↑ absent • Chronic Infectious Diseases deficiency hypochromia – Osteomyelitis

– Tuberculosis • Familial Mediterranean Fever *including anemia due to renal disease and AIDS • Renal Failure

Anemia Workup - MCV ANEMIA - Microcytic (MCV < 80)

• Iron Deficiency - High RDW (Red cell Anemia distribution width) • Thalassemia minor - Normal RDW Normocytic Macrocytic Microcytic •Rare – Sideroblastic anemia Iron Deficiency Anemia of chronic disease Megaloblastic anemias Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol – Metal poisoning (esp lead, aluminum) Thalassemias Hemoglobinopathies Hemoglobinopathies – Occasional hemoglobinopathies Hemoglobinopathies Primary marrow disorders Metabolic disorders – Thalassemia major Sideroblastic Anemia Combined deficiencies Primary marrow disorders Increased destruction Increased destruction

4 Anemia MCV, Retics, Blood film Ferritin Ferritin < Ferritin ≥ 120 15 Ferritin 15-120 TIBC High Normal or low

trial of Fe Rx

anemia anemia corrected not corrected examine marrow Fe stores

Fe absent Fe present

Fe deficiency anemia Fe deficiency excluded

Anemia Workup - MCV Anemia - Macrocytic (MCV > 100)

Anemia

Microcytic Normocytic Macrocytic • If MCV 100-110 fl, must look for other causes of macrocytosis

Iron Deficiency Anemia of chronic disease Megaloblastic anemias • If MCV > 110 fl, almost always folate or Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol cobalamin deficiency Thalassemias Hemoglobinopathies Hemoglobinopathies Hemoglobinopathies Primary marrow disorders Metabolic disorders Sideroblastic Anemia Combined deficiencies Primary marrow disorders Increased destruction Increased destruction

5 Macrocytosis (MCV > 100 fl) Macrocytosis of Alcoholism

•Common – Drugs (cytotoxics, immunosuppressants, AZT, anticonvulsants) • 25-96% of alcoholics – Alcohol – Liver disease • MCV elevation usually slight (100-110 fl) – Reticulocytosis • Minimal or no anemia –B12/folate deficiency – Myelodysplastic syndrome • Macrocytes round (not oval) – Marrow infiltration (malignancy, fibrosis) • Less common • Neutrophil hypersegmentation absent –Aplasia • ‘Artifactual’ • Folate stores normal – Cold agglutinins – Hyperglycemia – Hyperleukocytosis

Megaloblastic Hematopoiesis Evolving Cobalamin Deficiency

• Marrow failure due to: disrupted DNA synthesis • Usual sequence: & ineffective hematopoiesis – Serum Cobalamin falls • Giant precursors and nuclear:cytoplasmic – Serum methylmalonic acid & homocysteine rise dyssynchrony in marrow – MCV rises within the normal range, with • Neutrophil hypersegmentation & macroovalocytes hypersegmentation of neutrophils in blood – MCV rises above normal • Anemia (and often leukopenia & – Anemia and/or neuropathy thrombocytopenia) –Symptoms • Almost always due to Cbl or folate deficiency

6 ‘Dimorphic’ Anemias

• Folate & Fe deficiency (eg, pregnancy, alcoholism)

•B12 & Fe deficiency (eg, pernicious anemia with atrophic gastritis)

• Thalassemia minor & B12 or folate deficiency • Fe deficiency & hemolysis (eg, prosthetic valve) • Folate deficiency & hemolysis (eg, HgbSS disease) • Blood smear critical to assess these

Tests Used to Diagnose Hemolytic Anemia Hemolysis

• Reticulocyte count (combined with serial Hb) • Anemia of increased destruction • Haptoglobin – Normochromic, normochromic anemia • Urine hemosiderin – Shortened RBC survival • Also helpful: – Reticulocytosis - Response to increased RBC – Serum bilirubin destruction –Serum LDH – Hemoglobinuria

Blood morphology in hemolytic Findings Consistent with Hemolysis anemias

Serum unconjugated bilirubin Increased Sickle cells Sickle cell anemia Serum LDH (and LDH1:LDH2) Increased Hb crystals Hb CC disease Serum haptoglobin Decreased Urine hemoglobin Present Fragments, helmets Microangiopathic hemolysis Urine hemosiderin Present Microspherocytes Hereditary spherocytosis Urine urobilinogen Increased Immune hemolysis

51 Cr -RBC lifespan Decreased Elliptocytes Hereditary elliptocytosis

Reticulocyte count Increased

(problems with sensitivity and specificity; none define cause) N.B., hemolysis is not excluded by a normal blood smear.

7 Tests to define the cause of Anemia hemolysis Summary

• Hemoglobin electrophoresis • Check reticulocyte count 1st • Hemoglobin A (beta-thalassemia trait) – If elevated, look for causes of increased 2 destruction or bleeding • RBC enzymes (G6PD, PK, etc) – If normal or decreased, look for causes of • Direct & indirect antiglobulin tests (immune) marrow failure • Workup for marrow failure tailored by MCV, RDW, • Cold agglutinins and peripheral blood smear • Osmotic fragility (spherocytosis) – If low, iron problems or globin problems – If high, megaloblastic or DNA problems • Acid hemolysis test (PNH) – If normal, need to look for combined anemias • Clotting profile (DIC) NB: These tests do not demonstrate the presence of hemolysis