„Update on (Approach to) Anemia „October 2, 2003 10:00 am

Anemia Workup - Exaggerated Update on (Approach to) Anemia • Iron/TIBC/Ferritin •Acid hemolysis • Folate/B12 • Osmotic fragility • LDH/Bilirubin • Rx iron/folate/B How to efficiently and accurately 12 • Haptoglobin/Urine for •Type & Cross work up the anemic patient hemosiderin • Transfuse 2-4 units • Coombs Test – Direct & indirect • GI Consult David L. Diuguid, MD Associate Professor of Clinical Medicine • Hemoglobin • Hematology Consult – College of Physicians & Surgeons of Columbia electrophoresis Bone Marrow University

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Anemia - Definition ANEMIA

• Decrease in the number of circulating red blood cells • Most common hematologic disorder by far ANEMIA • Almost always a secondary disorder Decreased Production Increased Destruction • As such, critical for internist to know how to evaluate/determine cause

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Anemia - Causes

• Blood loss • Decreased production of red blood cells (Marrow failure) • Increased destruction of red blood cells –Hemolysis

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„1 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Reticulocyte Count - Absolute Anemia Value

• History and Exam • Reticulocyte count • = Retic % x RBC Count • Blood film – eg 0.01 x 5x1012/l = 5x 1010/l •MCV • Normal up to 1.2x1011/l (120,000/μl) • Ferritin • More accurate way to assess body’s • WBC, diff, platelets response to anemia

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Anemia Workup - 1st Test Anemia Workup

• If retic count is elevated, following RETICULOCYTE tests not needed: COUNT – Iron/Iron Binding Capacity/Ferritin – Folate/Vitamin B12 –Acid Hemolysis – GI Consult – Bone Marrow

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Anemia - Peripheral Blood Smear Findings

• Look for size and shape of RBC’s - esp for variability in sizes & shapes • Is there polychromasia present? (Often implies reticulocytosis) • Is there a dimorphic population of RBCs? • Are there platelet and WBC abnormalities?

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„2 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Anemia Workup - MCV

Anemia

Microcytic Normocytic Macrocytic

Iron Deficiency Anemia of chronic disease Megaloblastic anemias Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol Thalassemias Hemoglobinopathies Hemoglobinopathies Hemoglobinopathies Primary marrow disorders Metabolic disorders Sideroblastic Anemia Combined deficiencies Primary marrow disorders Increased destruction Increased destruction 13 16

Anemia – Normocytic (MCV 80-100)

• Most commonly caused by anemia of chronic disease • Early iron deficiency often causes normocytic anemia as well • Anemia of chronic investigation – particular hazard of ICU patients • Combined deficiencies

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Mean Corpuscular Volume Anemia of Chronic Disease

•Common

MCV • Develops over 1 to 2 months Macrocytic >100 fl • Non-progressive • Usually mild to moderate Normocytic 80-100 fl – but hematocrit < 0.20 occasionally Microcytic < 80 fl • 30% mildly microcytic • WBC, platelets normal or increased

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„3 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Anemia of Chronic Disease - Marrow Failure Pathophysiology Normocytic Anemia (MCV 80-100 fl)

Type of Marrow ƒ Cytokine effects (eg, IL-1, TNF) anemia Blood film Ferritin Fe TIBC Fe stores ƒ DNA & RNA iron-response elements ƒ ↓ erythropoietin responsiveness (& production) Chronic Normochromic, Nl or ↑ ↓ ↓ Nl or ↑, ƒ ↓ transferrin synthesis disease* normocytic clumped ƒ ↓ Fe mobilization from macrophages ƒ ↓ Fe re-utilization in erythropoiesis ƒ ↓ serum Fe despite adequate stores Early Fe Mild anisocytosis, Nl or ↓ ↓ ↑ absent ƒ ↑ serum ferritin deficiency hypochromia ƒ Reticulocytopenia ƒ Anemia *including anemia due to renal disease and AIDS

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Effects of Interleukin-1 (IL-1) Anemia Workup - MCV

Stimulates Inhibits Anemia ƒ fever ƒ erythropoiesis ƒ granulopoiesis ƒ thrombopoiesis Microcytic Normocytic Macrocytic ƒ synthesis of: ƒ ferritin ƒ synthesis of: Iron Deficiency Anemia of chronic disease Megaloblastic anemias ƒ Ig ƒ transferrin Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol ƒ fibrinogen, VIII ƒ albumin Thalassemias Hemoglobinopathies Hemoglobinopathies ƒ CRP Hemoglobinopathies Primary marrow disorders Metabolic disorders ƒ IL-2, IL-6 Sideroblastic Anemia Combined deficiencies Primary marrow disorders

20 Increased destruction Increased destruction23

ANEMIA OF CHRONIC DISEASE - Causes ANEMIA - Microcytic (MCV < 80)

• Thyroid disease • Collagen Vascular Disease • Iron Deficiency - High RDW (Red cell – Rheumatoid Arthritis – Systemic Lupus Erythematosus distribution width) – Polymyositis – Polyarteritis Nodosa • Thalassemia minor - Normal RDW • Inflammatory Bowel Disease •Rare – Ulcerative Colitis – Crohn’s Disease – Sideroblastic anemia • Malignancy – Metal poisoning (esp lead, aluminum) • Chronic Infectious Diseases – Osteomyelitis – Occasional hemoglobinopathies – Tuberculosis – Thalassemia major • Familial Mediterranean Fever

• Renal Failure 21 24

„4 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Anemia MCV, Retics, Blood film Ferritin Ferritin < 33 pmol/l Ferritin ≥ 270 pmol/l Ferritin 33-270 pmol/l

TIBC High Normal or low

trial of Fe Rx

anemia anemia corrected not corrected examine marrow Fe stores

Fe absent Fe present

25 Fe deficiency anemia Fe deficiency excluded28

Anemia Workup - MCV

Anemia

Microcytic Normocytic Macrocytic

Iron Deficiency Anemia of chronic disease Megaloblastic anemias Anemia of Chronic Disease Early iron deficiency Liver disease/alcohol Thalassemias Hemoglobinopathies Hemoglobinopathies Hemoglobinopathies Primary marrow disorders Metabolic disorders Sideroblastic Anemia Combined deficiencies Primary marrow disorders

26 Increased destruction Increased destruction29

Anemia - Macrocytic (MCV > 100)

• If MCV 100-110 fl, must look for other causes of macrocytosis • If MCV > 110 fl, almost always folate or cobalamin deficiency

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„5 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Macrocytosis (MCV > 100 fl) Evolving Cobalamin Deficiency

•Common – Drugs (cytotoxics, immunosuppressants, AZT, anticonvulsants) • Usual sequence: – Alcohol – Serum Cobalamin falls – Liver disease – Reticulocytosis – Serum methylmalonic acid & homocysteine rise

–B12/folate deficiency – MCV rises within the normal range, with – Myelodysplastic syndrome hypersegmentation of neutrophils – Marrow infiltration (malignancy, fibrosis) – MCV rises above normal • Less common –Aplasia – Anemia and/or neuropathy • ‘Artifactual’ –Symptoms – Cold agglutinins – Hyperglycemia – Hyperleukocytosis 31 34

Macrocytosis of Alcoholism

• 25-96% of alcoholics • MCV elevation usually slight (100-110 fl) • Minimal or no anemia • Macrocytes round (not oval) • Neutrophil hypersegmentation absent • Folate stores normal

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Megaloblastic Hematopoiesis

• Marrow failure due to: disrupted DNA synthesis & ineffective hematopoiesis • Giant precursors and nuclear:cytoplasmic dyssynchrony in marrow • Neutrophil hypersegmentation & macroovalocytes in blood • Anemia (and often leukopenia & thrombocytopenia) • Almost always due to Cbl or folate deficiency

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„6 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Tests Used to Diagnose Hemolysis

• Reticulocyte count (combined with serial Hb) • Haptoglobin • Urine hemosiderin • Also helpful: – Serum bilirubin –Serum LDH – Hemoglobinuria

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‘Dimorphic’ Anemias Findings Consistent with Hemolysis

• Folate & Fe deficiency (eg, pregnancy, Serum unconjugated bilirubin Increased alcoholism) Serum LDH (and LDH1:LDH2) Increased •B12 & Fe deficiency (eg, pernicious anemia with Serum haptoglobin Decreased atrophic gastritis) Urine hemoglobin Present • Thalassemia minor & B12 or folate deficiency • Fe deficiency & hemolysis (eg, prosthetic valve) Urine hemosiderin Present • Folate deficiency & hemolysis (eg, HgbSS Urine urobilinogen Increased disease) Cr51-RBC lifespan Decreased • Blood smear critical to assess these Reticulocyte count Increased

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Blood morphology in hemolytic Hemolytic Anemia anemias

Sickle cells Sickle cell anemia

• Anemia of increased destruction Hb crystals Hb CC disease – Normochromic, normochromic anemia Fragments, helmets Microangiopathic hemolysis – Shortened RBC survival Microspherocytes Hereditary spherocytosis – Reticulocytosis - Response to increased RBC Immune hemolysis destruction Elliptocytes Hereditary elliptocytosis

39 N.B., hemolysis is not excluded by a normal blood smear. 42

„7 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Tests to define the cause of hemolysis Anemia – Clinical Consequences 3

• Hemoglobin electrophoresis • Degree of anemia often a marker for degree

• Hemoglobin A2 (beta-thalassemia trait) of illness • RBC enzymes (G6PD, PK, etc) • Below hemoglobin 100 grams/l, most will • Direct & indirect antiglobulin tests (immune) have some symptoms of fatigue • Cold agglutinins • Pharmacologic doses of erythropoietin • Osmotic fragility (spherocytosis) clearly will improve hemoglobin in most • Acid hemolysis test (PNH) with anemia of chronic disease • Clotting profile (DIC)

NB: These tests do not demonstrate the presence of hemolysis43 46

Anemia – Clinical Consequences Anemia – Clinical Consequences 4

• General • Other vitamins/minerals need to be repleted – Slowly developing anemia is well tolerated for erythropoietin to work – Rapidly developing anemia is not well tolerated • Not clear that increasing hemoglobin level – No specific hemoglobin level necessary for increases survival or prevents other optimized oxygen delivery to tissues complications of underlying disease – People with congenital abnormal hemoglobins tolerate much lower levels than most

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Anemia Anemia – Clinical Consequences 2 Summary

• Oxygen delivery increases linearly with increasing • Check reticulocyte count 1st hemoglobin – If elevated, look for causes of increased • Blood viscosity increases exponentially, & flow destruction or bleeding decreases exponentially, with increasing – If normal or decreased, look for causes of hemoglobin marrow failure • Workup for marrow failure tailored by MCV, RDW, • Optimum oxygen delivery occurs with and peripheral blood smear hemoglobin level c. 150 grams/liter – If low, iron problems or globin problems • Significant decreases in oxygen delivery don’t – If high, megaloblastic or DNA problems happen until hemoglobin is > 180 grams/liter – If normal, need to look for combined anemias

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„8 „Update on (Approach to) Anemia „October 2, 2003 10:00 am

Anemia – Summary 2

• If vitamins/minerals replete & patient still anemic, erythropoietin can be used to raise hemoglobin level • ? If raising hemoglobin level alters underlying disease process

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