Case # 1. RBC Loss. CASE #1 (Continued) Blood Loss Is the Most Common Cause of Anemia. AGA Definition of Occult Blood Loss

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1 Case # 1 A 42-yo woman with heavy menses presents with rectal bleeding. Except for pallor, exam is normal. HCT = 17.1% (normal, 36-48) HGB = 5.3 g/dl (normal, ) MCV = 76 fl (normal, 82-98) RBC = 2.25 M/ L (normal, ) WBC = 5.3 K/ L (normal, ) Platelets = 355 K/ L (normal, ) Iron deficiency anemia CASE #1 (Continued) Reticulocyte count = 7.1% (normal, ) Absolute retic # = 160K/ L Fe = 9 g/dl (normal, ) TIBC = 460 g/dl (normal, ) Ferritin = 5 ng/ml (normal, ) RBC Loss Blood loss leads to iron deficiency once tissue stores of iron have been depleted 1200 ml or more in males 600 ml or more in females Blood loss of any amount in the 25% of menstruating females with absent iron stores Iron availability is rate-limiting for RBC production, thereby worsening the anemia Blood Loss Is the Most Common Cause of Anemia Obvious bleeding Trauma, melena, hematemesis, menometrorrhagia Bleeding that is not always obvious Surgical bleeding, bleeding into the upper thigh or retroperitoneum, factitious bleeding Iatrogenic bleeding Repeated phlebotomy, hemodialysis, blood donation Occult bleeding AGA Definition of Occult Blood Loss The initial presentation of a positive fecal occult blood test result and/or iron deficiency anemia, when there is no evidence of visible blood loss to the patient or physician Zuckerman GR et al. Gastroenterology 2000;118:201

2 When Bleeding Is Not Evident Decreased iron absorption Malabsorption Diet Intravascular hemolysis PNH Malfunctioning heart valves Pulmonary hemosiderosis Anti-glomerular basement membrane antibody disease Erythropoietin administration Iron Deficiency Happens in Stages Iron deficiency without anemia Ferritin < 20 ng/ml; Fe/TIBC > 15% Iron deficiency with mild anemia Ferritin < 15 ng/ml; Fe/TIBC < 15% Severe iron deficiency with severe anemia Ferritin < 10 ng/ml; Fe/TIBC < 10% Bone marrow iron absent in all stages Ferritin Levels in IDA Virtually all patients with serum ferritin levels < 10 to 15 ng/ml are iron deficient Sensitivity 59%, specificity 99% 25% of women with absent stainable bone marrow iron have ferritin levels > 15 ng/ml Assuming no inflammation, higher ferritin cutoff limits provide improved diagnostic efficiency 30 ng/ml: sensitivity 92%, specificity 98% 41 ng/ml: sensitivity 98%, specificity 98% Polysaccharide-iron Complex Iron is best absorbed from the duodenum and proximal jejunum Enteric coated or sustained release capsules, which release iron further down the GI tract, are counterproductive and expensive Case # 2 A 49-yo male with urticarial vasculitis and h/o myositis is referred for evaluation of anemia. Except for urticaria, exam is unremarkable. HCT = 36% HGB = 12.0 g/dl MCV = 80 fl RBC = 4.50 M/ L WBC = 6.3 K/ L Platelets = 242 K/ L CASE #2 (Peripheral Smear) Hypochromia occasional Anisocytosis normal Poikilocytosis normal Macrocytosis normal Microcytosis occasional Polychromasia normal RDW = 14.2% (normal, )

3 CASE #2 (Continued) Reticulocyte count = 1.2% (normal, ) LDH = 157 IU/L (normal, ) Total bili = 0.3 mg/dl (normal, 0-1.5) Fe = 25 g/dl (normal, ) TIBC = 277 g/dl (normal, ) Fe/TIBC = 0.09 Ferritin = 187 ng/ml (normal, ) Anemia of Inflammation Inflammation decreases serum iron and plasma transferrin concentrations Transferrin saturations are in the iron deficiency range in 20% of patients with anemia of inflammation (Guyatt GH et al. Am J Med 1990;88:205) Ferritin Levels in Iron Deficiency AND Inflammatory States Inflammation increases ferritin levels by about 3-fold If ferritin levels divided by 3 are 20 or less, iron deficiency should be suspected in patients with inflammatory states In anemic patients with rheumatoid arthritis, ferritin levels < 60 ng/ml predicted a response to oral iron therapy with 83% accuracy (Hansen TM, Hansen NE. Ann Rheum Dis 1986;45:596) Iron and TIBC in Pregnancy Pregnancy and oral contraception increase plasma transferrin concentrations Percent transferrin saturations may be low in the absence of iron deficiency Transferrin saturations < 15% are 80% sensitive and 50 to 65% specific Other Indicators of Iron Deficiency Reticulocyte hemoglobin content < 26 pg Bone marrow iron Gold standard Expensive, invasive, usually unnecessary Case # 3 A 24-year old, in her second trimester of pregnancy, is referred for anemia evaluation. She is otherwise well. Exam is unremarkable except for her gravid state. HCT = 22.4% Case # 1 HGB = 7.2 g/dl MCV = 63 fl HCT = 17.1% RBC = 3.57 M/ L HGB = 5.3 g/dl WBC = 7.1 K/ L MCV = 76 fl Platelets = 209 K/ L RBC = 2.25 M/ L

4 Basophilic Stippling -thalassemia minor CASE #3 (Continued) RDW = 22.5% (normal, ) Reticulocyte count = 5.3% (normal, ) Absolute retic # = 189K/ L Fe = 196 g/dl (normal, ) TIBC = 304 g/dl (normal, ) Ferritin = 107 ng/ml (normal, ) Hemoglobins in Normal Adults Hgb A 2 2 > 95% Hgb A % Hgb F 2 2 < 2% Hgb H 4 absent Hgb Barts 4 absent Indications for Hemoglobin Electrophoresis in the Adult Patient Nathan DG. Thalassemia. N Engl J Med 1972;286:586 Prenatal counseling Unexplained microcytosis Thalassemia Hgb EE Hgb S/ thal Unexplained anemia Hgb SS Hgb SC Hgb CC Hgb SS

5 Case # 4 An 84-year old male has had progressive fatigue over several years. Except for pallor, exam is unremarkable. HCT = 22.4%; HGB = 7.4 g/dl; MCV = 100 fl WBC = 9.8 K/ L with 21 polys, 7 bands, 8 lymphs, 1 eo, 58 metas, 3 myelos, 1 promyelo Platelets = 74 K/ L Reticulocyte count = 1.8% Absolute retic number = 40 K/ L CASE # 4 (Peripheral Smear) Anisocytosis 2+ Poikilocytosis 2+ Hypochromia 2+ Microcytosis 2+ Macroovalocytosis 1+ Bizarre-shaped RBCs occasional Tear drops 1+ Hypogranulated polys, pelgeroid cells, toxic granulation, Döhle bodies MCVs in MDS Neutrophils in MDS Low Ringed sideroblasts Abnormal heme synthesis Thalassemic defect High Megaloblastic maturation Pelgeroid cells Döhle body Toxic granulation Case # 4 (Continued) Bone marrow aspiration and biopsy performed Hypercellularity (80%) with < 5% blasts Dyserythropoiesis, no ringed sideroblasts Dyspoietic granulocytic maturation Dysmegakaryocytopoiesis Diagnosis Refractory anemia with multilineage dysplasia Disorders of Heme Synthesis Hereditary sideroblastic anemia Secondary sideroblastic anemias Drug-induced Alcohol-induced Lead poisoning Idiopathic sideroblastic anemia

6 Case # 5 A 35-yo African-American woman has taken dapsone for aphthous ulcers without hematologic effect. Pre-dapsone G6PD level was normal at 10.0 U/g/hb (normal, ). She now presents with SOB following IV lidocaine injection for diffuse myofascial pain. On exam, she appears tachypneic. Cyanosis is not obvious. po 2 = 84; pco 2 = 42; ph = 7.42 O 2 sat = 82% Case # 5 (Continued) HCT = 31.5% HGB = 10.4 g/dl MCV= 100 fl RBC = 3.15 M/ L WBC = 10.3 K/ L with normal differential Platelets = 325 K/ L Retic count = 8.1%; abs retic # = 255K/ L Case # 5 (Continued) Bite cell LDH = 225 IU/L (normal, ) Total bili = 1.3 (normal, 0-1.5) Haptoglobin < 20 DAT negative Methemoglobin = 14% Case # 6 A 24-yo woman develops headaches and fevers. On exam, she appears restless with dysarthric speech. T = F. HCT = 28%; HGB = 9.7 g/dl; MCV = 102 fl WBC = 6.6 K/ L with 55% polys, 3% bands, 30% lymphs, 8% monos, 4% NRBCs Platelets = 5 K/ L; PT = 12.1 sec; aptt = 24.3 sec Retic count = 6.6%; LDH = 546 IU/L; total bili = 1.1 mg/dl; haptoglobin < 20 mg/dl Creatinine = 0.5 mg/dl Schistocytes, NRBC, decreased platelets

7 RBCs Lassoed on Fibrin Strands Bull BS, Kuhn IN. Blood 1970;35:104. Microangiopathic Hemolytic Anemia alias Thrombotic Microangiopathy Disseminated intravascular coagulation Infections Obstetrical disorders Other causes Malignant hypertension Disseminated carcinoma Giant hemangioma TPP Pregnancy Autoimmune disorders HIV E. coli O157:H7 HUS Immunologic vasculitis Antiphospholipid antibody syndrome Mitomycin, ticlopidine, quinine, cyclosporine Macrophage Ingesting an IgG-Coated RBC Bessis M. Corpuscles. Atlas of Red Cell Shape. Berlin, Springer-Verlag, 1974 Spherocytes IgG and IgM Binding RBC Antigens Hereditary pyropoikilocytosis Mohandas, N. Blood 2005;106:4017 Copyright 2005 American Society of Hematology. Copyright restrictions may apply.

8 Case # 7 A 40-yo woman presents with fatigue. On exam, she appears thin. HCT = 26.0%; HGB = 9.5 g/dl; MCV = 109 fl WBC = 3.2 K/ L with normal differential Platelets = 143 K/ L Folate (serum) = 2.2 ng/ml (normal, ) Vitamin B12 = 263 pg/ml (normal, ) Case # 7 (continued) Methylmalonic acid level 612 nmol/l (normal, ) Homocysteine level 52.8 mol/l (normal, 0-8.9) Normal Macroovalocytes Hypersegmented neutrophil Actions of Cobalamin and Folate Degree of Elevation of MCV Often a clue to whether a vitamin deficiency is present Probability of folate and/or cobalamin deficiency is greater with higher MCVs Normal ( fl), < 25% 115 to 129 fl, 50% > 130 fl, 100% Savage DG et al. Am J Med 1994;96:239 From UpToDate

9 Serum Folate Levels In absence of recent anorexia or fasting, serum folate level < 2 ng/ml is diagnostic of folate deficiency Confounded by meals One meal can normalize serum folate levels in patients who are folate deficient Pregnancy, alcohol intake, certain anticonvulsants, or a short period of decreased dietary intake Can lower serum folate levels despite the presence of adequate tissue stores Red Cell Folate Levels Useful when Serum folate levels are borderline (2 to 4 ng/ml) Combined cobalamin and folate deficiencies are suspected Folate deficiency is suspected and patients have had a recent meal or period of anorexia Not necessary if serum folate levels are > 4 ng/ml Cobalamin Levels > 300 pg/ml Cbl deficiency unlikely (1-5%) pg/ml Borderline result; Cbl deficiency is possible < 200 pg/ml Consistent with Cbl deficiency (specificity, %) May fall during pregnancy without hematologic evidence of deficiency Serum Methylmalonic Acid and Homocysteine Levels Help clarify diagnosis when cobalamin and folate levels are equivocal Serum MMA and homocysteine levels elevated in 98 and 96% of 434 episodes of Cbl deficiency 12 and 91% of 123 episodes of folate deficiency Elevated MMA in all but one folate deficient patient was due to renal insufficiency or hypovolemia Savage DG et al. Am J Med 1994;96:239 Hereditary homocysteinemia can raise serum homocysteine levels Oral Replacement of Cobalamin 2000 g daily Appears to be as or more effective than parenteral therapy Takes advantage of a second, lower efficiency transport system for Cbl that does not require intrinsic factor or a terminal ileum Requires patient compliance Kuzminski AM et al. Blood 1998;92:1191