6 HEMATOLOGY Section Editor: Dr. Michael Kroll Polycythemia DIFFERENTIAL DIAGNOSIS INVESTIGATIONS SPURIOUS—stress (Geisbo¨ck’s syndrome), BASIC decrease intravascular volume LABS—CBCD, lytes, urea, Cr, LAP, vitamin B12, PRIMARY—polycythemia rubra vera RBC mass (total blood volume  Hct, to rule out SECONDARY wHERAw spurious causes), carboxyhemoglobin level, cor- HYPOXIA—obstructive sleep apnea, COPD, smok- tisol level, peripheral blood smear ing, high altitude IMAGING—CXR EPO-SECRETING TUMORS—renal, hepatoma, cere- SPECIAL bellar, pheochromocytoma JAK2 MUTATION—JAK2 is a cytoplasmic tyrosine RENAL—polycystic kidney disease, hydronephro- kinase activated by EPO binding to its receptor; sis, post-transplant the V617F mutation activates JAK2 and thereby ADRENAL—Cushing’s syndrome drives EPO-independent erythropoiesis EPO LEVEL—low in PRV, high if secondary causes PATHOPHYSIOLOGY HYPOXIA WORKUP—oximetry, ABG, CO-hemoglobin SOLID TUMOR WORKUP—CT abd, MRI head (if DEFINITION OF POLYCYTHEMIA—hematocrit >0.6 tumors) in ?, hematocrit >0.5 in / BONE MARROW BIOPSY—rule out myelofibrosis and CML Related Topics Hypoxemia (p. 92) DIAGNOSTIC ISSUES Myeloproliferative Disorders (p. 165) CRITERIA FOR POLYCYTHEMIA RUBRA VERA (PRV) ABSOLUTE—" RBC mass, no secondary cause (nor- mal PaO2, EPO not elevated) MAJOR—splenomegaly, JAKV617F CLINICAL FEATURES 3 3 MINOR—WBC >12Â10 /mL, platelet >400 Â10 /mL, HISTORY—hyperviscosity (headache, blurred vision, LAP >100U/L and vitamin B12 >650pmol/L epistaxis), dyspnea, epigastric pain, weight loss, fever, [>880 pg/mL] night-sweats, pruritus, erythromelalgia, recent travel DIAGNOSIS—need absolute criteria plus one major to high-altitude areas, past medical history (respira- or two minor criteria for the diagnosis of poly- tory diseases, myeloproliferative disorders, myocar- cythemia rubra vera. See myeloproliferative disor- dial infarction, stroke, pulmonary embolism, DVT, ders (p. 165) for more details renal disorders, smoking), medications (androgens, EPO) MANAGEMENT PHYSICAL—hypertension, oxygen saturation, facial TREAT UNDERLYING CAUSE—relative (hydration), plethora, conjunctival injections, engorgement of the CO hemoglobinemia (smoking cessation. See veins of the optic fundus, abdominal mass, hepato- p. 418), sleep apnea (CPAP. See p. 17), polycythe- megaly, splenomegaly, excoriations, stigmata of a mia vera (cytoreduction with hydroxyurea is prefer- prior arterial or venous thrombotic event, gouty able to phlebotomy to keep hematocrit <0.45 in ? arthritis, and tophi and <0.42 in /, ASA 81 mg PO daily prevents thrombosis—but watch out for bleeding) D. Hui, Approach to Internal Medicine, DOI 10.1007/978-1-4419-6505-9_6, 143 Ó Springer ScienceþBusiness Media, LLC 2006, 2007, 2011 144 Microcytic Anemia Microcytic Anemia NEJM 2005 352:10 DIFFERENTIAL DIAGNOSIS INVESTIGATIONS (CONT’D) wTAILSw LIVER BIOPSY THALASSEMIA BONE MARROW ASPIRATE AND BIOPSY WITH IRON ANEMIA OF CHRONIC DISEASE—infection, STAIN malignancy, inflammatory disorders IRON DEFICIENCY—blood loss (GI, GU, vaginal, DIAGNOSTIC ISSUES trauma), iron-deficient diet, celiac disease, atrophic IRON INDICES gastritis, renal failure on EPO, pulmonary hemosi- Ferritin Iron TIBC % sat derosis, intravascular hemolysis Iron deficiency ##"# LEAD POISONING Anemia of "/N # N/# N/# SIDEROBLASTIC chronic disease PATHOPHYSIOLOGY Thalassemia "/N "# " DEFINITION OF MICROCYTIC ANEMIA—Hb Sideroblastic N/" N/# N/# N/# <135 g/L [<13.5 g/dL], MCV <80 fL SEQUENCE OF IRON DEFICIENCY—# iron !"TIBC DISTINGUISHING FEATURES BETWEEN IRON !#Hb !#MCV ! hypochromia DEFICIENCY AND THALASSEMIA ANEMIA OF CHRONIC DISEASE—chronic inflamma- RDW—red cells in thalassemia tend to have a tory states such as malignancy, infection and rheu- narrower distribution than in iron deficiency matologic diseases !"INFg, TNFa, IL-1, IL-6, IL-10 ! MCV—red cells in thalassemia tend to be smaller " hepatic expression of hepcidin which inhibits duo- than in iron deficiency denal absorption of iron, " uptake and storage of iron RBC—RBC high or normal if thalassemia but tend into monocytes and macrophages, # production of to decrease proportionally to Hb in iron deficiency EPO !#availability of iron for erythrocytes ! THALASSEMIA INDEX—MCV/RBC. Suggests thalasse- anemia (microcytic or normocytic) mia if <13 and iron deficiency if >13 MORPHOLOGY—thalassemia causes microcytic tar- CLINICAL FEATURES get cells HISTORY—shortness of breath, chest pain, dizziness, DISTINGUISHING FEATURES BETWEEN IRON DEFI- fatigue, bleeding (GI, menstrual), pica (ice, dirt), diet CIENCY AND ANEMIA OF CHRONIC DISEASE—fer- history, fever, night sweats, weight loss, past medical ritin is indicative of marrow iron stores and is key to history (malignancy, chronic infections, rheumatolo- the diagnosis of iron deficiency anemia as serum iron gic disorders), medications (NSAIDs, ASA, anticoagu- and TIBC levels may change with other diseases lants), family history (thalassemia) <30 ng/ml—iron deficiency anemia (PPV 92–98%) PHYSICAL—vitals, koilonychia (spoon nails), alope- 30–100 ng/ml—combination of anemia of cia, blue sclerae, conjunctival pallor, angular chloro- chronic disease and true iron deficiency if (sTfR/ sis, atrophic glossitis, lymphadenopathy (anemia of log ferritin)>2. Anemia of chronic disease alone if chronic disease), rectal examination for occult blood (sTfR/log ferritin) <1 and pelvic examination for blood loss 100 ng/ml—anemia of chronic disease INVESTIGATIONS MANAGEMENT BASIC SYMPTOM CONTROL—transfusion 2 U PRBC IV LABS—CBCD, peripheral smear, reticulocyte over 2 h count, serum iron, serum ferritin, TIBC (transfer- TREAT UNDERLYING CAUSE—iron deficiency (iron rin), % sat, Hb electrophoresis, fecal occult blood gluconate 300 mg PO TID, iron sulfate 325 mg PO (if suspect GI bleed) TID, sodium ferric gluconate complex in sucrose SPECIAL 125 mg IV, ferumoxytol 510 mg IV). It may take up ENDOSCOPY—gastroscopy and/or colonoscopy to 6 weeks to correct anemia and 6 months to targeting symptoms in any man or post-meno- replete iron stores pausal woman with iron deficiency or in anyone SPECIFIC ENTITIES with suspected GI bleeding SOLUBLE TRANSFERRIN RECEPTOR (sTfR)—helps to PLUMMER–VINSON SYNDROME—iron deficiency distinguish between iron deficieny and anemia anemia, atrophic glossitis and esophageal web. of chronic disease Increased risk of esophageal squamous cell carcinoma Normocytic Anemia 145 Normocytic Anemia DIFFERENTIAL DIAGNOSIS INVESTIGATIONS (CONT’D) ACUTE BLOOD LOSS—GI, GU, pelvis/abdomen, SPECIAL skin, CNS URINE TESTS—urinalysis (hemoglobinuria) # PRODUCTION BONE MARROW BIOPSY PRIMARY MARROW DISORDERS—bone marrow suppression from drugs (esp. chemotherapy), DIAGNOSTIC ISSUES multiple myeloma, myelodysplasia, myeloproli- MCHC—" MCHC suggests spherocytosis ferative disorders, lymphoma, metastasis, infec- MCV—a rise in MCV suggests reticulocytosis; """ tions (esp. TB) MCV indicates the presence of cold agglutinins caus- DECREASED EPO—renal failure ing agglutination in the laboratory specimen before ANEMIA OF CHRONIC DISEASE blood is run through the analyzer SEQUESTRATION—splenomegaly COOMBS TEST " DESTRUCTION DIRECT COOMBS TEST (DAT)—patient’s washed RBC IMMUNE—autoimmune hemolytic anemia (warm incubated with anti-IgG and anti-C3. A positive agglutinins, cold agglutinins) result (i.e. agglutination) indicates that IgG and/ NON-IMMUNE or C3 have bound to RBC surface in vivo. DAT RBC MEMBRANE—spherocytosis positivity suggests immune rather than non- RBC ENZYMES—G6PD, pyruvate kinase defi- immune causes of hemolysis ciency IMMUNE HEMOLYTIC ANEMIA (DAT positive)— RBC HEMOGLOBIN—sickle cell anemia autoimmune hemolytic anemia, drug-induced MICROANGIOPATHIC—DIC, HUS/TTP, prosthetic hemolytic anemia, alloimmune hemolytic ane- valve, hypertensive crisis mia (acute hemolytic reaction) BLOOD—toxins, infections (malaria), immune NON-IMMUNE HEMOLYTIC ANEMIA (DAT nega- MIXED PICTURE—combined microcytic and macro- tive)—TTP/HUS, DIC, hemoglobinopathies, her- cytic anemia (e.g. malnutrition causing iron defi- editary spherocytosis ciency and vitamin B12 deficiency) INDIRECT COOMBS TEST—normal RBC incubated with patient’s serum. It is mainly used to detect PATHOPHYSIOLOGY low concentrations of antibodies in a patient’s DEFINITION OF NORMOCYTIC ANEMIA— serum prior to blood transfusion Hb < 135 g/L [>13.5 g/dL], MCV 80–100 fL RETICULOCYTE PRODUCTION INDEX (RPI, corrected reticulocyte count)—more accurate than raw reticulo- CLINICAL FEATURES cyte count to evaluate if bone marrow response to HISTORY—shortness of breath, chest pain, dizziness, anemia is appropriate or hypoproliferative fatigue, bleeding, fever, night sweats, weight loss, RPI = [retic count  (hematocrit in %/45)]/ diet history, past medical history (malignancy, chronic maturation factor infections, rheumatologic disorders, liver disease, renal disease, alcohol, hypothyroidism, myelodyspla- Maturation factor Hematocrit sia), medications (NSAIDs, ASA, chemotherapy, anti- 1.0% 45% biotics, antiepileptics), family history (thalassemia) 1.5% 35% PHYSICAL—vitals, jaundice, conjunctival pallor, car- 2.0% 25% diac examination, liver examination. Check for macro- 2.5% 20% glossia, subacute combined degeneration and periph- INTERPRETATION—RPI >2% suggests adequate mar- eral neuropathy. Rectal examination for occult blood row response, < 2% suggests hypoproliferative (i.e. # production) INVESTIGATIONS BASIC MANAGEMENT LABS—CBCD, peripheral smear, reticulocyte count, TREAT UNDERLYING CAUSE iron, ferritin, TIBC, % sat, Cr, TSH, AST,