® TRANSFUSION MEDICINE NO. TM 11-4 (TM-328) TRANSFUSION MEDICINE Volume 54 Number 4 Brian Nagao, MD Pathology Resident ISSN 1056-5949 © ASCP May 2011 Shan Yuan, MD Assistant Professor of Pathology and Laboratory Medicine Assistant Director, Transfusion Medicine & Blood Banking Qun Lu, MD Assistant Professor of Pathology and Laboratory Medicine Assistant Director, Transfusion Medicine & Blood Banking Department of Pathology and Laboratory Medicine David Geffen School of Medicine University of California at Los Angeles Los Angeles, California If you wish to obtain an MOC self-assessment module (SAM) credit for this exercise, please log-in to www.ascp.org, go to My Courses, and select the appropriate course now to take your pre-test. 41 LEARNING OBJECTIVES Upon completion of this exercise, the participant should be able to • recognize immune-mediated hemolysis. TRANSFUSION MEDICINE TM 11-4 • develop a differential diagnosis for immune-mediated hemolysis. © ASCP 2011 • diagnose drug-induced immune hemolytic anemia. • diagnose drug-induced immune thrombocytopenia. • recommend appropriate management for both conditions. Copyright © 20102011 by the American Society for Clinical Pathology. All rights reserved. Copyright law allows for multiple copy duplication of the Check Sample exercises and color images (printed or digital) for classroom use and for in-service continuing education by nonprofit groups. Written permission is not required in these cases as long as copies made do not exceed the number of students or participants and copies are not charged for. All other uses including reproduction, storage in a retrieval system, or transmission in any form or by any means (including electronic, mechanical, photocopying, or recording) require prior written permission of the American Society for Clinical Pathology, [email protected]. 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Credit for 2011 CreditCheck Samplefor 2010 exercises Check Sample may be exercisesearned through may be Decemberearned through 31, 2013. December 31, 2012. 42 HISTORY A 73-year-old woman underwent surgical repair of a ventral hernia. After an uneventful postoperative course, she was discharged on postoperative day 4. Around day 9, she developed progressive weakness, lightheadedness, and dark urine, and had 1 episode of emesis of clear fluid. She presented to the authors’ institution on day 14. TRANSFUSION MEDICINE Review of all other systems was unremarkable. Her medical history was significant TM 11-4 for colon cancer 7 years earlier treated with surgical resection and chemotherapy, © ASCP 2011 hypertension, hyperlipidemia, hypothyroidism, and gastroesophageal reflux disease. Her outpatient medications included carvedilol, nifedipine, captopril, losartan- hydrochlorothiazide, ezetimibe-simvastatin, thyroxine, esomeprezole, ranitidine, aspirin, and tramadol. Her vital signs were: blood pressure, 128/93 mmHg; pulse rate, 81/min; respirations, 18/min; and temperature, 98.4°F (36.9°C). Oxygen saturation on room air was 100%. Her abdominal wound was healing with no evidence of bleeding or infection. No skin rashes, petechiae, ecchymoses, or mucosal hemorrhages were present. The fecal occult blood test result was negative. The rest of her physical examination results were unremarkable. Relevant admission laboratory results are shown in Laboratory Data. The patient had severe anemia with evidence of hemolysis, including reticulocytosis, unconjugated hyperbilirubinemia, a low haptoglobin level, an elevated level of lactate dehydrogenase, and hemoglobinemia. The peripheral smear showed abundant microspherocytes and no schistocytes. Her blood type was group A Rh+. The antibody screen result was negative. The direct antiglobulin test (DAT) result was positive for IgG and negative for C3. An acid elution was performed, and the eluate was nonreactive with reagent red blood cells (RBCs). She was admitted for RBC transfusions and evaluation of her hemolytic anemia. LABORATORY DATA. Test Patient Result Reference Range White blood cell count, ×103/µL (×109/L) 5.50 (5.50) 3.28-9.29 (3.28-9.29) Red blood cell count, ×106/µL (×1012/L) 1.96 (1.96) 3.76-4.93 (3.76-4.93) Hemoglobin, g/dL (g/L) 6.2 (62) 11.5-14.6 (115-146) Hematocrit, % 18.7 34.0-42.1 Platelet count, ×103/µL (×109/L) 207 (207) 143-398 (143-398) Mean corpuscular volume, fL 95.4 79.0-95 Absolute reticulocyte count, ×106/µL (×109/L) 0.1942 (194.2) 0.0273-0.1072 (27.3-107.2) Haptoglobin, mg/dL (µmol/L) <8 (<0.8) 30-190 (3.0-19.0) Lactate dehydrogenase, U/L 1575 91-223 Total bilirubin, mg/dL (µmol/L) 4.0 (68.4) 0.2-1.1 (3.4-18.8) Conjugated bilirubin, mg/dL (µmol/L) 0.6 (10.3) 0.0-0.2 (0-3.4) Plasma free hemoglobin, mg/dL (g/L) 20.0 (200) 0.5-5.0 (5-50) Ferritin, ng/mL (pmol/L) 740 (1663) 8-150 (18-337) Iron, µg/L (µmol/L) 198 (35.4) 23-182 (4.1-32.6) Iron binding capacity, µg/dL (µmol/L) 308 (55.1) 240-520 (43.0-93.1) Prothrombin time, s 10.6 9.1-11.1 International normalized ratio 1.1 0.8-1.3 Partial thromboplastin time, s 23.6 24.6-30.9 43 DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA AND THROMBOCYTOPENIA Recognition of Immune-Mediated Hemolysis TRANSFUSION MEDICINE In immune-mediated hemolysis, RBCs are coated in vivo with antibodies; leading to TM 11-4 either extravascular or complement-associated intravascular destruction. The presence © ASCP 2011 of IgG antibodies or complement proteins on the surface of RBCs results in a positive DAT reaction, making the DAT the most useful tool to distinguish immune-mediated A positive DAT result hemolysis from nonimmune hemolysis. There are 2 important caveats, however. A is the most useful tool weakly positive reaction can be seen in up to 7% to 8% of hospitalized patients and to distinguish immune- may be a nonspecific finding, particularly if no evidence of hemolysis is present.1 The mediated hemolysis from nonimmune DAT result may be negative in cases of immune-mediated hemolysis if all the IgG- or hemolysis. complement-coated RBCs have been destroyed and in the rare cases of autoimmune hemolytic anemia (AIHA) mediated by IgA or IgM antibodies. Tests to confirm IgA- or IgM-mediated AIHA are usually available only at specialized laboratories. Otherwise, a negative result on the DAT strongly favors nonimmune hemolysis, and clinical history and laboratory tests are used to identify the specific cause. Differential Diagnosis and Laboratory Testing of Immune-Mediated Hemolysis A diagnostic algorithm for immune-mediated hemolysis is shown in the Figure. When the DAT result When the DAT result is positive for IgG in a patient with hemolytic anemia, an is positive for IgG in a elution test should be performed to elute off the antibody and determine its specificity patient with hemolytic anemia, an elution test should be performed to elute off the antibody Hemolysis and determine its specificity with a panel of reagent RBCs of Positive C3 DAT Negative Consider non- Cold immune etiology known phenotype. agglutinin titer Nonimmune Positive IgG or etiology ruled Positive Negative IgG and C3 out Thermal * amplitude Donath- Consider DIIHA Elution testing Landsteiner Positive and IgM- or IgA- test alloantibody mediated AIHA Reactive Reactive at ≥ 30°C at <30°C Negative Positive Acute or delayed autoantibody hemolytic transfusion Cold Cold auto- reaction† Positive agglutinin antibodies, Negative disease not clinically Warm AIHA significant Paroxysmal cold Consider hemoglobinuria DIIHA* Figure. Diagnostic algorithm for immune-mediated hemolysis. AIHA indicates autoimmune hemolytic anemia; DAT, direct antiglobulin test; DIIHA, drug-induced immune hemolytic anemia. *Obtain drug history, confirm diagnosis with drug-dependent antibody tests if appropriate. †Obtain history of recent transfusion. 44 with a panel of reagent RBCs of known phenotype. The differential diagnosis