Hemolytic Anemia: Evaluation And Differential Diagnosis

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Hemolytic Anemia: Evaluationand Differential DiagnosisJames Phillips, MD, and Adam C. Henderson, MD, Womack Army Medical Center, Fort Bragg, North CarolinaHemolytic anemia is defined by the premature destruction of red blood cells, and can be chronic or life-threatening. Itshould be part of the differential diagnosis for any normocytic or macrocytic anemia. Hemolysis may occur intravascularly,extravascularly in the reticuloendothelial system, or both. Mechanisms include poor deformability leading to trappingand phagocytosis, antibody-mediated destruction through phagocytosis or direct complement activation, fragmentationdue to microthrombi or direct mechanical trauma, oxidation, or direct cellular destruction. Patients with hemolysis maypresent with acute anemia, jaundice, hematuria, dyspnea, fatigue, tachycardia, and possibly hypotension. Laboratory testresults that confirm hemolysis include reticulocytosis, as well as increased lactate dehydrogenase, increased unconjugated bilirubin, and decreased haptoglobin levels. The direct antiglobulin test further differentiates immune causes fromnonimmune causes. A peripheral blood smear should be performed when hemolysis is present to identify abnormal redblood cell morphologies. Hemolytic diseases are classified into hemoglobinopathies, membranopathies, enzymopathies,immune-mediated anemias, and extrinsic nonimmune causes. Extrinsic nonimmune causes include the thrombotic microangiopathies, direct trauma, infections, systemic diseases, and oxidative insults. Medications can cause hemolytic anemiathrough several mechanisms. A rapid onset of anemia or significant hyperbilirubinemia in the neonatal period shouldprompt consideration of a hemolytic anemia. (Am Fam Physician. 2018;98(6):354-361. Copyright 2018 American Academy of Family Physicians.)Hemolytic anemia is defined as the destruction of redblood cells (RBCs) before their normal 120-day life span. Itincludes many separate and diverse entities whose commonclinical features can aid in the identification of hemolysis.Hemolytic anemia exists on a spectrum from chronic tolife-threatening, and warrants consideration in all patientswith unexplained normocytic or macrocytic anemia.PathophysiologyPremature destruction of RBCs can occur intravascularly or extravascularly in the reticuloendothelial system, although the latter is more common. The primaryextravascular mechanism is sequestration and phagocytosis due to poor RBC deformability (i.e., the inability to change shape enough to pass through the spleen).Antibody-mediated hemolysis results in phagocytosis orcomplement-mediated destruction, and can occur intravascularly or extravascularly. The intravascular mechanisms include direct cellular destruction, fragmentation,CME This clinical content conforms to AAFP criteria forcontinuing medical education (CME). See CME Quiz onpage 345.Author disclosure: No relevant financial affiliations.and oxidation. Direct cellular destruction is caused bytoxins, trauma, or lysis. Fragmentation hemolysis occurswhen extrinsic factors produce shearing and rupture ofRBCs. Oxidative hemolysis occurs when the protectivemechanisms of the cells are overwhelmed.1The etiologies of hemolysis are numerous (Table 1). Thehemoglobinopathies lead to splenic destruction and, inthe case of sickle cell disease, likely multiple mechanismsof destruction. Inherited protein deficits lead to increaseddestruction in membranopathies. Enzymopathies resultin hemolysis due to overwhelming oxidative stress ordecreased energy production. In immune-mediated hemolytic anemia, antibodies bind with the RBCs, resulting inphagocytosis or complement-mediated destruction. Theextrinsic nonimmune causes include microangiopathichemolytic anemia (MAHA), infections, direct trauma, anddrug-induced hemolysis, among others.Clinical PresentationHemolysis should be considered when a patient experiencesacute jaundice or hematuria in the presence of anemia.Symptoms of chronic hemolysis include lymphadenopathy,hepatosplenomegaly, cholestasis, and choledocholithiasis. Other nonspecific symptoms include fatigue, dyspnea,hypotension, and tachycardia.Downloadedfrom theAmericanFamily Physician website at www.aafp.org/afp.Copyright 2018 American Academyof Familythe private, 15,noncom pVolume98, Physicians.Number 6For2018mercial use of one individual user of the website. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

HEMOLYTIC ANEMIATABLE 1Differential Diagnosis of HemolysisClass/typeDiseasesMechanismSiteLaboratory testsTreatmentAlloimmuneTransfusion reactions, hemolytic disease of the fetus cularNeonatal DATHalt transfusion,supportiveAutoimmunehemolytic anemiaWarm or cold autoimmunehemolytic ror intravascularDATSteroids, avoidance, treatment ofother diseaseDrug inducedDrug-induced thromboticmicroangiopathy, drug-induced immune hemolyticanemia, oxidative hemolysisDirect, toxin,phagocytosis,fragmentationExtravascularor intravascularSchistocytes, DAT,Heinz bodiesDrug withdrawalEnvenomationInsects, cobra, brown reclusespiderDirectExtravascularor intravascular——EnzymopathyG6PD or pyruvate kinasedeficienciesOxidative lysisIntravascularEnzyme opathySickle cell disease, thalassemias, hemoglobin sisDisease-specifictreatmentInfectionMalaria, Babesia, Bartonella,Clostridia, Rickettsia, Haemophilus influenzae, humanimmunodeficiency virusDirect, toxin,phagocytosis,fragmentationExtravascularor cifictreatmentMembranopathyHereditary spherocytosis, hereditaryelliptocytosis, paroxysmalnocturnal hemoglobinuriaTrappingExtravascularOsmotic fragility b(Soliris; paroxysmal nocturnalhemoglobinuria)Microangiopathichemolytic anemia/thromboticmicroangiopathyThrombotic thrombocytopenic purpura, hemolyticuremic syndrome, disseminated intravascularcoagulation, HELLP syndrome, drug-inducedthrombotic l bloodsmear (showingschistocytes), assessment of ADAMTS13activity, liver enzymetests, coagulationstudy, culturePlasma exchange,steroids, delivery,drug withdrawalOsmoticFreshwater drowningOsmotic lysisIntravascular——Systemic diseaseMalignant hypertension, systemic lupus erythematosus,scleroderma, liver disease,vasculitides, hypersplenismTrapping,fragmentationExtravascularor ictreatmentTraumaEndovascular devices, aorticstenosis, extracorporealmembrane oxygenation,arteriovenous malformation,march hemoglobinuria, burnsFragmentation, directIntravascular—Stop traumaDAT direct antiglobulin test; G6PD glucose-6-phosphate dehydrogenase; HELLP hemolysis, elevated liver enzymes, and low platelet count.EvaluationWhen hemolysis is suspected, the history should includeknown medical diagnoses, medications, personal or familyhistory of hemolytic anemia, and a complete review of systems. The physical examination should focus on identifyingassociated conditions, such as infections or malignancies(Table 2).September 15, 2018 Volume 98, Number 6The initial workup of hemolytic anemia begins with acomplete blood count illustrating normocytic (mean corpuscular volume of 80 to 100 µm3 [80 to 100 fL]) or macrocytic (mean corpuscular volume greater than 100 µm3)anemia (Figure 1). When anemia is identified, testing shouldinclude measurement of lactate dehydrogenase, haptoglobin, reticulocyte, and unconjugated bilirubin levels, as wellwww.aafp.org/afp American Family Physician 355

SORT: KEY RECOMMENDATIONS FOR PRACTICEEvidenceratingClinical recommendationReferencesas urinalysis (Table 3). Lactate dehydrogenase is intracellular, and levelsincrease when RBCs rupture. HaptoGlucocorticoids are the first-line treatment of warmC4globin binds to free hemoglobin, andautoimmune hemolytic anemia.levels decrease in hemolysis. UnconjuThe PLASMIC score can be used to assess the likeliC10gated bilirubin levels rise as its produchood of thrombotic thrombocytopenic purpura whention exceeds elimination capability.ADAMTS13 cannot be easily measured.Hemolysis usually induces a reticuloDo not give antibiotics to children with Escherichia coliB15cytosis causing macrocytosis, unlessdiarrhea because antibiotics increase the risk of hemosignificant iron deficiency or marlytic uremic syndrome.row suppression is present. UrinalysisG6PD activity should be measured in infants withC28may be positive for hemoglobinuria injaundice and a family history or geographic backgroundhemolytic anemia despite no visiblesuggestive of possible deficiency.RBCs on microscopy. The constellaG6PD glucose-6-phosphate dehydrogenase.tion of reticulocytosis, increased lacA consistent, good-quality patient-oriented evidence; B inconsistent or limited-qualitytate dehydrogenase levels, increasedpatient-oriented evidence; C consensus, disease-oriented evidence, usual practice, expertunconjugated bilirubin levels, andopinion, or case series. For information about the SORT evidence rating system, go to https:// www.aafp.org/afpsort.decreased haptoglobin levels confirmshemolysis. The absence of these findings should prompt a search for othercauses. Supportive care should be initiated as required afterTABLE 2hemolysis is confirmed.Identifying the specific etiology of hemolytic aneDiagnostic Clues for Hemolytic Anemiamia begins with a peripheral blood smear for abnormalHistory and physicalRBCs, such as spherocytes, schistocytes, or bite or blisterexamination findingsSuggested diagnosiscells1 (Figures 2 and 3). Spherocytes are caused by membrane deficits or repeated small membrane removals byDiarrheaHemolytic uremic syndromemacrophages. Spherocytosis is not diagnostic for hemoFamily history of hemoSickle cell disease, hereditarylytic anemia because both hereditary spherocytosis andlytic anemiaspherocytosis, thalassemias,immune etiologies (e.g., autoimmune hemolytic anemiaG6PD deficiency[AIHA], drug-induced immune hemolytic anemia) mayFeverAutoimmune hemolytic anemia,cause spherocytes. Schistocytes are fragmented cells thatdisseminated intravascularresult from intravascular destruction, which occurs incoagulation, hemolytic uremicMAHA syndromes. Bite and blister cells result from parsyndrome, infectiontial phagocytosis, and occur in oxidative causes, such asHematuriaParoxysmal nocturnal hemogloglucose-6-phosphate dehydrogenase (G6PD) deficiency.2binuria, intravascular hemolysisThe direct antiglobulin test (DAT) further differentiatesMedications (Table 4)Drug-induced thromboticimmune causes of hemolytic anemia from nonimmunemicroangiopathic anemia,causes.After hemolytic anemia is confirmed, a peripheral bloodsmear should be ordered to determine the etiology.Cdrug-induced immune hemolytic anemia, G6PD deficiencyNew-onset jaundiceAny hemolytic anemiaPersonal history of cancerWarm autoimmune hemolyticanemiaPersonal history of mononucleosis or Mycoplasmapneumoniae infectionCold autoimmune hemolyticanemiaRecent transfusion historyHemolytic transfusion reactionG6PD glucose-6-phosphate dehydrogenase.356 American Family Physician1Immune Hemolytic AnemiaAUTOIMMUNE HEMOLYTIC ANEMIAAIHA is caused by autoantibody-mediated destruction.The hallmark of AIHA is a positive DAT result (Figure 4).3AIHA is organized into two primary subgroups based onbinding temperatures, referred to as cold and warm agglutinins. Many causes of AIHA are idiopathic; however, viraland bacterial infections, autoimmune conditions, connective tissue disorder, lymphoproliferative malignancies,blood transfusions, and transplantations have been associated with AIHA.www.aafp.org/afp Volume 98, Number 6 September 15, 2018

HEMOLYTIC ANEMIAFIGURE 1Clinical concern for hemolysis(jaundice, fatigue, anemia)Initial hemolysis workup (lactatedehydrogenase, haptoglobin, unconjugatedbilirubin, reticulocytes, urinalysis)Peripheral blood smearNot consistentwith hemolysisConsider other causesSchistocytesSickle cellsTrauma?Sickle celldiseaseYesBite cells,Heinz bodiesNormal redblood cellsG6PD activity,oxidative drugsNonspecificNoMarch hemoglobinuria,arteriovenous malformation, recent bypasssurgery, extracorporealmembrane oxygenation,mechanical stPositiveNoMicroangiopathichemolytic hemolyticanemiaPregnancyDiarrheaCausative drugReducedADAMTS13enzyme activityLiverfunction tests,urinalysisStool culture,Shiga toxin,renal functionDrug exposureHELLPsyndromeEosin-5maleimide testing,osmotic fragilityYesPLASMIC score sure?YesRickettsia, humanimmunodeficiencyvirus, remicsyndromeNoWarm vs. cold,primary luation of suspected hemolysis.G6PD glucose-6-phosphate dehydrogenase; HELLP hemolysis, elevated liver enzymes, and low platelet count.Warm AIHA is more common than cold AIHA andinvolves immunoglobulin G (IgG) antibodies, usuallyto the Rh complex, that react with the RBC membraneat normal body temperatures. The IgG-coated RBCs arethen removed by reticuloendothelial macrophages andSeptember 15, 2018 Volume 98, Number 6sequestered in the spleen, sometimes leading to splenomegaly. Treatment of warm AIHA typically includes theuse of glucocorticoids, management of the underlyingcondition, blood transfusion (if necessary), and supportive care.4www.aafp.org/afp American Family Physician 357

TABLE 3FIGURE 2Initial Laboratory Tests for HemolysisTestFinding in hemolysisCauseHaptoglobinDecreasedBinds freehemoglobinLactatedehydrogenaseElevatedReleased from lysisof red blood cellsPeripheralblood smearAbnormal red bloodcellsBased on cause ofanemiaReticulocytecountIncreasedMarrow response toanemiaUnconjugatedbilirubinIncreasedIncreased hemoglobin breakdownUrinalysisUrobilinogen, positive for bloodFree hemoglobinand its metabolitesCold AIHA involves IgM antibodies (cold agglutinintiters) that react with polysaccharide antigens on theRBC surface at low temperatures and then cause lysison rewarming by complement fixation and intravascularhemolysis. Development of these antibodies is associated with infectious or malignant processes. Mycoplasmal pneumonia and mononucleosis are the two mostcommon processes. Treatment of patients who have coldAIHA typically involves supportive measures, avoidanceof triggers, and underlying disease management.Wright-Giemsa peripheral blood smear (1,000 ). Aschistocyte (arrow) is present in the center of the image.FIGURE 3TRANSFUSION REACTIONSAcute transfusion reactions result from alloantibodies thatreact with incompatible RBCs. Hemolysis can range fromacute to delayed, and can be life-threatening. Transfusionreactions have been discussed previously in AmericanFamily Physician (https:// w ww.aafp.org/afp/2011/0315/p719.html).5DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIADrug-induced immune hemolytic anemia is a rare occurrence that results from drug-induced antibodies. A DATresult is positive in patients with this condition. Historically, methyldopa and penicillin are classic causes, butcefotetan (Cefotan), ceftriaxone, piperacillin (in combination piperacillin/tazobactam [Zosyn]), and nonsteroidal anti-inflammatory drugs currently predominate 6,7(Table 4). The progression of the condition is typicallygradual, and treatment involves removal of the offendingagent.Microangiopathic Hemolytic AnemiaMAHA is a descriptive term for hemolytic anemia thatoccurs when RBCs fragment, and results in schistocytesvisible on the peripheral blood smear. This can be causedby trauma from an endovascular device or microthrombi.358 American Family PhysicianWright-Giemsa peripheral blood smear (1,000 ).Sickle cells, schistocytes, and acanthocytes. Lower leftshows a polychromatic erythrocyte that may representa reticulocyte (a supravital stain is needed to confirm).Thrombotic microangiopathies (TMAs) are a diverse groupof clinical entities that share MAHA as a central feature(Table 1).THROMBOTIC THROMBOCYTOPENIC PURPURAThrombotic thrombocytopenic purpura (TTP) is characterized by significantly reduced ADAMTS13 enzyme activity. The ADAMTS13 enzyme cleaves von Willebrand factoraggregations and, when it is not present or functional, largevon Willebrand factor multimers form. These multimerstrap platelets, causing microthrombi and RBC destructionby shearing, creating schistocytes. Approximately 95% ofwww.aafp.org/afp Volume 98, Number 6 September 15, 2018

TABLE 4FIGURE 4Hemolysis-Inducing AgentsDirect antiglobulin test, demonstrating the presenceof autoantibodies (shown here) or complement onthe surface of the red blood cell.MechanismDrugsDrug-inducedimmune hemolyticanemiaBeta lactamase inhibitors, cefotetan(Cefotan), ceftriaxone, fludarabine,intravenous immunoglobulin, methlydopa, nonsteroidal anti-inflammatorydrugs, penicillin, piperacillinDrug-inducedthrombotic microangiopathic anemia3,4-methylenedioxymethamphetamine(Ecstasy), bupropion (Wellbutrin),chemotherapy, clopidogrel (Plavix),cocaine, cyclosporine (Sandimmune),ibuprofen, interferon, mefloquine,metronidazole (Flagyl), nitrofurantoin,quetiapine (Seroquel), quinine, simvastatin (Zocor), tacrolimus apsone, nitrofurantoin, phenazopyridine, primaquine, recreational nitrates,ribavirin, rifampinIllustration by Dave KlemmReprinted with permission from Dhaliwal G, Cornett PA, TierneyLM Jr. Hemolytic anemia. Am Fam Physician. 2004; 69(11): 2602.TTP cases are associated with acquired autoantibodies,often without an inciting event or disorder.8,9TTP is life-threatening and requires timely diagnosisand treatment. Thrombocytopenia, fever, renal injury,MAHA, and neurologic dysfunction are hallmarks ofTTP. Additional laboratory findings include a negativeDAT result and normal coagulation testing. Assessmentof ADAMTS13 enzyme activity is diagnostic for TTP, butresults usually are delayed, making a presumptive diagnosis imperative. The PLASMIC score can be used to predictseverely reduced ADAMTS13 enzyme activity and initiateearly treatment (Table 5).10 Once a presumptive diagnosisis made, treatment with plasma exchange and glucocorticoids should begin immediately. Plasma exchange removesaffected platelets and autoantibodies while replenishingADAMTS13 enzyme levels. Although plasma exchangeis superior, fresh frozen plasma infusion is beneficial andshould be started if transfer to a plasma exchange–capablecenter is delayed.11HEMOLYTIC UREMIC SYNDROME Volume 98, Number 6PLASMIC Score for Predicting ADAMTS13Enzyme ActivityPlatelet count 30 103 per µL (30 109 per L)HemolysisNo cancer historyNo transplantation historyMean corpuscular volume 90 µm3 (90 fL)Creatinine 2.0 mg per dL (177 µmol per L)International normalized ratio 1.5PLASMIC score (one point per item present)0 to 4: low risk (4.3%)5 to 6: intermediate risk (56.8%)7: high risk (96.2%)Note: Low ADAMTS13 enzyme activity is defined as 10%.Information from reference 10.Hemolytic uremic syndrome (HUS) is characterized byMAHA and acute kidney injury, and commonly thrombocytopenia and neurologic dysfunction. HUS is a separateentity from TTP based on ADAMTS13 enzyme activity.Shiga toxin–producing Escherichia coli HUS (STEC-HUS,also known as typical HUS) accounts for 90% of HUS casesand is caused by STEC organisms such as O157: H7 andShigella dysenteriae.12 It predominantly affects children.STEC-HUS has a classic prodrome of abdominal pain withdiarrhea, often preceding MAHA, acute kidney injury, andthrombocytopenia by five to 10 days. STEC urinary tractinfections can cause a diarrhea-negative STEC-HUS.13 Streptococcus pneumoniae, human immunodeficiency virus,and influenza have also been associated with HUS in rarecases, which presents without the classic prodrome. Thereis an atypical HUS that also does not have the prodrome,September 15, 2018TABLE 5is caused by complement dysregulation and not infection,and can be hereditary. Exacerbations can be triggered by anupper respiratory tract infection.14Inadequately cooked ground beef is the primary source ofSTEC infection, but fruits, vegetables, poultry, and contaminated drinking water have also been implicated. In STECHUS, the Shiga toxin is absorbed and attaches to specificreceptors, most expressed in the glomerulus and brain inchildren, causing endothelial cell damage, which initiates acascade resulting in large von Willebrand factor multimersthat induce MAHA. Treatment of STEC-HUS is supportivecare and continued evaluation of renal function. Antibiotics are not recommended for gastrointestinal STEC becausethey may increase the risk of HUS.15www.aafp.org/afp American Family Physician 359

HEMOLYTIC ANEMIAOTHER MICROANGIOPATHIC HEMOLYTIC ANEMIASYNDROMESOther clinical entities that cause MAHA include HELLPsyndrome (hemolysis, elevated liver enzymes, and lowplatelet count) and disseminated intravascular coagulation. HELLP syndrome is pregnancy related and sharesmany characteristics with TTP and HUS, both of which canalso occur during pregnancy. TTP and HUS do not usuallyinduce liver-associated enzyme elevations as in HELLPsyndrome.16 A low lactate dehydrogenase–to–aspartatetransaminase ratio can aid in distinguishing HELLP syndrome, because the rate of hemolysis is higher in the otherTMAs and hepatic involvement is higher in HELLP syndrome.17 Disseminated intravascular coagulation also canresult in MAHA due to fibrin-rich microthrombi. Disseminated intravascular coagulation causes prolonged coagulation studies, positive d-dimer test results, and decreasedfibrinogen levels.18DRUG-INDUCED THROMBOTIC MICROANGIOPATHYDrug-induced TMA occurs when a compound causes theformation of platelet microthrombi, resulting in MAHAthrough induced antibodies or direct toxicity. These antibodies interact strongly only in the presence of the drug.The clinical features are similar to those of other MAHAsyndromes. In a 2015 review, the overall incidence ofdrug-induced TMA was 5% of all MAHA cases.19 Anotherreview found 78 medications suspected of causing druginduced TMA. Quinine, cyclosporine (Sandimmune), andtacrolimus (Prograf) constituted more than one-half of alldrug-induced TMA cases20 (Table 4). The management ofdrug-induced TMA includes discontinuing the offendingagent and providing supportive care; plasma exchange isnot beneficial, except in the case of ticlopidine.21Oxidative Hemolytic AnemiaOxidative hemolysis occurs when normal processes areunable to reduce ferric (3 ) iron, also known as methemoglobin, to ferrous (2 ) iron, which carries oxygen. Thisresults in methemoglobinemia (i.e., the denaturing of ferrichemoglobin into multimers, called Heinz bodies), leadingto premature RBC destruction by phagocytosis. G6PD isintegral to these protective systems, and when it is deficient,oxidative insults may cause hemolysis. G6PD deficiency isan X-linked disorder and is common in individuals of Mediterranean and African descent. Classically, fava beans, sulfadrugs, and primaquine were the primary triggers of oxidative hemolysis, but the list of medications to avoid in personswith G6PD deficiency is extensive22,23 (see https:// w 277-t3). Thediagnosis is made by G6PD activity testing, although this360 American Family Physicianmay be normal during or just after a hemolytic episode.24Amyl and butyl nitrate, topical benzocaine, phenazopyridine, dapsone, ribavirin, and paraquat ingestion can alsocause oxidative hemolysis, even with normal G6PD levels(Table 4). Treatment is discontinuation of the drug and supportive care. Methylene blue is indicated for the treatmentof severe methemoglobinemia from a non-G6PD cause, butit is possibly harmful and contraindicated in persons withG6PD deficiency.25Considerations in ChildrenA rapid onset of anemia or significant hyperbilirubinemia(i.e., based off of physiologic norms depending on age) inthe neonatal period should prompt consideration of hemolytic anemia. Hemolytic disease of the fetus and newbornis an alloimmune hemolysis caused by maternal antibodiesin the neonate’s plasma, is most commonly anti-Rh, and isDAT-positive. Hemolytic disease of the fetus and newbornis treated with supportive care and hyperbilirubinemiamanagement. Severe G6PD deficiency can also cause acutehemolysis, accounting for nearly 30% of all kernicteruscases in one observational study.26 G6PD deficiency is a keypart of the differential diagnosis of neonatal hyperbilirubinemia, particularly in high-incidence populations.27,28Hereditary spherocytosis is the most common inheritedmembranopathy and is caused by one of several defectiveproteins. In severe cases, it can cause hemolysis in the neonatal period but typically presents later as chronic hemolysis.The mutations are largely autosomal dominant, making thefamily history important. In the setting of a DAT-negativehemolysis and spherocytes on peripheral blood smear, anincreased mean corpuscular hemoglobin concentration–to–mean corpuscular volume ratio (greater than 0.35) shouldprompt consideration of hereditary spherocytosis and further testing with osmotic fragility and eosin-5-maleimidebinding to confirm the diagnosis.29 Treatment is supportive, with splenectomy often required in moderate to severehereditary spherocytosis.Inherited hemoglobinopathies, such as sickle cell disease and thalassemias, can present in the neonatal periodor later, depending on their severity. They should alwaysbe considered in the workup of a child with hemolysis,and have been reviewed in previous articles in AmericanFamily Physician30,31 (https:// w ww.aafp.org/afp/2015/1215/p1069.html and https:// w ww.aafp.org/afp/2009/0815/p339.html).This article updates a previous article on this topic by Dhaliwal, et al.3Data Sources: We searched PubMed with the terms MAHA, TMA,TTP, HUS, DIC, hyperbilirubinemia, and G6PD deficiency. Relevant UpToDate articles were also accessed to provide references.An Essential Evidence Plus search was provided to the authorswww.aafp.org/afp Volume 98, Number 6 September 15, 2018

HEMOLYTIC ANEMIAas well. The Cochrane database was also queried. Search dates: April and May 2017, and March 2018.Figures 2 and 3 provided by Lyndon P. Bowden, MD, MPH,Department of Pathology, Womack Army Medical Center.The views expressed in this article are those of the authors anddo not necessarily reflect the official policy of the Department ofthe Army, the Department of Defense, or the U.S. government.The AuthorsJAMES PHILLIPS, MD, is a hospitalist fellow at Womack ArmyMedical Center, Fort Bragg, N.C., and an assistant professor inthe Department of Family Medicine at the Uniformed ServicesUniversity of the Health Sciences, Bethesda, Md.ADAM C. HENDERSON, MD, is a third-year resident in theDepartment of Family Medicine, Womack Army Medical Center.Address correspondence to James Phillips, MD, Womack ArmyMedical Center, 2817 Reilly Rd., Fort Bragg, NC 28310 (e-mail: james.d.phillips2.mil@ mail.mil). Reprints are not available from theauthors.References1. Mentzer WC, Schrier SL. Extrinsic nonimmune hemolytic anemias. In: Hoffman R, Benz EJ Jr., Silberstein LE, et al., eds. Hematology: BasicPrinciples and Practice. 7th ed. Philadelphia, Pa.: Elsevier; 2018: 663-672.2. Bain BJ. Diagnosis from the blood smear. N Engl J Med. 2005; 353(5): 498-507.3. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004; 69(11): 2599-2606.4. Michel M, Jäger U. Autoimmune hemolytic anemia. In: Hoffman R,Benz EJ Jr., Silberstein LE, et al., eds. Hematology: Basic Principles andPractice. 7th ed. Philadelphia, Pa.: Elsevier; 2018: 6 48-662.5. Sharma S, Sharma P, Tyler LN. Transfusion of blood and blood products: indications and complications. Am Fam Physician. 2011; 83(6): 719-724.6. Garratty G. Drug-induced immune hemolytic anemia. Hematology AmSoc Hematol Educ Program. 2009: 73-79.7. Johnson ST, Fueger JT, Gottschall JL. One center’s experience: theserology and drugs associated with drug-induced immune hemolyticanemia—a new paradigm. Transfusion. 2007; 47(4): 697-702.8. George JN, Nester CM. Syndromes of thrombotic microangiopathy. NEngl J Med. 2014; 371(7): 654-666.9. Blombery P, Scully M. Management of thrombotic thrombocytopenicpurpura: current perspectives. J Blood Med. 2014; 5: 15-23.10. Bendapudi PK, Li A, Hamdan A, et al. Derivation and prospective validation of a predictive score for the rapid diagnosis of thrombotic thrombocytopenic purpura: the Plasmic Score. Blood. 2014; 1 24(21): 231.11. Rock GA, Shumak KH, Buskard NA, et al.; Canadian Apheresis Study Group.Comparison of plasma exchange with plasma infusion in the treatmentof thrombotic thrombocytopenic purpura. N Engl J Med. 1991; 325(6): 393-397.13. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal disease andhemolytic uremic syndrome. Pediatrics. 2002; 1 10(2 pt 1): 371-376.14. Jokiranta TS. HUS and atypical HUS. Blood. 2017; 1 29(21): 2847-2856.15. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of thehemolytic-uremic syndrome after antibiotic treatment of Escherichiacoli O157: H7 infections. N Engl J Med. 2000; 3 42(26): 1930-1936.16. Pourrat O, Coudroy R, Pierre F. Differentiation between severe HELLPsyndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators. Eur J Obstet Gynecol Reprod Biol.2015; 189: 68-72.17. Keiser SD, Boyd KW, Rehberg JF, et al. A high LDH to AST ratio helps todifferentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome. J Matern Fetal Neonatal Med. 2012; 25(7): 1059-10

Sep 15, 2018 · uremic syndrome, dis-seminated intravascular coagulation, HELLP syn - drome, drug-induced thrombotic microangiopathy Fragmentation Intravascular Peripheral blood smear (showing schistocytes), assess -

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