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Hemolytic anemia in a 26-year-old woman with vomiting and fatigue

Malik Elharram MD, Vladimir Sapon-Cousineau MD, Vicky Tagalakis MD MSc n Cite as: CMAJ 2018 August 27;190:E1013-7. doi: 10.1503/cmaj.171147

26-year-old black woman underwent evaluation in the emer- normal fibrinogen level and normal coagulation studies. To evaluate gency department after two weeks of worsening nausea, for autoimmune hemolytic anemia, we ordered a direct Coomb test, vomiting and fatigue. Her medical history included having which was negative. This result, combined with a normal total com- hadA malaria at eight years of age, for which she had received treat- plement test, allowed us to conclude that a diagnosis of autoim- ment in Eritrea. A complete review of systems was unremarkable mune hemolytic anemia was unlikely. Direct Coomb tests have a aside from a two-day history of a mild bitemporal headache. The sensitivity of 90%–95% and specificity of 99% in diagnosing autoim- patient stated no recent changes in her dietary habits or bowel move- mune hemolytic anemia.1 We chose to order a rapid malaria antigen ments. She did not take any medication or over-the-counter products, test even in the absence of recent travel, given our patient’s medical and she had never used illicit drugs. She had no history of venous history. The test was negative. To assess for underlying microangio- thromboembolism. pathic hemolytic anemia, we requested a peripheral blood smear, Our patient’s vital signs were as follows: temperature 36.7°C, which showed polychromatophilia, macro-ovalocytes, hyperseg- heart rate 87 beats/min, blood pressure 105/71 mm Hg, respira- mented neutrophils and large platelets (Figures 1 and 2). In addi- tory rate 16 breaths/min and oxygen saturation 100% on room air. tion, schistocytes and fragmented cells were present (Figure 2). She appeared fatigued and showed signs of pallor on her palms and nail beds. A complete neurologic examination that included Given the results of the peripheral blood smear, cranial nerves, gait, reflexes, proprioception and sensation was which of the following diagnoses should be unremarkable. The rest of the physical examination results were considered? normal, including the absence of hepatosplenomegaly. Laboratory investigations in the emergency department a. Microangiopathic anemia showed normocytic anemia (mean corpuscular volume [MCV] 89.9 b. Sickle cell crisis [normal 80–96] fL), with hemoglobin 57 [normal 120–152] g/L, mild c. Thalassemia thrombocytopenia (platelets 119 [normal 150–400] × 109/L) and d. Paroxysmal nocturnal hemoglobinuria normal leukocyte count and differential. A preliminary workup for e. Cobalamin deficiency anemia showed elevated lactate dehydrogenase (> 1800 [normal 110–220] U/L) and mildly elevated total bilirubin (23 [normal 3–17] μmol/L), with a conjugated bilirubin of 6 (normal 0–5) μmol/L. The reticulocyte count was normal (26 [normal 7–31] × 103/L). These results, taken in totality, were consistent with hemolytic anemia. There were no previous laboratory results for comparison.

What further evaluation should this patient undergo? a. Fibrinogen level b. Coomb test c. Peripheral blood smear d. Malaria antigen test e. All of the above

The answer is (e). All of the above are appropriate diagnostic tests Figure 1: Peripheral blood smear from a 26-year-old black woman show- for further workup of a hemolytic anemia for this patient. We ing anisocytosis, poikilocytosis, macro-ovalocytes, hypersegmented neu- excluded disseminated intravascular coagulation on the basis of a trophils and large platelets.

© 2018 Joule Inc. or its licensors CMAJ | AUGUST 27, 2018 | Volume 190 | Issue 34 E1013 practice E1014 cobalamin (vitaminB The answerisboth(a)and(e).Bothmicroangiopathicanemia ovalocytes andfragmentedcells. Figure 2:Peripheralbloodsmearfromthesamepatientshowingmacro- however, it was unlikely, given our patient’s negative history for however, itwasunlikely,givenourpatient’snegativehistoryfor possible giventhepresenceofhemolysiswithirondeficiency; on our differential. Paroxysmal nocturnal hemoglobinuria was red bloodcellsonperipheralsmear,thisdiagnosisremainedlow had nohistoryofsicklecellcrisisand,withanabsencesickled Although ourpatientwasoriginallyfromSub-SaharanAfrica,she *Adapted from George JN,Nester CM.Syndromes ofthrombotic microangiopathy. NEnglJMed 2014;371:654–66. Coagulation-mediated Metabolism-mediated Complement-mediated purpura Thrombotic thrombocytopenic Hereditary disorders (non-immune reaction) Drug-mediated (immune reaction) Drug-mediated Complement-mediated (Shiga toxin–mediated) Hemolytic uremic syndrome purpura Thrombotic thrombocytopenic Acquired disorders Diagnosis Box 1:Differential diagnosis thrombotic of primary microangiopathy 12 ) deficiencyshouldbeconsidered. Homozygous mutations inDGKE Homozygous mutations inMMACHC pathway uncontrolled activation ofalternative complement Mutations incomplement genes causing heterozygous for ADAMST13 mutations) ADAMTS13 (homozygous deficiency orcompound Multiple mechanisms drug-dependent antibodies Quinine andpossiblyother drugs withformation of activity Autoantibody inhibitionofcomplement factor H Escherichia coli orShigelladysenteriae Enteric infection withShiga toxin–secreting strain of Autoantibody inhibitionofADAMTS13 activity CMAJ | AUGUST 27, 2018 Cause | Vol differential diagnosisofthromboticmicroangiopathy. ney injurycommonlyassociatedwithHUS.Box1summarizesthe tively mildthrombocytopeniawithouttheevidenceofacutekid- any precedingepisodeofdiarrhea.Furthermore,shehadrela- food-borne illness,exposuretoacontaminatedwatersupplyor mind. RegardingHUS,thepatientdidnothaveanyhistoryof which cautionedustokeepthislife-threateningdiagnosisin sented withabitemporalheadacheandmildthrombocytopenia, mental status,renalfailureandfever.However,ourpatientpre- given the absence of other associated features, such as altered botic thrombocytopenic purpura was lower on our differential pathic hemolyticanemiaontheperipheralbloodsmear.Throm- thrombocytopenia and the findings consistent with microangio- purpura/hemolytic uremicsyndrome(HUS)giventhepresenceof our differentialdiagnosisincludedthromboticthrombocytopenic a diagnosisofmicroangiopathichemolyticanemia.Atthispoint, seen inthalassemia. opposed tomicrocytichypochromicanemia,whichisclassically ever, ourpatient’speripheralsmearshowedmacrocytosisas penia. Thalassemiacouldpresentwithhemolyticanemia;how- venous andarterialthromboembolism,theabsenceofleuko- inappropriately normalreticulocytecountinthecontextof platelets and hypersegmented neutrophils. Furthermore, the peripheral bloodsmear,includingmacro-ovalocytes,giant nosis giventhepresenceofmegaloblasticchangeson The presence of schistocytes and fragmented cells supported The presenceofschistocytesandfragmentedcellssupported We consideredvitaminB ume 190 2 | Issu e 34 acute injury kidney Usually presents inchildren younger than1year with acute injury kidney 1 case reported inanadultwithhypertension and Usually presents inchildren younger than1year; iscommonacute injury kidney Usually presents inchildren (alsopossibleinadults); isuncommonacute injury kidney Usually presents inchildren (alsopossibleinadults); Gradual onset ofrenal failure over weeks ormonths anuric renal failure Sudden onset ofsevere systemic symptoms and Acute injury kidney after anepisodeofdiarrhea injury kidney More common inchildren; presents withacute isuncommon injury kidney symptoms, purpura andneurologic symptoms; acute Diverse, includingweakness, gastrointestinal 12 Clinical presentation deficiencyinourdifferentialdiag- 2 practice E1015 linical Clinical presentation Patient 1: Patient Lethargy, confusion, exertional dyspnea, walking, difficulty lower moderate edema extremity 2: Patient Progressively increasing bilateral fatigue, paresthesias, icterus scleral 3: Patient Increasing fatigue, exertional right dyspnea, upper quadrant pain Asthenia and 6 dyspnea: (100%); patients 5 jaundice: (83%); patients mild peripheral sensitive 3 neuropathy: (50%); patients mental impaired 1 patient status: (17%); peripheral infiltrated cutaneous 1 purpura: (17%) patient Asymptomatic: Asymptomatic: of one-third patients; mild sensory polyneuropathy 92 or confusion: patients(46%); physical 40 weakness: (20%); patients edema bilateral 24 of the legs: (12%); patients 4 jaundice: (2%) patients deficiency, we gave our gave we deficiency, 12 eripheral smear eripheral P Patient 1: Patient and Schistocytes hypersegmented neutrophils 2: Patient with Macrocytosis anisopoikilocytosis, single hyperpigmented neutrophil/ with granulocyte schistocyte 3: NR Patient Megaloblastic Megaloblastic anemia and schistocytes Hypersegmented Hypersegmented and neutrophils in macrocytosis of two-thirds patients g/L, which could have been the reason reason the been have could which g/L, μ ; 3 ; 3 parenterally and folic acid supplementation. and folic acid supplementation. parenterally 12 /L; 9 ; ; 3 3 e 34 Issu | ; 3 values mol/L; mol/L; LDH μ Other laboratory Other laboratory ume 190 Given the finding of severe vitamin B vitamin severe of finding the Given platelets 123 000/mm platelets homocysteine homocysteine 129.7 < 7 mg/dL haptoglobin platelets 99 000/mm platelets homocysteine homocysteine 16.2 μmol/L; anti-intrinsic positive antibodies 4 factor (67%) patients reticulocytes 6.3%; reticulocytes 134 fL; MCV homocysteine 62.4 μmol/L; < 6 mg/dL; haptoglobin LDH 3152 U/L 2: Hg 7.7 g/dL; Patient WBC 3400/mm 6%; MCV reticulocytes 115 fL; homocysteine 88.8 μ serum 788 U/L; < 7 mg/dL haptoglobin 3: Hg 6.6 g/dL, Patient 146 fL; platelets MCV 97 000/mm Mean hemoglobin Mean 10.3 g/dL; no hematological abnormalities (56 [28%]); 12 (5%); pancytopenia pseudothrombotic 5 microangiopathy (3%); hemolytic anemia 3 (2.5%); anti-intrinsic positive antibodies 3 factor (2.5%) Hemoglobin 68 g/L; 70 × 10 platelets Patient 1: Hg 5.0 g/dL; Patient WBC 3100 mm for our patient’s normal MCV. for our patient’s patient vitamin B patient vitamin of 38 (normal 50–300) 50–300) (normal 38 of Vol | deficiency and hemolysis deficiency 12 level, pg/mL* level, Mean cobalamin cobalamin Mean 52 (normal 12–74) Patient 1: 167 Patient 2: 100 Patient 3: 162 Patient Pseudothrombotic Pseudothrombotic microangiopathy: 50 AUGUST 27, 2018 AUGUST | CMAJ age, yr age, Mean or median or median Mean 77 (range 47–89) 77 (range Patient 1: 55 Patient 2: 58 Patient 3: 91 Patient 67 (SD ± 6) 6 3 201 No. of of No. patients 4 7 5 deficiency was subsequently confirmed with a serum confirmed with a serum was subsequently deficiency 12 Andrès et al. et Andrès Andrès et al. et Andrès Study ase series and reports of vitamin B vitamin of 2): Case series and reports 1 of 2 (part Box Acharya et al. Acharya et level of 62 (normal 140–700) pmol/L. In addition, the patient was 62 (normalof level was patient the addition, In pmol/L. 140–700) ferritin level deficiency, with a concomitant iron found to have severe anemia pointed to underlying bone marrow failure. Vita- failure. marrow bone underlying to pointed anemia severe min B practice folic acid(5mg orally daily)andironsulfate(300 mgorallydaily). E1016 B symptoms. Shewassubsequently dischargedhomewithvitamin globin increased to 73 g/L with marked improvement in her We administered1unitofpacked redbloodcells,andherhemo- 12 Chhabra et al. Kollipara et al. *Unless otherwisespecified. Note: LDH =lactate dehydrogenase, volume, MCV=meancorpuscular NR=notrecorded, SD=standard deviation, WBC =white blood cells. Study Box 2(part 2of 2):Caseseriesandreports of vitamin B Noël et al. et al. Prueksaritanond Garderet et al. Y eruva et al. (1000µgsubcutaneouslydaily forsixweeks,thenmonthly), 11 9 12 6 8 10 patients No. of 1 1 1 7 1 1 22 52 42 72 (range 43–78) 38 52 Mean ormedian age, yr CMAJ | AUGUST 27, 2018 60 < 30 59 45 µmol/L Undetectable 116 Mean cobalamin level, pg/mL* 12 deficiency andhemolysis | Vol level normalized, suggestingrecoveryofhertissue stores. dehydrogenase andtotalbilirubin). Ofnote,herserumvitaminB platelets 279×10 with normalizationofherblood counts(hemoglobin137g/L, cell antibodies positive antiparietal anti-intrinsic factor; 22.4 homocysteine LDH 1868IU/L; haptoglobin 2mg/dL; platelets 91 000; Hemoglobin 4.8g/dL; 161 ×10 701 IU/L; platelets MCV 87.1fL;LDH Hemoglobin 5.9g/dL; WBC 1.3×10 Hemoglobin 6.8g/dL; platelets 73×10 Hemoglobin 42g/L; WBC 2.2×10 Hemoglobin 4.5g/dL; platelets 76×10 Hemoglobin 4.2g/dL; 13.1 ×10 reticulocytes 0.1 g/L; 7310 IU/L; haptoglobin MCV 110.6fL;LDH factor antibodies positive anti-intrinsic total bilirubin12mg/dL; haptoglobin 7mg/dL; factor antibodies cell andanti-intrinsic positive antiparietal haptoglobin <10mg/dL; LDH 1155U/L; reticulocytes 13.1×10 antibodies anti-intrinsic factor positive < 10 mg/dL; 4050 U/L; haptoglobin > 50 μmol/L;LDH homocysteine reticulocytes 2.48%; MCV 136.8.8 fL; 90 fL;platelets 5×10 platelets 112×10 10 index 0.4% 100 homocysteine undetectable; At six weeks’ follow-up, her symptoms had completely resolved, At sixweeks’follow-up,hersymptoms hadcompletelyresolved, ume 190 9 Other laboratory /L; serumhaptoglobin μ μ mol/L; reticulocyte mol/L; reticulocyte mol/L; positive mol/L; positive 9 /L; WBC 4.7 × /L; WBC4.7× values 9 /L 3 9 /L; MCV /L; MCV | /L; Issu e 34 9 9 /L; /L; /L; 9 /L; 9 /L) andnosignsofhemolysis(normal lactate 3 9 /L; /L; /L; /L; Schistocytes schistocytes poikilocytosis, few hypochromasia with Marked anisocytosis, poikilocytosis schizocytes, and anisocytosis, neutrophils, Hypersegmented blood cells tear-shaped red ovalocytes; anemia with normochromic Normocytic, neutrophils hypersegmented schistocytes with stippling, occasional slight basophilic blood cells with dysmorphic red Macrocytic schistocytes multiple elliptocytes and tear drop cells, and poikilocytoisis; Marked anisocytosis P eripheral smear patients (28.6%) Mild confusion: 2 icteric sclera conjunctiva with exertion; pale onset dyspnea on fatigue andnew Generalized Asthenia Asymptomatic pain Fatigue andchest jaundice weakness; fatigue and generalized Increasing presentation Clinical 12

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­ - J 12 60. 149- E1017 Other Other 4 Case Rep Case Rep 368: 2013; In our litera- Case Rep Hematol 3–11 A puzzle of hemolytic deficiency can be 12 et al. Varying blood smear Varying blood smear , N Engl J Med 11 AE Current hematological findings in Current hematological findings in Schizocytosis in pernicious anemia Schizocytosis in pernicious anemia Pseudo-thrombotic microangiopathy A case of asymptomatic pancytopenia Pernicious anemia with autoimmune Pernicious anemia with autoimmune Hemolysis and hyperhomocysteinemia Hemolysis and hyperhomocysteinemia . et al. P , et al. et al. Hemolysis and schistocytosis in the emer- J et al. , Mirrakhimov L, or autoimmune hemolytic anemia anemia hemolytic autoimmune or et al. M D, 9 , A, Cobalamin deficiency causing severe hemolytic Oneal et al. W deficiency as the cause of the anemia. G, EG. 12 RP, Zimmer Federici , S Gemmel S, The direct antiglobulin test: indications, interpretation, The direct antiglobulin test: indications, interpretation, Lagrange , Horvath Barbaryan E PL, Tertian Sakalis CA. S, JT, S, G, Brine e 34 Issu Maury | Lee Gau Manchandani , Clinical practice. Vitamin B12 deficiency. Affenberger , Affenberger L Tormey VK, levels of less than 100 pg/mL. A few case reports, 100 pg/mL. A few case reports, levels of less than N, , U Maigné 12 E SL, E, SP. V, N, Acharya and review of the litera- caused by cobalamin deficiency: three case reports ture. J Hematol Oncol 2008;1:26. Andrès Stabler and pitfalls. Arch Pathol Lab Med 2017;141:305-10. N Engl J George JN, Nester CM. Syndromes of thrombotic microangiopathy. Med 2014;371:654–66. :e5-6. anemia: a pernicious presentation. Am J Med 2015;128 Andrès . related to cobalamin deficiency. Am J Med 2006;119:e3 Garderet cobalamin deficiency. A study of 201 consecutive patients with documented with documented cobalamin deficiency. A study of 201 consecutive patients . cobalamin deficiency. Clin Lab Haematol 2006;28:50-6 Chhabra with clinical features of hemolysis as a presentation of pernicious anemia. Community Hosp Intern Med Perspect 2016;6:32493. Prueksaritanond hemolytic anemia: a case report and literature review. 2016;2016:7231503 anemia, iron and vitamin B12 deficiencies in a 52-year-old male. Hematol 2013;2013:708489. Yeruva Parker 2003;114:423-5. mimicking thrombotic thrombocytopenic purpura. Am J Med Noël gency department: consider pseudothrombotic microangiopathy related to related to gency department: consider pseudothrombotic microangiopathy vitamin B12 deficiency. QJM 2013;106:1017-22. Kollipara ume 190 The presentation of patients with vitamin B The presentation of patients

. 4. 5. 7. 8. 6. 1. 9.

2. 2. 3

11. however, have described hemolysis in patients with vitamin B hemolysis in patients with vitamin however, have described ician to suspect vitamin B quite diverse, with varying clinical and hematologic findings thatquite diverse, with varying smear is an essen- can mimic other illnesses. The peripheral blood and evidencetial first step in investigating the cause of hemolysis, phys a direct should schistocytes and changes megaloblastic of 12. ture review, patients who presented with hemolysis usually had who presented with hemolysis usually had ture review, patients vitamin B References Affiliations: Division of General Internal Medicine (Sapon-Cousineau, Tagalakis), Jewish General Hospital; Faculty of Medicine (Sapon- Cousineau, Elharram, Tagalakis), McGill University, Montréal, Que. Contributors: Malik Elharram and Vladimir Sapon-Cousineau contrib- uted equally to the production of the manuscript. Vicky Tagalakis con­ tributed to drafting the manuscript and provided editorial review of the publishedversion to be reviewed the final authors the of All manuscript. and agreed to act as guarantors of the work. Correspondence to: Malik Elharram, [email protected] levels between 100 and 200 pg/mL (Box 2). levels between 100 and 10. studies in the literature have reported varying hematologic find- hematologic varying reported have literature the in studies pancytopenia including ings hypersegmented neutrophils on peripheral blood smear. Nearly smear. blood on peripheral neutrophils hypersegmented find- without any hematologic of patients presented one-third symptom- findings including hematologic ings. Life-threatening and microangiopathy pseudothrombotic pancytopenia, atic patients. of 10% about in found were anemia hemolytic chromic anemia, anisocytosis and poikilocytosis. chromic anemia, anisocytosis - including hypersegmented neutro features have been reported, normo and normocytic schistocytosis, macrocytosis, and phils with a positive direct Coomb test result. with a positive direct Vol | - - In our

3–11 12 deficiency deficiency 12 AUGUST 27, 2018 AUGUST | deficiency. 12 and iron deficiency, we deficiency, iron and CMAJ 12 The results showed that The results showed that 4 levels are borderline or incon- levels are borderline deficiency are often subtle; how- 12 12 deficiency, as the findings typically do 12 deficiency, and are typically reserved for deficiency, and are typically 12 deficiency, she underwent a gastroscopy with biop with gastroscopy a underwent she deficiency, 12 deficiency, Andrès and colleagues examined hematologic 12 Bone marrow aspiration Bone marrow electrophoresis Hemoglobin cell antibodies Anti-intrinisc/antiparietal Genetic testing homocysteine levels Methylmalonic acid and In the context of combined vitamin B vitamin combined of context the In In the largest study involving patients with documented vita- Competing interests: Dr. Tagalakis reports personal fees from advi- sory boards (Sanofi, Pfizer, Bayer, Britsol–Myers Squibb and Servier), personal fees from speakers bureaus (Sanofi, Pfizer, Bristol–Myers Squibb), grants or honoraria from a commercial organization (Sanofi), outside years, two past the within trial clinical a in participation and the submitted work. No other competing interests were declared. This article has been peer reviewed. The authors have obtained patient consent. had the classical hematologic features of macrocytosis and had the classical hematologic features of macrocytosis and

Clinical manifestations of vitamin B Discussion - cell antibodies. Homo The answer is (c), anti-intrinsic/antiparietal acid are metabolic intermediates thatcysteine and methylmalonic B accumulate in vitamin a. b. c. d. e. n the context of the patient’s vitamin B vitamin patient’s of the context In the findings in 201 consecutive patients. strongly suspected a gastrointestinal malabsorption disorder. disorder. strongly suspected a gastrointestinal malabsorption but she did Our patient had no anti-intrinsic factor antibodies, but is not diag- have antiparietal cell antibodies, which suggests workup for her severe nostic of pernicious anemia. As part of the B vitamin cases in which the initial vitamin B cases in which the initial less than half of patients presenting with vitamin B clusive. Genetic testing should not be performed in this patient, as should not be performed in this patient, clusive. Genetic testing - for an underlying hereditary hemoglobinopa there is no suspicion - marrow aspirate or biopsy is not appro thy. Furthermore, a bone priate to evaluate vitamin B not distinguish these deficiencies from other hematologic disor- not distinguish these deficiencies from other appropriate for a sus- ders. Hemoglobin electrophoresis would be picion of sickle cell anemia (b) or thalassemia. deficiency, what additional workup should be workup should what additional deficiency, done? review of the literature, these patients most commonly presentedreview of the literature, these patients most with fatigue, asthenia, sensory neuropathy or jaundice. A small pro- portion of patients, however, presented asymptomatically, with evi dence of hemolysis noticed incidentally on blood work (Box 2). min B ever, the consequences of this condition can be serious, with theever, the consequences of this condition can and demyelinating dis- potential of reversible bone marrow failure and case series haveease of the nervous system. Existing case reports clinical presentation ofreported substantial heterogeneity in the B patients with hemolysis secondary to vitamin sies that were consistent with autoimmune atrophic gastritis. sies that were consistent with autoimmune