a 38 year old woman

8/13/2019 A 38 Year Old Woman

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case records of the massachusetts general hospital

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 369;21 nejm.org november 21, 20132032

Founded by Richard C. CabotEric S. Rosenberg, m.d., Editor Nancy Lee Harris, m.d., Editor

Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

From the Departments of Medicine(D.E.W., R.P.R.) and Pathology (M.Y.P.),Massachusetts General Hospital, and theDepartments of Medicine (D.E.W., R.P.R.)and Pathology (M.Y.P.), Harvard MedicalSchool — both in Boston.

N Engl J Med 2013;369:2032-43.

DOI: 10.1056/NEJMcpc1215972

Copyright © 2013 Massachusetts Medical Society.

Presentation of Case

Dr. Joanna Lopez (Medicine): A 38-year-old woman was admitted to this hospital be-cause of anemia and thrombocytopenia.

The patient had been well until approximately 3 months before admission, when fatigue, malaise, and light-headedness developed that she attributed to a viral illness. Three weeks before admission, fatigue worsened, and dyspnea onexertion, bruising on the legs, dark urine, and headache developed. She reportedthat she “felt like staying in a bed all day” and needed assistance with showering.Two days before admission, she went to another hospital. The physical examina-tion was reportedly normal, as were the results of coagulation tests. Screening forantibodies to the human immunodeficiency virus (HIV) and a rapid plasma reagintest were negative; other test results are shown in Table 1. She was admitted to theother hospital.

Examination of the peripheral-blood smear reportedly revealed normal mor-phologic features of the white cells, a reduced platelet count, spherocytes, andpolychromatic red cells. A direct antiglobulin test (Coombs’ test) was positive, and warm-reacting and cold-reacting autoantibodies were reportedly present. Resultsof serum and urinary protein electrophoresis were normal. Glucocorticoids (methyl-prednisolone at a dose of 150 mg twice daily for 2 days, followed by prednisoneat a dose of 70 mg twice daily) were administered, as were ondansetron and folate,but the patient’s condition did not improve (Table 1). Computed tomographic (CT)

scans of the abdomen and pelvis, obtained after the intravenous administration ofcontrast material, were normal. On the second night, hypotension developed butimproved after the intravenous administration of fluids. On the third day, thehematocrit was 16.8%. One unit of packed red cells was transfused, and pantopra-zole was administered. The patient was transferred to this hospital because ofdiff iculty finding additional red-cell units that were compatible with her antibodyscreen.

On admission, the patient reported a weight loss of 2.3 kg during the previous week, intermittent blurred or double vision in both eyes, and for the previous3 months, transient vesicular lesions on the thighs that resolved spontaneously

Case 36-2013: A 38-Year-Old Woman with Anemia and Thrombocytopenia

Douglas E. Wright, M.D., Ph.D., Rachel P. Rosovsky, M.D., M.P.H.,and Mia Y. Platt, M.D., Ph.D.

The New England Journal of Medicine

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Copyright © 2013 Massachusetts Medical Society. All rights reserved.



Th e n e w e n g l a n d j o u r n a l o f medicine


pneumonia) or an episode of a relapsing andremitting illness (e.g., intermittent hemolyticanemia). A chronic illness might explain theepistaxis during childhood and pregnancy andthe bleeding after a cesarean section. A diagno-

sis of major depressive disorder could be madeonly after a thorough search for a systemic ill-ness has been performed.

As we analyze the present illness, we mustremember that the patient may have an underly-

Table 1. Laboratory Data.*

Variable

ReferenceRange,Adults†

OtherHospital,

on Admission

OtherHospital,

Day 2This Hospital,on Admission

This Hospital,First Admission,

Days 7–9

Hematocrit (%) 36.0–46.0 20.0 20.1 19.4 32.9

Hemoglobin (g/dl) 12.0–16.0 7.5 7.2 11.1

White-cell count (per mm3) 4500–11,000 10,300 27,200 14,500

Differential count (%)

Neutrophils 40–70 79 85

Band forms 0–10 8

Lymphocytes 22–44 10 6

Monocytes 4–11 2 5Myelocytes 0 1 2

Metamyelocytes 0 2

Nucleated red cells (per 100 white cells) 0 7 1

Platelet count (per mm3) 150,000–400,000

53,000 87,000 122,000 67,000

Erythrocyte count (per mm3) 4,000,000–5,200,000

2,200,000 3,450,000

Red-cell distribution width (%) 11.5–14.5 22.5 20.7

Reticulocytes (%) 0.5–2.5 Elevated,by report

10.7 10.3 (manual)

Erythrocyte sedimentation rate (mm/hr) 0–17 104

Fibrinogen (mg/dl) 161–393 353

D-Dimer (mg/liter) 0.00–0.52 1.25

Fibrin-degradation products ( µg/ml) <10 <10

Haptoglobin (mg/dl) 16–199 <6 <6

Glucose (mg/dl) 70–110 140 112

Bilirubin (mg/dl)

Total 0.0–1.0 4.9 2.0 1.5

Direct 0.0–0.4 0.4 0.3

Indirect 4.3

Aspartate aminotransferase (U/liter) 9–32 59 36 138

Alanine aminotransferase (U/liter) 7–30 77 52 349

Lactate dehydrogenase (U/liter) 110–210 461 484 444 416

Iron (µg/dl) 30–160 176

Total iron-binding capacity (µg/dl) 230–404 229

Ferritin (ng/ml) 10–200 775

Epstein–Barr virus DNA, by PCR Negative Positive <300‡

Antibodies to double-stranded DNA Negative at1:10 dilution

8 IU/ml§ Negative at1:10 dilution







n engl j med 369;21 nejm.org november 21, 2013 2035

Table 1. (Continued.)

Variable

ReferenceRange,Adults†

OtherHospital, onAdmission

OtherHospital,

Day 2This Hospital,on Admission

This Hospital,First Admission,

Days 7–9

Antibodies to SSA (Ro) (OD units) 0.0–19.99 3.9(AI ref 0.0–0.9)

10.27

Antibodies to SSB (La) (OD units) 0.0–19.99 0.7(AI ref 0.0–0.9) 8.89

Antibodies to smooth muscle Negative at1:20 dilution

Positive at1:20 dilution

Antimitochondrial antibodies Negative at1:20 dilution

Negative at1:20 dilution

Cytomegalovirus DNA, by quantitative PCR(copies per ml)

None detected Nonedetected

Anticardiolipin IgM antibodies (MPL units) 0–15 31.6

Anticardiolipin IgG antibodies (GPL units) 0–15 14.9

Antinuclear antibodies Negative at1:40 and 1:160

dilutions

Positive at 1:40and 1:160 dilutions,

homogeneous pattern

Hepatitis B surface antibodies Nonreactive Nonreactive Reactive

Hepatitis B surface antigen Nonreactive Nonreactive Negative

Hepatitis B core antibodies Negative Positive

Hepatitis A total antibodies Negative Positive

Hepatitis A IgM antibodies Negative Negative

Hepatitis C antibodies Negative Negative Negative

Hepatitis B e antigen Negative Negative

Hepatitis B e antibodies Negative Negative

Hepatitis B nucleic acid Negative Negative

IgM antibodies to Epstein–Barr virus VCA Negative Negative

IgG antibodies to Epstein–Barr virus VCA Negative Positive

Antibodies to Epstein–Barr virus nuclearantigen

Negative Positive

Heterophile antibodies Negative Negative

Varicella IgG antibodies Negative Positive

Mycoplasma pneumoniae IgG antibody index ≤0.90 1.71

M. pneumoniae IgM antibody index ≤0.90 0.81

* AI ref denotes antibody index reference range, GPL IgG phospholipid, MPL IgM phospholipid, OD optical density, PCR polymerase chain reac-tion, and VCA viral capsid antigen. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for biliru-bin to micromoles per liter, multiply by 17.1. To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791.

† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at

Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. Theymay therefore not be appropriate for all patients.‡ PCR assay for Epstein–Barr virus DNA detects levels ranging from 300 to 150,000 copies per milliliter.§ The following reference ranges for antibodies to double-stranded DNA are used at the other hospital: a value lower than 5 IU per milliliter is

negative, a value of 5 to 9 IU per milliliter is equivocal, and a value greater than 9 IU per milliliter is positive.

ing relapsing and remitting condition associ-ated with a bleeding disorder. Over a period of3 months, the patient noted malaise, light-head-edness, and transient vesicular lesions on thethighs, followed by severe fatigue, headache,

visual symptoms, dyspnea, bruising, and darkurine. When considered individually, each ofthese symptoms is nonspecific, but nonspecificsymptoms must be evaluated in terms of theirseverity and in the context of concurrent symp-








toms. The constellation of fatigue, dyspnea, easybruising, and dark urine is consistent with hemo-lytic anemia and a bleeding disorder.

We have already found clues in the history tosuggest a diagnosis, but the diagnosis must beconfirmed by laboratory data. The most strikinglaboratory data in this case are consistent with

hemolytic anemia (most likely autoimmune he-molytic anemia) and thrombocytopenia.

Hemolytic Anemia

Hemolytic anemia (anemia that is principally dueto the shortened survival of red cells)2 has nu-merous causes (Table 2). On presentation at theother hospital, the patient had a hematocrit of20%. Levels of lactate dehydrogenase and indi-rect bilirubin were elevated, and the haptoglobin

level was low. On the basis of these results, a di-agnosis of hemolytic anemia can be made,4 and

Table 2. Selected Causes of Hemolytic Anemia.*

CauseMajor Site

of HemolysisFindings on Peripheral-Blood Smear

and Laboratory Tests

Associated with intrinsically normal red cells

Autoimmune hemolytic anemia Extravascular Spherocytes, reticulocytes, nucleated red cells,positive direct antiglobulin test

Complement-induced lysis Extravascular

Direct trauma (seen in runners, bongo drummers,

patients with burns)

Intravascular Hemoglobinuria, myoglobinuria

Drug-induced immune hemolytic anemia Extravascular Spherocytes, positive direct antiglobulin test

Hemolytic transfusion reactions Intravascular Spherocytes

Hypersplenism Extravascular

Hypotonic lysis Intravascular

Infection (e.g., malaria, babesia, bartonella) Extravascular Red-cell inclusion bodies

Clostridial sepsis Intravascular Red-cell ghosts

Infusion of intravenous immune globulin Extravascular

Microangiopathic hemolytic anemia (e.g.,hemolytic–uremic syndrome, thromboticthrombocytopenic purpura, DIC, HELLP

syndrome, hypertensive emergency)

Intravascular Schistocytes (i.e., helmet cells); acute DIC isassociated with abnormal prothrombin timeand partial-thromboplastin time; acute and

chronic DIC are associated with elevatedlevels of fibrin-degradation products andd-dimer

Oxidant injury (due to exposure to dapsone,phenazopyridine, aniline dyes)

Extravascular

Shearing by prosthetic heart valves Intravascular Schistocytes

Cold-agglutinin disease (in some cases) Intravascular Red-cell agglutination

Paroxysmal cold hemoglobinuria Intravascular Erythrophagocytosis

Associated with intrinsically abnormal red cells†

Hemoglobinopathy (e.g., sickle cell anemia,thalassemias, unstable hemoglobins)

Extravascular Target cells, abnormal hemoglobin electro-phoresis, abnormal genetic-test results

Metabolic deficiency (e.g., G6PD deficiency,

pyruvate kinase deficiency)

Extravascular In G6PD deficiency: bite cells, blister cells, low

level of G6PD activityDefect in the red-cell membrane

Hereditary spherocytosis Extravascular Spherocytes

Paroxysmal nocturnal hemoglobinuria Intravascular Glycosylphosphatidylinositol-linked proteins onflow cytometry

* DIC denotes disseminated intravascular coagulation; G6PD glucose-6-phosphate dehydrogenase; and HELLP hemoly-sis, elevated liver-enzyme levels, and a low platelet count.

† Disorders associated with intrinsically abnormal red cells are inherited, with the exception of paroxysmal nocturnalhemoglobinuria, which is caused by an acquired defect in the red-cell membrane.3








such a diagnosis is consistent with the patient’sdisabling fatigue, dyspnea, and dark urine.

The first question to ask when consideringthe cause of hemolytic anemia is whether the redcells are intrinsically normal or abnormal (Table

2). Hemolytic anemia associated with normal redcells can be caused by the destruction of red

cells by antibodies or complement, the shearingof red cells in the microvasculature or by pros-thetic heart valves, and infections of red cells.Abnormal red cells may break down because ofproblems with their hemoglobin, metabolic ma-chinery, or cell membranes,4 and disorders as-sociated with abnormal red cells are nearly allinherited. Nothing in this patient’s history sug-gests that she has an inherited red-cell disorder;she reportedly had a normal hematocrit 6 yearsbefore presentation, and thus it is unlikely thatshe has intrinsically abnormal red cells.

The second question to ask when consideringthe cause of hemolytic anemia is whether hemo-lysis is occurring within the blood vessels or out-side the blood vessels (in the liver, spleen, or bonemarrow) (Table 2). During intravascular hemoly-sis, hemoglobin is released into the blood, bind-ing to haptoglobin and reducing haptoglobinlevels, and unbound alpha-globin dimers andbeta-globin dimers cause both plasma and urineto turn reddish-brown. If intravascular hemoly-sis is incomplete, spherocytes form. As com-pared with the uncontrolled lysis of red cellsthat occurs during intravascular hemolysis, ex-travascular hemolysis is a more controlled pro-cess that involves phagocytosis of red cells bymacrophages, the breakdown of hemoglobin tobilirubin, and the release of unconjugated biliru-bin, iron, and carbon monoxide into the blood.However, haptoglobin levels can be low and un-conjugated bilirubin levels can be elevated in pa-tients with intravascular hemolysis, extravascularhemolysis, or both. This patient has laboratoryevidence consistent with intravascular hemolysis

(e.g., spherocytes and dark urine) and may alsohave extravascular hemolysis (e.g., elevated levelsof indirect bilirubin).

Autoimmune Hemolytic Anemia

The peripheral-blood smear, coagulation tests,and direct antiglobulin test are helpful in deter-mining the cause of hemolytic anemia (Table 2).In this patient, the positive direct antiglobulintest with warm-reacting and cold-reacting auto-

antibodies, the presence of spherocytes but noschistocytes on the peripheral-blood smear, andnormal results on coagulation tests are f indingsconsistent with autoimmune hemolytic anemia.Autoimmune hemolytic anemia can be idiopathicor associated with connective-tissue disease (es-pecially systemic lupus erythematosus [SLE]), viral

infection, drug use (especially the use of cepha-losporins and piperacillin), malignant diseases(especially chronic lymphocytic leukemia), immu-nodeficiency (e.g., common variable immunode-ficiency), or a previous transfusion or transplan-tation.5 This patient was not taking any of thedrugs that have been implicated in antibody-mediated hemolytic anemia.6 Nothing in her his-tory suggests immunodeficiency. She had nohistory of solid-organ or stem-cell transplanta-tion, and she had not undergone a blood transfu-sion immediately before the present illness.

Viral and mycoplasma infections must be con-sidered as possible causes of autoimmune hemo-lytic anemia. In this patient, results of serologicand DNA testing for viruses and mycoplasmadid not suggest an infectious cause of autoim-mune hemolytic anemia, but some of the testresults are inconsistent. For instance, testing forEpstein–Barr virus (EBV) DNA was initially posi-tive but was negative on repeat testing; sinceother test results for EBV are consistent withpast infection, the initial result was likely to bea false positive result.7 A second inconsistency isthat testing for hepatitis B virus (HBV) surfaceantibody was initially nonreactive and later reac-tive; the most plausible interpretation of the se-rologic and DNA test results for HBV is a resolvedinfection.8 Finally, a culture of the vesicular le-sion on the thigh was positive for HSV-2. Thetransience of the lesions on the patient’s thigh ismore consistent with recurrent HSV infectionthan with primary infection.9 Neither primarynor recurrent HSV infection has been implicatedin the development of autoimmune hemolytic

anemia. By a process of elimination and on thebasis of the history and laboratory-test results, Ithink that SLE is the underlying cause of auto-immune hemolytic anemia in this patient.

Systemic Lupus Erythematosus

According to American College of Rheumatologyguidelines,10,11 at least 4 of 11 criteria must bemet for a diagnosis of SLE to be made. In thiscase, 3 of the criteria have been met: the presence








of a hematologic disorder (i.e., hemolytic ane-mia, with reticulocytosis and thrombocytopenia[a platelet count of <100,000 per cubic millime-ter]), an immunologic disorder (i.e., a positivetest for antiphospholipid antibodies), and an ab-normal titer of antinuclear antibodies (ANA).These 3 criteria, taken together with the f luctuat-

ing course of illness, the bleeding during andafter pregnancy, the transiently positive tests forantibodies to SSA (Ro), and the presence of auto-immune hemolytic anemia, indicate that the pa-tient most likely has SLE or a similar condition.

Thrombocytopenia

The patient had not only autoimmune hemolyticanemia but also thrombocytopenia; the plateletcount was 53,000 per cubic millimeter on presen-tation and rose to a maximum count of 122,000per cubic millimeter after treatment with gluco-

corticoids. She had epistaxis during childhoodand pregnancy, severe bleeding after a cesareansection, and recent bruising. In light of these fac-tors, we wonder whether her previous bleeding-related events are associated with the currentthrombocytopenia, and whether the thrombocy-topenia and the autoimmune hemolytic anemiaare causally related. We cannot answer the firstquestion without more information from her his-tory. However, I think that the thrombocytope-nia and the autoimmune hemolytic anemia arecausally related; the patient has evidence of activeimmune-mediated red-cell destruction, normalcoagulation indexes and markers of fibrinolysis,and a robust reticulocyte response that suggestshealthy bone marrow. Patients with autoimmunehemolytic anemia and immune thrombocytope-nic purpura, neutropenia, or both were describedby Evans and Duane in 194912 and by Evans et al.in 1951.13 The Evans syndrome can be primary(i.e., idiopathic) or associated with SLE or otherimmune disorders, immunodeficiencies, or lym-phoproliferative disorders. In a 2009 review of 68

cases, half the cases were primary, and many ofthe secondary cases were associated with SLE.14

In summary, my diagnosis in this case is theEvans syndrome, possibly associated with SLE.

Dr. Nancy Lee Harris (Pathology): Dr. Rosovsky, would you tell us your impression when you sawthe patient?

Dr. Rachel P. Rosovsky: When we saw the pa-tient, we agreed with Dr. Wright’s diagnosis ofthe Evans syndrome. At the time of this hospital-ization, rheumatology consultants did not think

that the patient met the criteria for an underlyingrheumatologic disease.

DR. DOUGLAS E. WRIGHT’S

DIAGNOSIS

Autoimmune hemolytic anemia and thrombocy-

topenia (Evans syndrome), possibly due to sys-temic lupus erythematosus.

Clinical Di agnosis

Autoimmune hemolytic anemia and thrombocy-topenia (Evans syndrome).

Pathological Discussion

Dr. Mia Y. Platt: On the day of admission, a speci-men of the patient’s blood was sent to the blood

bank for routine typing and screening. The bloodtype was O, Rh-positive. An antibody screen (in-direct antiglobulin test) was performed to detectunexpected antibodies to red-cell antigens thatare not part of the ABO blood group. A plasmasample was mixed with a screening panel ofthree type-O reagent red cells, each with a knownantigenic composition, and incubated at 37°C.An antiglobulin reagent containing anti-IgG wasadded, and after centrifugation, agglutination ofthe red cells was assessed. The antibody screenshowed reactivity to all three cells in the screen-ing panel.

A direct antiglobulin test was performed todetect bound antibody, complement, or both onthe patient’s red cells. The red cells were washedand incubated with an antiglobulin reagent con-taining anti-IgG and anti-C3d, and agglutination was assessed. The direct antiglobulin test wasstrongly positive for both IgG and complement.Follow-up testing included an elution step, in which bound antibody was stripped from the redcells. The resultant eluate was reactive to an ex-

tended panel of reagent red cells in an indirectantiglobulin test.These findings were consistent with the pres-

ence of a warm-reacting autoantibody, with or without the presence of a cold-reacting autoanti-body. Warm-reacting autoantibodies are opti-mally reactive at 37°C; they usually bind proteinantigens and may be associated with hemolysis.In contrast, cold-reacting autoantibodies are opti-mally reactive at 0 to 4°C; they usually bindcarbohydrate antigens and are very rarely associ-








ated with hemolysis. Cold-reacting autoantibod-ies associated with hemolytic anemia usuallyhave a broad thermal range that enables them tobind target antigens at near-physiologic tem-peratures. In view of the patient’s unusual reac-tion of acute pain during the transfusion and thereport by the other hospital of the presence of

a cold-reacting autoantibody, we evaluated forcold-reacting autoantibodies; the titer of cold-reacting autoantibodies, obtained at a 1:16 dilu-tion at 4°C, was negative.

Discussion of M anagement

Dr. Rosovsky: Identifying a secondary cause of theEvans syndrome in this patient could help deter-mine the treatment strategy. Secondary causeshave been reported in 50% of patients14; most areautoimmune diseases, immunodeficiencies, lym-

phomas, or infections (Table 3). In this case,there was no clear evidence of an associated sys-temic disorder, and so we are left with a diagno-sis of idiopathic Evans syndrome.

Finding an effective treatment for idiopathicEvans syndrome can be diff icult for several rea-sons. First, spontaneous remissions or exacerba-tions of the disease can occur, and the responseto treatment varies, even among different epi-sodes in an individual patient. Second, there is alack of high-quality research; we are aware of norandomized, controlled trials and only a few pro-spective trials and long-term follow-up studies.There are no established criteria on how to definea complete response. Finally, the treatment strat-egy is largely based on the strategy for isolatedimmune thrombocytopenic purpura or autoim-mune hemolytic anemia. It is appropriate andusually necessary to treat symptomatic patients,such as this one, who have low blood counts; thetreatment of asymptomatic patients with lowcounts is not so straightforward and depends onthe choices of the patient and clinician.

First-line Treatment for Patients

with the Evans Syndrome

One of the first questions to ask before treatinga patient with the Evans syndrome is whether ared-cell transfusion is required. This decision isbased on the severity of the anemia and the ageand clinical condition of the patient. This patientreceived a transfusion when the hematocrit wasat a nadir of 16.8% and she had dyspnea, severefatigue, and headaches.

We know of no randomized clinical trials

showing the effectiveness of glucocorticoids inthe treatment of the Evans syndrome, but gluco-corticoids have remained the standard treatmentoption since they were first described for thisindication by Dameshek et al. in the Journal in1950.14-18 Prednisone is usually administered (ata dose of 1 to 2 mg per kilogram of body weightper day) until the hematocrit is higher than 30%or the hemoglobin level is higher than 10 g perdeciliter; prednisone is subsequently tapered at arate of 10 mg per week, as long as the hemato-

Table 3. Secondary Causes of the Evans Syndrome.

Autoimmune diseases

Systemic lupus erythematosus

Antiphospholipid antibody syndrome

Sjögren’s syndrome

Infections

Cytomegalovirus

Influenza A

Parvovirus

Hepatitis

Varicella

Nocardia

Leishmaniasis

Epstein–Barr virus

Malignant diseases

Chronic lymphocytic leukemia

B-cell and T-cell non-Hodgkin’s lymphomas

Plasma-cell myelomaMonoclonal gammopathy of undetermined significance

Amyloidosis

Chronic myelomonocytic leukemia

Kaposi’s sarcoma

Pancreatic adenocarcinoma

Immunodeficiency disorders

Common variable immunodeficiency

IgA deficiency

Other

Graves’ disease

Dermatomyositis

Pregnancy

Guillain–Barré syndrome

Ulcerative colitis

Bronchiolitis obliterans with organizing pneumonia

Castleman’s disease

Acute inflammatory demyelinatingpolyradiculoneuropathy

Celiac disease








crit and hemoglobin level are stable, to a dose of20 mg per day. Then, the main goal is to slowlytaper the medication over a period of severalmonths and eventually discontinue it. If thehematocrit is still below 30% after 1 month, theinitiation of second-line therapy is generally in-dicated.

This patient was treated with glucocorticoidsand intravenous immune globulin (IVIG) duringher hospitalization. After she was discharged,the tapering of prednisone was begun. Unfortu-nately, she had a relapse 3 months later, whileshe was still taking prednisone.

Second-line Treatment for Patients

with the Evans Syndrome

Second-line treatment can include IVIG, splenec-tomy, immunosuppressive agents, therapeuticantibodies, and chemotherapy (Table 4). We areaware of no studies of single-agent IVIG, butthere are several studies that show the effective-ness of IVIG in conjunction with glucocorti-coids.14,16,19,20 In this patient, the dose of predni-sone was increased and another course of IVIG was administered; however, we determined thatshe needed additional treatment, in view of therefractory nature of the disease.

Rituximab

Rituximab, a monoclonal antibody to the B-cell

antigen CD20, has been reported to be an effec-tive second-line treatment for the Evans syn-drome in single case reports and case series. Ad- verse events include but are not limited to reactionsto infusion, HBV reactivation, infections, and onrare occasions progressive multifocal leukoenceph-alopathy. The duration of response ranges from11 weeks to 42 months.14,21-24 Second and thirdremissions have been seen with repeated doses.

The patient was given rituximab after testingfor HBV DNA was negative. The usual dose ofrituximab is 375 mg per square meter of body-surface area per week for 4 weeks, but after twoinfusions, the hematocrit was 14% and the pa-tient was symptomatic. She was readmitted tothis hospital. Severe arthralgias and myalgias,

low-grade fevers, and bilateral knee effusions with no crystals (determined by patellar arthro-centesis) developed. She had elevated levels ofanticardiolipin antibodies (anticardiolipin IgMantibody level, 142.5 IgM phospholipid units[MPL units] [normal value, <15]; anticardiolipinIgG antibody level, 23.8 IgG phospholipid units[GPL units] [normal value, <15]), elevated levelsof β2-glycoproteins (>100 U per milliliter [normal value, <15]), low levels of complement (C3 level,82 mg per deciliter [normal range, 86 to 184];C4 level, 8 mg per deciliter [normal range, 16 to

38]), and positive tests for ANA (at 1:40 and1:160 dilutions). Testing for infectious diseases(HIV, cytomegalovirus, EBV, and parvovirus) wasnegative, as was testing performed as part of arheumatologic workup, including tests for anti-bodies to SSA (Ro), SSB (La), double-strandedDNA, smooth muscle, and ribonucleoprotein.Thyrotropin levels and results of coagulationtests and serum protein electrophoresis werenormal, and testing for cryoglobulins was nega-tive. A bone marrow–biopsy specimen revealed ahypercellular marrow with maturing trilineagehematopoiesis. Because of the refractory courseof the disease, we considered splenectomy.

Splenectomy

The role of splenectomy in the treatment of theEvans syndrome is not clearly established.25 Insmall case series of the Evans syndrome (autoim-mune hemolytic anemia and immune thrombo-cytopenic purpura), an immediate response isusually produced but can be transient, and theoverall remission rates are 20 to 40%.12,14 Preop-

erative vaccinations, including pneumococcal,meningococcal, and Haemophilus influenzae vacci-nations, are necessary. Risks associated with theprocedure include death and the usual effects as-sociated with general anesthesia, as well as post-operative bleeding, sepsis, venous thromboem-bolism, and a lifelong risk of infections. Afterthe appropriate vaccinations were administeredto the patient, splenectomy was performed.

Table 4. Second-line Therapies for the Evans Syndrome.

Intravenous immune globulin

Therapeutic antibodies (rituximab)

Splenectomy

Danazol

Immunosuppressive agents (mycophenolate mofetil,

cyclosporine)Chemotherapy (vincristine, cyclophosphamide)

Azathioprine

Bone marrow transplantation








Dr. Platt: Pathological examination of the bonemarrow–biopsy specimen (Fig. 1A) showed hyper-cellular marrow with normal maturing trilineagehematopoiesis. The findings were consistent witha compensatory marrow response to cytopenias, with no evidence of an underlying abnormalityin the bone marrow. Cytogenetic analysis re-

vealed a normal female karyotype. Pathologicalexamination of the spleen (Fig. 1B and 1C)showed congestion, extramedullary hematopoi-esis, and hemosiderin-laden macrophages, find-ings consistent with splenic sequestration of redcells and a compensatory response to peripheraldestruction of blood cells.

Dr. Rosovsky: After splenectomy, the adminis-tration of glucocorticoids was tapered andstopped. The vaccinations were readministered.Unfortunately, 5 months later, the patient had arelapse.

recurrent evans syndrome after splenectomy

A workup for recurrent Evans syndrome aftersplenectomy involves ruling out the presence ofan accessory spleen and continuing to look forsecondary causes. Options for treatment includeretreatment with glucocorticoids or rituximab (if>1 year has passed since the last infusion), im-munosuppressive agents, chemotherapy, dan-azol, azathioprine, and bone marrow transplan-tation (Table 4).14,16,26-33

Repeat testing revealed persistent positiveresults on the direct antiglobulin test and nega-tive results on screening for cold agglutinins, ascan of the liver and spleen, and a viral sero-logic test. The patient continued to have highlevels of anticardiolipin antibodies (anticardio-lipin IgM antibody level, 189 MPL units), highlevels of β2-glycoproteins (>100 U per milliliter),and low levels of complement (C3 level, 69 mgper deciliter; C4 level, 6 mg per deciliter). TheANA titer rose to 1:320, and antibodies to dou-ble-stranded DNA were elevated at a 1:20 dilution

(normal value, <1:10). The rheumatology depart-ment was again consulted.

Thoughts from the Rheumatology

Department

Dr. Eli Miloslavsky (Rheumatology): When consid-ering a diagnosis of SLE, we start with a thor-ough evaluation of clinical manifestations thatmay be attributed to SLE. The guideline that re-

A

B

C

l

Figure 1. Bone Marrow–Biopsy and Splenectomy Speci-mens (Hematoxylin and Eosin).

Pathological examination of a bone marrow–biopsy

specimen (Panel A) shows hypercellular marrow with

normal maturing trilineage hematopoiesis. The find-ings are consistent with a compensatory marrow re-sponse to cytopenias, with no evidence of an underly-

ing abnormality of the bone marrow. Pathologicalexamination of the spleen (Panels B and C) shows con-

gestion, extramedullary hematopoiesis, and hemosid-erin-laden macrophages, findings consistent with

splenic sequestration of red cells and a compensatoryresponse to peripheral destruction of blood cells.








quires 4 of 11 criteria for the diagnosis of SLE10,11 is useful, but these criteria were created for usein clinical studies; in clinical practice, a patient with SLE often does not meet 4 criteria at once.

Initially, the diagnosis of SLE could not bemade with confidence in this patient becausethe only manifestations were hematologic ab-

normalities, which have a broad differential di-agnosis, and a low ANA titer. Subsequently, therising titers of antiphospholipid antibodies, hypo-complementemia, elevated inflammatory mark-ers, and positive test for antibodies to double-stranded DNA (which is more than 95% specificfor SLE in the appropriate clinical setting) madethe diagnosis of SLE much more likely. It is pos-sible that she did not have other manifestationsof SLE because of the immunosuppressive agentsshe received throughout her illness.

Autoantibodies can be present in patients with

SLE for as long as a decade before the onset ofsymptoms34 and can continue to develop afterthe onset of symptoms. This patient had a lowANA titer and a moderate level of anticardiolipinIgM antibodies at symptom onset; as the illnessprogressed, autoantibodies continued to develop, with rising titers of ANA and antiphospholipidantibodies and a positive test for antibodies todouble-stranded DNA, findings that eventuallyconfirmed the diagnosis.

In consultation with Dr. Rosovsky, we initiatedthe administration of azathioprine as a gluco-corticoid-sparing agent. There are reports of theefficacy of azathioprine in patients with theEvans syndrome as well as in those with SLE,although large controlled trials for the treatmentof SLE manifestations unrelated to the kidney

are lacking. We recommended adding hydroxy-chloroquine, which has been shown to preventflares of SLE. Because of the elevated risk ofthrombosis in patients with SLE and antiphos-pholipid antibodies, administration of a dailybaby aspirin was begun. An important aspect oftreating patients with SLE is monitoring for ad-

ditional disease manifestations; the most nota-ble of these is nephritis, which requires moni-toring with periodic urinalysis.

Dr. Rosovsky: We initially administered a lowdose of azathioprine (50 mg per day). The pa-tient’s thiopurine methyltransferase genotype wasnormal; as we tapered the prednisone dose, weincreased the azathioprine to a therapeutic dose(2 to 2.5 mg per kilogram per day). After severalmonths, as the prednisone dose was being ta-pered, the hematocrit dropped again. We increasedthe dose of prednisone and added hydroxychlo-

roquine. Six months later, the patient was nolonger taking glucocorticoids. The hematocritand platelet levels have remained normal, andshe has continued to take azathioprine and hy-droxychloroquine without any adverse events.

Final Di agnosis

Autoimmune hemolytic anemia and thrombocy-topenia (Evans syndrome) due to systemic lupuserythematosus.

This case was presented at the Medical Case Conference.

No potential conflict of interest relevant to this article was re-ported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Drs. David Dudzinski, Lloyd Axelrod, Mandako-lathur Murali, Hasan Bazari, and Yi-Bin Chen for helping to or-ganize the conference.

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