Evans SLE NEJM Cabot2013

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m e dic i n e
case records of the massachusetts general hospital

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Eric S. Rosenberg, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Nancy Lee Harris, m.d., Editor

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Emily K. McDonald, Assistant Editor
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.
Pr e sen tat ion of C a se

From the Departments of Medicine
(D.E.W., R.P.R.) and Pathology (M.Y.P.),
Massachusetts General Hospital, and the
Departments of Medicine (D.E.W., R.P.R.)
and Pathology (M.Y.P.), Harvard Medical
School both in Boston.
N Engl J Med 2013;369:2032-43.
DOI: 10.1056/NEJMcpc1215972
Copyright 2013 Massachusetts Medical Society.
2032
Dr. Joanna Lopez (Medicine): A 38-year-old woman was admitted to this hospital because 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 on
exertion, bruising on the legs, dark urine, and headache developed. She reported
that 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 examination was reportedly normal, as were the results of coagulation tests. Screening for
antibodies to the human immunodeficiency virus (HIV) and a rapid plasma reagin
test were negative; other test results are shown in Table 1. She was admitted to the
other hospital.
Examination of the peripheral-blood smear reportedly revealed normal morphologic features of the white cells, a reduced platelet count, spherocytes, and
polychromatic red cells. A direct antiglobulin test (Coombs test) was positive, and
warm-reacting and cold-reacting autoantibodies were reportedly present. Results
of serum and urinary protein electrophoresis were normal. Glucocorticoids (methylprednisolone at a dose of 150 mg twice daily for 2 days, followed by prednisone
at a dose of 70 mg twice daily) were administered, as were ondansetron and folate,
but the patients condition did not improve (Table 1). Computed tomographic (CT)
scans of the abdomen and pelvis, obtained after the intravenous administration of
contrast material, were normal. On the second night, hypotension developed but
improved after the intravenous administration of fluids. On the third day, the
hematocrit was 16.8%. One unit of packed red cells was transfused, and pantoprazole was administered. The patient was transferred to this hospital because of
difficulty finding additional red-cell units that were compatible with her antibody
screen.
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 previous
3 months, transient vesicular lesions on the thighs that resolved spontaneously
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case records of the massachuset ts gener al hospital
within 2 or 3 days. She did not have hematuria,

dysuria, chest pain, abdominal pain, fevers, chills,
nausea, vomiting, arthralgias, myalgias, melena,
or hematochezia. Approximately 3 years earlier,
she had had a similar illness, with dyspnea, lightheadedness, and an unintentional weight loss of
18 kg, which had gradually resolved spontaneously. She had a history of depression, anemia
(a hematocrit 6 years before admission was reportedly normal), and during childhood and pregnancy, epistaxis; she had had a hysterectomy at
22 years of age because of metrorrhagia after a
cesarean section. Medications at home included
bupropion, a multivitamin, and occasionally flaxseeds. She had no known allergies. She was born
in South America, moved to the United States
more than 10 years earlier, and worked with
children. She had recently traveled to Central
America and the Caribbean. She did not smoke,
drink alcohol, or use illicit drugs. Her father had
hyperthyroidism, and her mother had diabetes
mellitus; her siblings and child were healthy.
On examination, the patients blood pressure
was 105/55 mm Hg, and the other vital signs and
oxygen saturation were normal. She had mild
conjunctival icterus and a single vesicular lesion
(1 cm in diameter) with an erythematous base
on the posterior right thigh. The remainder of
the examination was normal. The red-cell indexes
(mean corpuscular volume, mean corpuscular
hemoglobin, and mean corpuscular hemoglobin
concentration) were normal, as were the prothrombin time, the prothrombin-time international normalized ratio, results of renal-function
tests, and blood levels of electrolytes, phosphorus, magnesium, calcium, total protein, albumin, globulin, alkaline phosphatase, C-reactive
protein, lipase, amylase, folate, and vitamin B12.
Testing for partial-thromboplastin time to detect
a lupus anticoagulant was negative; other test
results are shown in Table 1. Examination of the
peripheral-blood smear revealed macrocytes, polychromatocytes, microspherocytes, very few metamyelocytes, predominantly normal platelets, and
no schistocytes or malignant cells. Urinalysis
revealed 3+ urobilinogen and was otherwise
normal. The blood type was O, Rh-positive; an
antibody screen (indirect antiglobulin test) and a
direct antiglobulin test were positive. The administration of prednisone, folate, and bupropion were continued. A swab of the lesion on
the right thigh was sent for culture.
Transfusion of 1 unit of leukoreduced red cells

was begun, but pain and burning developed immediately at the site of the infusion. Another
attempt was made, on the contralateral side; however, after the infusion of a few milliliters, pain,
burning, and facial flushing occurred, and the
systolic blood pressure fell from 94 to 84 mm Hg
within 15 minutes. The transfusion was stopped,
and the symptoms resolved. The culture of the
lesion on the right thigh revealed herpes simplex
virus type 2 (HSV-2), a urine culture grew more
than 100,000 mixed flora, and blood cultures
were sterile. Additional test results are shown in
Table 1.
Diagnostic tests were performed, and management decisions were made.
Differ en t i a l Di agnosis
Dr. Douglas E. Wright: An overview of the patients
medical history provides clues to the cause of the
present illness. Four noteworthy events in the
history are epistaxis during childhood, epistaxis
during pregnancy at 21 years of age, a cesarean
section complicated by metrorrhagia that required
hysterectomy, and an illness consisting of dyspnea, light-headedness, and a weight loss of 18 kg
that occurred 3 years before admission.
These four events may be episodes of a
chronic illness that is related to the present illness, or they may be unrelated. Epistaxis during
childhood and pregnancy can result from serious chronic diseases, such as bleeding disorders,
but without more detailed information, these are
not helpful clues. However, a cesarean section
followed by metrorrhagia that is severe enough
to require hysterectomy, in the absence of complications during the labor or the surgery, is
highly unusual1 and would warrant a diagnostic
workup for a bleeding disorder.
The illness that occurred 3 years before admission, with dyspnea, light-headedness, and
weight loss, is also worrisome and raises concern that the patient has a malignant disease, a
severe nonmalignant systemic illness, or a major
depressive disorder. If she previously had a malignant tumor that caused dyspnea, light-headedness, and weight loss, she probably would not
have recovered without treatment. If she previously had a nonmalignant systemic illness, it
could have been either a discrete illness that resolved and would not be expected to recur (e.g.,

2033
The
pneumonia) or an episode of a relapsing and

remitting illness (e.g., intermittent hemolytic
anemia). A chronic illness might explain the
epistaxis during childhood and pregnancy and
the bleeding after a cesarean section. A diagno-
of
m e dic i n e
sis of major depressive disorder could be made

only after a thorough search for a systemic illness has been performed.
As we analyze the present illness, we must
remember that the patient may have an underly-
Table 1. Laboratory Data.*
Variable
Reference
Range,
Adults
Other
Hospital,
on Admission
Other
Hospital,
Day 2
This Hospital,
on Admission
This Hospital,
First Admission,
Days 79
Hematocrit (%)
36.046.0
20.0
20.1
19.4
32.9
Hemoglobin (g/dl)
White-cell count (per mm3)
12.016.0
7.5
7.2
11.1
450011,000
10,300
27,200
14,500
85
Differential count (%)

Neutrophils
4070
79
Band forms
010
Lymphocytes
2244
10
Monocytes
411
Myelocytes
Metamyelocytes
Nucleated red cells (per 100 white cells)

Platelet count (per mm3)
0
150,000
400,000
2
2
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 (%)
11.514.5
22.5
20.7
10.7
10.3 (manual)
Reticulocytes (%)
0.52.5
Erythrocyte sedimentation rate (mm/hr)

Fibrinogen (mg/dl)
d-Dimer
(mg/liter)
Fibrin-degradation products (g/ml)
Elevated,
by report
017
104
161393
353
0.000.52
1.25
<10
<10
Haptoglobin (mg/dl)
16199
<6
<6
Glucose (mg/dl)
70110
140
112
Bilirubin (mg/dl)
Total
0.01.0
Direct
0.00.4
Indirect
4.9
2.0
1.5
0.4
0.3
36
138
52
349
444
416
4.3
Aspartate aminotransferase (U/liter)

Alanine aminotransferase (U/liter)
Lactate dehydrogenase (U/liter)
932
59
730
77
110210
461
484
Iron (g/dl)
30160
176
Total iron-binding capacity (g/dl)
230404
229
Ferritin (ng/ml)
10200
EpsteinBarr virus DNA, by PCR

Antibodies to double-stranded DNA
2034
775
Negative
Positive
Negative at
1:10 dilution
8 IU/ml
<300
Negative at
1:10 dilution

Table 1. (Continued.)
Variable
Reference
Range,
Adults
Other
Hospital, on
Admission
Other
Hospital,
Day 2
Antibodies to SSA (Ro) (OD units)
0.019.99
3.9
(AI ref 0.00.9)
10.27
Antibodies to SSB (La) (OD units)
0.019.99
0.7
(AI ref 0.00.9)
8.89
This Hospital,
on Admission
This Hospital,
First Admission,
Days 79
Antibodies to smooth muscle
Negative at
1:20 dilution
Positive at
1:20 dilution
Antimitochondrial antibodies
Negative at
1:20 dilution
Negative at
1:20 dilution
Cytomegalovirus DNA, by quantitative PCR

(copies per ml)
None detected
Anticardiolipin IgM antibodies (MPL units)
015
Anticardiolipin IgG antibodies (GPL units)

Antinuclear antibodies
None
detected
31.6
015
14.9
Negative at
1:40 and 1:160
dilutions
Positive at 1:40
and 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
Hepatitis B e antigen
Negative
Negative
Hepatitis B e antibodies
Negative
Negative
Hepatitis B nucleic acid
Negative
Negative
IgM antibodies to EpsteinBarr virus VCA
Negative
Negative
IgG antibodies to EpsteinBarr virus VCA
Negative
Positive
Antibodies to EpsteinBarr virus nuclear

antigen
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
Negative
Negative
* AI ref denotes antibody index reference range, GPL IgG phospholipid, MPL IgM phospholipid, OD optical density, PCR polymerase chain reaction, and VCA viral capsid antigen. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for bilirubin 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. They
may therefore not be appropriate for all patients.
PCR assay for EpsteinBarr 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 associated with a bleeding disorder. Over a period of
3 months, the patient noted malaise, light-headedness, and transient vesicular lesions on the
thighs, followed by severe fatigue, headache,
visual symptoms, dyspnea, bruising, and dark

urine. When considered individually, each of
these symptoms is nonspecific, but nonspecific
symptoms must be evaluated in terms of their
severity and in the context of concurrent symp-

2035
The
toms. The constellation of fatigue, dyspnea, easy

bruising, and dark urine is consistent with hemolytic anemia and a bleeding disorder.
We have already found clues in the history to
suggest a diagnosis, but the diagnosis must be
confirmed by laboratory data. The most striking
laboratory data in this case are consistent with
hemolytic anemia (most likely autoimmune hemolytic anemia) and thrombocytopenia.
of
m e dic i n e
Hemolytic Anemia
Hemolytic anemia (anemia that is principally due

to the shortened survival of red cells)2 has numerous causes (Table 2). On presentation at the
other hospital, the patient had a hematocrit of
20%. Levels of lactate dehydrogenase and indirect bilirubin were elevated, and the haptoglobin
level was low. On the basis of these results, a diagnosis of hemolytic anemia can be made,4 and
Table 2. Selected Causes of Hemolytic Anemia.*

Major Site
of Hemolysis
Cause
Findings 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.,

hemolyticuremic syndrome, thrombotic
thrombocytopenic purpura, DIC, HELLP
syndrome, hypertensive emergency)
Intravascular
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
Schistocytes (i.e., helmet cells); acute DIC is

associated with abnormal prothrombin time
and partial-thromboplastin time; acute and
chronic DIC are associated with elevated
levels of fibrin-degradation products and
d-dimer
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 activity
Defect in the red-cell membrane

Hereditary spherocytosis
Extravascular
Paroxysmal nocturnal hemoglobinuria
Intravascular
Spherocytes
Glycosylphosphatidylinositol-linked proteins on
flow cytometry
* DIC denotes disseminated intravascular coagulation; G6PD glucose-6-phosphate dehydrogenase; and HELLP hemolysis, elevated liver-enzyme levels, and a low platelet count.
Disorders associated with intrinsically abnormal red cells are inherited, with the exception of paroxysmal nocturnal
hemoglobinuria, which is caused by an acquired defect in the red-cell membrane.3
2036

such a diagnosis is consistent with the patients

disabling fatigue, dyspnea, and dark urine.
The first question to ask when considering
the cause of hemolytic anemia is whether the red
cells are intrinsically normal or abnormal (Table
2). Hemolytic anemia associated with normal red
cells can be caused by the destruction of red
cells by antibodies or complement, the shearing
of red cells in the microvasculature or by prosthetic heart valves, and infections of red cells.
Abnormal red cells may break down because of
problems with their hemoglobin, metabolic machinery, or cell membranes,4 and disorders associated with abnormal red cells are nearly all
inherited. Nothing in this patients history suggests that she has an inherited red-cell disorder;
she reportedly had a normal hematocrit 6 years
before presentation, and thus it is unlikely that
she has intrinsically abnormal red cells.
The second question to ask when considering
the cause of hemolytic anemia is whether hemolysis is occurring within the blood vessels or outside the blood vessels (in the liver, spleen, or bone
marrow) (Table 2). During intravascular hemolysis, hemoglobin is released into the blood, binding to haptoglobin and reducing haptoglobin
levels, and unbound alpha-globin dimers and
beta-globin dimers cause both plasma and urine
to turn reddish-brown. If intravascular hemolysis is incomplete, spherocytes form. As compared with the uncontrolled lysis of red cells
that occurs during intravascular hemolysis, extravascular hemolysis is a more controlled process that involves phagocytosis of red cells by
macrophages, the breakdown of hemoglobin to
bilirubin, and the release of unconjugated bilirubin, iron, and carbon monoxide into the blood.
However, haptoglobin levels can be low and unconjugated bilirubin levels can be elevated in patients with intravascular hemolysis, extravascular
hemolysis, or both. This patient has laboratory
evidence consistent with intravascular hemolysis
(e.g., spherocytes and dark urine) and may also
have extravascular hemolysis (e.g., elevated levels
of indirect bilirubin).
antibodies, the presence of spherocytes but no

schistocytes on the peripheral-blood smear, and
normal results on coagulation tests are findings
consistent with autoimmune hemolytic anemia.
Autoimmune hemolytic anemia can be idiopathic
or associated with connective-tissue disease (especially systemic lupus erythematosus [SLE]), viral
infection, drug use (especially the use of cephalosporins and piperacillin), malignant diseases
(especially chronic lymphocytic leukemia), immunodeficiency (e.g., common variable immunodeficiency), or a previous transfusion or transplantation.5 This patient was not taking any of the
drugs that have been implicated in antibodymediated hemolytic anemia.6 Nothing in her history suggests immunodeficiency. She had no
history of solid-organ or stem-cell transplantation, and she had not undergone a blood transfusion immediately before the present illness.
Viral and mycoplasma infections must be considered as possible causes of autoimmune hemolytic anemia. In this patient, results of serologic
and DNA testing for viruses and mycoplasma
did not suggest an infectious cause of autoimmune hemolytic anemia, but some of the test
results are inconsistent. For instance, testing for
EpsteinBarr virus (EBV) DNA was initially positive but was negative on repeat testing; since
other test results for EBV are consistent with
past infection, the initial result was likely to be
a false positive result.7 A second inconsistency is
that testing for hepatitis B virus (HBV) surface
antibody was initially nonreactive and later reactive; the most plausible interpretation of the serologic and DNA test results for HBV is a resolved
infection.8 Finally, a culture of the vesicular lesion on the thigh was positive for HSV-2. The
transience of the lesions on the patients thigh is
more consistent with recurrent HSV infection
than with primary infection.9 Neither primary
nor recurrent HSV infection has been implicated
in the development of autoimmune hemolytic
anemia. By a process of elimination and on the
basis of the history and laboratory-test results, I
think that SLE is the underlying cause of autoimmune hemolytic anemia in this patient.
Autoimmune Hemolytic Anemia
The peripheral-blood smear, coagulation tests,

and direct antiglobulin test are helpful in determining the cause of hemolytic anemia (Table 2).
In this patient, the positive direct antiglobulin
test with warm-reacting and cold-reacting auto-
Systemic Lupus Erythematosus
According to American College of Rheumatology

guidelines,10,11 at least 4 of 11 criteria must be
met for a diagnosis of SLE to be made. In this
case, 3 of the criteria have been met: the presence

2037
The
of a hematologic disorder (i.e., hemolytic anemia, with reticulocytosis and thrombocytopenia

[a platelet count of <100,000 per cubic millimeter]), an immunologic disorder (i.e., a positive
test for antiphospholipid antibodies), and an abnormal titer of antinuclear antibodies (ANA).
These 3 criteria, taken together with the fluctuating course of illness, the bleeding during and
after pregnancy, the transiently positive tests for
antibodies to SSA (Ro), and the presence of autoimmune hemolytic anemia, indicate that the patient most likely has SLE or a similar condition.
Thrombocytopenia
The patient had not only autoimmune hemolytic

anemia but also thrombocytopenia; the platelet
count was 53,000 per cubic millimeter on presentation and rose to a maximum count of 122,000
per cubic millimeter after treatment with glucocorticoids. She had epistaxis during childhood
and pregnancy, severe bleeding after a cesarean
section, and recent bruising. In light of these factors, we wonder whether her previous bleedingrelated events are associated with the current
thrombocytopenia, and whether the thrombocytopenia and the autoimmune hemolytic anemia
are causally related. We cannot answer the first
question without more information from her history. However, I think that the thrombocytopenia and the autoimmune hemolytic anemia are
causally related; the patient has evidence of active
immune-mediated red-cell destruction, normal
coagulation indexes and markers of fibrinolysis,
and a robust reticulocyte response that suggests
healthy bone marrow. Patients with autoimmune
hemolytic anemia and immune thrombocytopenic purpura, neutropenia, or both were described
by 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 other
immune disorders, immunodeficiencies, or lymphoproliferative disorders. In a 2009 review of 68
cases, half the cases were primary, and many of
the secondary cases were associated with SLE.14
In summary, my diagnosis in this case is the
Evans syndrome, possibly associated with SLE.
Dr. Nancy Lee Harris (Pathology): Dr. Rosovsky,
would you tell us your impression when you saw
the patient?
Dr. Rachel P. Rosovsky: When we saw the patient, we agreed with Dr. Wrights diagnosis of
the Evans syndrome. At the time of this hospitalization, rheumatology consultants did not think
2038
of
m e dic i n e
that the patient met the criteria for an underlying

rheumatologic disease.
DR . D OUGL A S E . W R IGH T S
DI AGNOSIS
Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome), possibly due to systemic lupus erythematosus.
Cl inic a l Di agnosis
Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome).
Pathol o gic a l Discussion

Dr. Mia Y. Platt: On the day of admission, a specimen of the patients blood was sent to the blood
bank for routine typing and screening. The blood
type was O, Rh-positive. An antibody screen (indirect antiglobulin test) was performed to detect
unexpected antibodies to red-cell antigens that
are not part of the ABO blood group. A plasma
sample was mixed with a screening panel of
three type-O reagent red cells, each with a known
antigenic composition, and incubated at 37C.
An antiglobulin reagent containing anti-IgG was
added, and after centrifugation, agglutination of
the red cells was assessed. The antibody screen
showed reactivity to all three cells in the screening panel.
A direct antiglobulin test was performed to
detect bound antibody, complement, or both on
the patients red cells. The red cells were washed
and incubated with an antiglobulin reagent containing anti-IgG and anti-C3d, and agglutination
was assessed. The direct antiglobulin test was
strongly positive for both IgG and complement.
Follow-up testing included an elution step, in
which bound antibody was stripped from the red
cells. The resultant eluate was reactive to an extended panel of reagent red cells in an indirect
antiglobulin test.
These findings were consistent with the presence of a warm-reacting autoantibody, with or
without the presence of a cold-reacting autoantibody. Warm-reacting autoantibodies are optimally reactive at 37C; they usually bind protein
antigens and may be associated with hemolysis.
In contrast, cold-reacting autoantibodies are optimally reactive at 0 to 4C; they usually bind
carbohydrate antigens and are very rarely associ-

ated with hemolysis. Cold-reacting autoantibodies associated with hemolytic anemia usually
have a broad thermal range that enables them to
bind target antigens at near-physiologic temperatures. In view of the patients unusual reaction of acute pain during the transfusion and the
report by the other hospital of the presence of
a cold-reacting autoantibody, we evaluated for
cold-reacting autoantibodies; the titer of coldreacting autoantibodies, obtained at a 1:16 dilution at 4C, was negative.
Discussion of M a nagemen t
Dr. Rosovsky: Identifying a secondary cause of the
Evans syndrome in this patient could help determine the treatment strategy. Secondary causes
have been reported in 50% of patients14; most are
autoimmune diseases, immunodeficiencies, lymphomas, or infections (Table 3). In this case,
there was no clear evidence of an associated systemic disorder, and so we are left with a diagnosis of idiopathic Evans syndrome.
Finding an effective treatment for idiopathic
Evans syndrome can be difficult for several reasons. First, spontaneous remissions or exacerbations of the disease can occur, and the response
to treatment varies, even among different episodes in an individual patient. Second, there is a
lack of high-quality research; we are aware of no
randomized, controlled trials and only a few prospective trials and long-term follow-up studies.
There are no established criteria on how to define
a complete response. Finally, the treatment strategy is largely based on the strategy for isolated
immune thrombocytopenic purpura or autoimmune hemolytic anemia. It is appropriate and
usually necessary to treat symptomatic patients,
such as this one, who have low blood counts; the
treatment of asymptomatic patients with low
counts is not so straightforward and depends on
the choices of the patient and clinician.
First-line Treatment for Patients
with the Evans Syndrome
One of the first questions to ask before treating

a patient with the Evans syndrome is whether a
red-cell transfusion is required. This decision is
based on the severity of the anemia and the age
and clinical condition of the patient. This patient
received a transfusion when the hematocrit was
at a nadir of 16.8% and she had dyspnea, severe
fatigue, and headaches.
Table 3. Secondary Causes of the Evans Syndrome.

Autoimmune diseases
Systemic lupus erythematosus
Antiphospholipid antibody syndrome
Sjgrens syndrome
Infections
Cytomegalovirus
Influenza A
Parvovirus
Hepatitis
Varicella
Nocardia
Leishmaniasis
EpsteinBarr virus
Malignant diseases
Chronic lymphocytic leukemia
B-cell and T-cell non-Hodgkins lymphomas
Plasma-cell myeloma
Monoclonal gammopathy of undetermined significance
Amyloidosis
Chronic myelomonocytic leukemia
Kaposis sarcoma
Pancreatic adenocarcinoma
Immunodeficiency disorders
Common variable immunodeficiency
IgA deficiency
Other
Graves disease
Dermatomyositis
Pregnancy
GuillainBarr syndrome
Ulcerative colitis
Bronchiolitis obliterans with organizing pneumonia
Castlemans disease
Acute inflammatory demyelinating
polyradiculoneuropathy
Celiac disease
We know of no randomized clinical trials

showing the effectiveness of glucocorticoids in
the treatment of the Evans syndrome, but glucocorticoids have remained the standard treatment
option since they were first described for this
indication by Dameshek et al. in the Journal in
1950.14-18 Prednisone is usually administered (at
a dose of 1 to 2 mg per kilogram of body weight
per day) until the hematocrit is higher than 30%
or the hemoglobin level is higher than 10 g per
deciliter; prednisone is subsequently tapered at a
rate of 10 mg per week, as long as the hemato-

2039
The
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
crit and hemoglobin level are stable, to a dose of

20 mg per day. Then, the main goal is to slowly
taper the medication over a period of several
months and eventually discontinue it. If the
hematocrit is still below 30% after 1 month, the
initiation of second-line therapy is generally indicated.
This patient was treated with glucocorticoids
and intravenous immune globulin (IVIG) during
her hospitalization. After she was discharged,
the tapering of prednisone was begun. Unfortunately, she had a relapse 3 months later, while
she was still taking prednisone.
Second-line Treatment for Patients
with the Evans Syndrome
Second-line treatment can include IVIG, splenectomy, immunosuppressive agents, therapeutic

antibodies, and chemotherapy (Table 4). We are
aware of no studies of single-agent IVIG, but
there are several studies that show the effectiveness of IVIG in conjunction with glucocorticoids.14,16,19,20 In this patient, the dose of prednisone was increased and another course of IVIG
was administered; however, we determined that
she needed additional treatment, in view of the
refractory nature of the disease.
Rituximab
Rituximab, a monoclonal antibody to the B-cell

antigen CD20, has been reported to be an effective second-line treatment for the Evans syndrome in single case reports and case series. Adverse events include but are not limited to reactions
to infusion, HBV reactivation, infections, and on
rare occasions progressive multifocal leukoencephalopathy. The duration of response ranges from
11 weeks to 42 months.14,21-24 Second and third
remissions have been seen with repeated doses.
2040
of
m e dic i n e
The patient was given rituximab after testing

for HBV DNA was negative. The usual dose of
rituximab is 375 mg per square meter of bodysurface area per week for 4 weeks, but after two
infusions, the hematocrit was 14% and the patient was symptomatic. She was readmitted to
this hospital. Severe arthralgias and myalgias,
low-grade fevers, and bilateral knee effusions
with no crystals (determined by patellar arthrocentesis) developed. She had elevated levels of
anticardiolipin antibodies (anticardiolipin IgM
antibody level, 142.5 IgM phospholipid units
[MPL units] [normal value, <15]; anticardiolipin
IgG antibody level, 23.8 IgG phospholipid units
[GPL units] [normal value, <15]), elevated levels
of 2-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 and
1:160 dilutions). Testing for infectious diseases
(HIV, cytomegalovirus, EBV, and parvovirus) was
negative, as was testing performed as part of a
rheumatologic workup, including tests for antibodies to SSA (Ro), SSB (La), double-stranded
DNA, smooth muscle, and ribonucleoprotein.
Thyrotropin levels and results of coagulation
tests and serum protein electrophoresis were
normal, and testing for cryoglobulins was negative. A bone marrowbiopsy specimen revealed a
hypercellular marrow with maturing trilineage
hematopoiesis. Because of the refractory course
of the disease, we considered splenectomy.
Splenectomy
The role of splenectomy in the treatment of the

Evans syndrome is not clearly established.25 In
small case series of the Evans syndrome (autoimmune hemolytic anemia and immune thrombocytopenic purpura), an immediate response is
usually produced but can be transient, and the
overall remission rates are 20 to 40%.12,14 Preoperative vaccinations, including pneumococcal,
meningococcal, and Haemophilus influenzae vaccinations, are necessary. Risks associated with the
procedure include death and the usual effects associated with general anesthesia, as well as postoperative bleeding, sepsis, venous thromboembolism, and a lifelong risk of infections. After
the appropriate vaccinations were administered
to the patient, splenectomy was performed.

Dr. Platt: Pathological examination of the bone

marrowbiopsy specimen (Fig. 1A) showed hypercellular marrow with normal maturing trilineage
hematopoiesis. The findings were consistent with
a compensatory marrow response to cytopenias,
with no evidence of an underlying abnormality
in the bone marrow. Cytogenetic analysis revealed a normal female karyotype. Pathological
examination of the spleen (Fig. 1B and 1C)
showed congestion, extramedullary hematopoiesis, and hemosiderin-laden macrophages, findings consistent with splenic sequestration of red
cells and a compensatory response to peripheral
destruction of blood cells.
Dr. Rosovsky: After splenectomy, the administration of glucocorticoids was tapered and
stopped. The vaccinations were readministered.
Unfortunately, 5 months later, the patient had a
relapse.
recurrent evans syndrome after splenectomy
A workup for recurrent Evans syndrome after

splenectomy involves ruling out the presence of
an accessory spleen and continuing to look for
secondary causes. Options for treatment include
retreatment with glucocorticoids or rituximab (if
>1 year has passed since the last infusion), immunosuppressive agents, chemotherapy, danazol, azathioprine, and bone marrow transplantation (Table 4).14,16,26-33
Repeat testing revealed persistent positive
results on the direct antiglobulin test and negative results on screening for cold agglutinins, a
scan of the liver and spleen, and a viral serologic test. The patient continued to have high
levels of anticardiolipin antibodies (anticardiolipin IgM antibody level, 189 MPL units), high
levels of 2-glycoproteins (>100 U per milliliter),
and low levels of complement (C3 level, 69 mg
per deciliter; C4 level, 6 mg per deciliter). The
ANA titer rose to 1:320, and antibodies to double-stranded DNA were elevated at a 1:20 dilution
(normal value, <1:10). The rheumatology department was again consulted.
Thoughts from the Rheumatology
Department
Dr. Eli Miloslavsky (Rheumatology): When considering a diagnosis of SLE, we start with a thorough evaluation of clinical manifestations that
may be attributed to SLE. The guideline that re-
n engl j med 369;21
Figure 1. Bone MarrowBiopsy and Splenectomy Specimens (Hematoxylin and Eosin).

Pathological examination of a bone marrowbiopsy
RETAKE with
1st
specimen
(Panel A) Wright
shows hypercellular marrow
AUTHOR
ICM
2nd
normal
hematopoiesis. The findREG Fmaturing
FIGURE trilineage
1a-c
3rd
ingsCASE
are consistent
with
a
compensatory
marrow
reTITLE
Revised
EMail to cytopenias, with no
sponse
4-C of an underlyLineevidence
SIZE
ing Enon
abnormality
marrow.H/T
Pathological
ARTIST:of the
mst boneH/T
16p6 conFILL
Combo B and C) shows
examination
of the spleen (Panels
gestion, extramedullary
AUTHOR,hematopoiesis,
PLEASE NOTE: and hemosidFigure
has been redrawn
and type
has been reset.
erin-laden
macrophages,
findings
consistent
with
Please check carefully.
splenic sequestration of red cells and a compensatory
response to peripheral destruction of blood cells.
nejm.org
JOB:
36921
ISSUE:
11-21-13
november 21, 2013

2041
The
quires 4 of 11 criteria for the diagnosis of SLE10,11

is useful, but these criteria were created for use
in clinical studies; in clinical practice, a patient
with SLE often does not meet 4 criteria at once.
Initially, the diagnosis of SLE could not be
made with confidence in this patient because
the only manifestations were hematologic abnormalities, which have a broad differential diagnosis, and a low ANA titer. Subsequently, the
rising titers of antiphospholipid antibodies, hypocomplementemia, elevated inflammatory markers, and positive test for antibodies to doublestranded DNA (which is more than 95% specific
for SLE in the appropriate clinical setting) made
the diagnosis of SLE much more likely. It is possible that she did not have other manifestations
of SLE because of the immunosuppressive agents
she received throughout her illness.
Autoantibodies can be present in patients with
SLE for as long as a decade before the onset of
symptoms34 and can continue to develop after
the onset of symptoms. This patient had a low
ANA titer and a moderate level of anticardiolipin
IgM antibodies at symptom onset; as the illness
progressed, autoantibodies continued to develop,
with rising titers of ANA and antiphospholipid
antibodies and a positive test for antibodies to
double-stranded DNA, findings that eventually
confirmed the diagnosis.
In consultation with Dr. Rosovsky, we initiated
the administration of azathioprine as a glucocorticoid-sparing agent. There are reports of the
efficacy of azathioprine in patients with the
Evans syndrome as well as in those with SLE,
although large controlled trials for the treatment
of SLE manifestations unrelated to the kidney
of
m e dic i n e
are lacking. We recommended adding hydroxychloroquine, which has been shown to prevent
flares of SLE. Because of the elevated risk of
thrombosis in patients with SLE and antiphospholipid antibodies, administration of a daily
baby aspirin was begun. An important aspect of
treating patients with SLE is monitoring for additional disease manifestations; the most notable of these is nephritis, which requires monitoring with periodic urinalysis.
Dr. Rosovsky: We initially administered a low
dose of azathioprine (50 mg per day). The patients thiopurine methyltransferase genotype was
normal; as we tapered the prednisone dose, we
increased the azathioprine to a therapeutic dose
(2 to 2.5 mg per kilogram per day). After several
months, as the prednisone dose was being tapered, the hematocrit dropped again. We increased
the dose of prednisone and added hydroxychloroquine. Six months later, the patient was no
longer taking glucocorticoids. The hematocrit
and platelet levels have remained normal, and
she has continued to take azathioprine and hydroxychloroquine without any adverse events.
Fina l Di agnosis
Autoimmune hemolytic anemia and thrombocytopenia (Evans syndrome) due to systemic lupus
erythematosus.
This case was presented at the Medical Case Conference.

No potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. David Dudzinski, Lloyd Axelrod, Mandakolathur Murali, Hasan Bazari, and Yi-Bin Chen for helping to organize the conference.
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The

case records of the massachusetts general hospital

Nancy Lee Harris, m.d., Editor

Case 36-2013: A 38-Year-Old Woman

Pr e sen tat ion of C a se

The New England Journal of Medicine

case records of the massachuset ts gener al hospital

within 2 or 3 days. She did not have hematuria,

Transfusion of 1 unit of leukoreduced red cells

n engl j med 369;21nejm.orgnovember 21, 2013

The New England Journal of Medicine

pneumonia) or an episode of a relapsing and

sis of major depressive disorder could be made

Table 1. Laboratory Data.*

Differential count (%)

Nucleated red cells (per 100 white cells)

Erythrocyte count (per mm3)

Red-cell distribution width (%)

Erythrocyte sedimentation rate (mm/hr)

Fibrin-degradation products (g/ml)

Aspartate aminotransferase (U/liter)

Total iron-binding capacity (g/dl)

EpsteinBarr virus DNA, by PCR

n engl j med 369;21nejm.orgnovember 21, 2013

The New England Journal of Medicine

case records of the massachuset ts gener al hospital

Antibodies to SSA (Ro) (OD units)

Antibodies to SSB (La) (OD units)

Antibodies to smooth muscle

Cytomegalovirus DNA, by quantitative PCR

Anticardiolipin IgM antibodies (MPL units)

Anticardiolipin IgG antibodies (GPL units)

Hepatitis B surface antibodies

Hepatitis B surface antigen

Hepatitis B core antibodies

Hepatitis A total antibodies

Hepatitis A IgM antibodies

Hepatitis B nucleic acid

IgM antibodies to EpsteinBarr virus VCA

IgG antibodies to EpsteinBarr virus VCA

Antibodies to EpsteinBarr virus nuclear

Varicella IgG antibodies

Mycoplasma pneumoniae IgG antibody index

M. pneumoniae IgM antibody index

visual symptoms, dyspnea, bruising, and dark

n engl j med 369;21nejm.orgnovember 21, 2013

The New England Journal of Medicine

toms. The constellation of fatigue, dyspnea, easy

Hemolytic anemia (anemia that is principally due

Table 2. Selected Causes of Hemolytic Anemia.*

Findings on Peripheral-Blood Smear

Associated with intrinsically normal red cells

Spherocytes, reticulocytes, nucleated red cells,

Direct trauma (seen in runners, bongo drummers,

Drug-induced immune hemolytic anemia

Spherocytes, positive direct antiglobulin test

Hemolytic transfusion reactions

Infection (e.g., malaria, babesia, bartonella)

Red-cell inclusion bodies

Infusion of intravenous immune globulin

Microangiopathic hemolytic anemia (e.g.,

Oxidant injury (due to exposure to dapsone,

Shearing by prosthetic heart valves

Cold-agglutinin disease (in some cases)