The n e w e ng l a n d j o u r na l of
case records of the massachusetts general hospital
From the Department of Emergency Med-
icine (W.D.B.), the Pediatric Nephrology
Service (A.Z.T.), the Blood Transfusion
Service (R.S.M.), and the Department of
Pathology (R.B.C.), Massachusetts Gen-
eral Hospital; and the Departments of
Medicine (W.D.B.), Pediatrics (A.Z.T.),
and Pathology (R.S.M., R.B.C.), Harvard
Medical School — both in Boston.
N Engl J Med 2010;363:2352-61.
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2352
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m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 37-2010: A 16-Year-Old Girl with
Confusion, Anemia, and Thrombocytopenia
William D. Binder, M.D., Avram Z. Traum, M.D., Robert S. Makar, M.D., Ph.D.,
and Robert B. Colvin, M.D.
Pr e sen tat ion of C a se
Dr. Michele S. Duke (Pediatrics): A 16-year-old girl was seen in the emergency depart-
ment of this hospital because of confusion, anemia, and thrombocytopenia.
The patient had lupus nephritis but had been well until approximately 7 days
before admission, when malaise developed, associated with frontal headaches,
light-headedness when rising, fatigue, palpitations, and shortness of breath. Epi-
sodes of nausea and vomiting occurred that prompted her to leave school early.
Two days before admission, she saw her primary care physician; the examination
was reportedly normal, and no laboratory tests were performed. The symptoms were
attributed to a recent tapering of prednisone and stress associated with school.
At approximately 9:30 p.m. on the night of admission, right-sided weakness and
numbness involving the face, limbs, and abdomen suddenly developed. The pa-
tient’s parents took her to the emergency room at another hospital, arriving at
11 p.m. On examination, the patient was awake and appeared in distress, moan-
ing. She reported abdominal pain. The temperature was 38.4°C, the blood pressure
109/56 mm Hg, the pulse 98 beats per minute, the respiratory rate 18 breaths per
minute, and the oxygen saturation 100% while she was breathing ambient air. The
oral mucous membranes were dry. Strength in the right arm was reportedly de-
creased, and the gait was unsteady; the examination was otherwise normal. Serum
levels of creatine kinase, creatine kinase isoenzymes, and troponin I were normal;
other results are shown in Table 1. Urinalysis showed 1+ protein. An electrocardio-
gram was normal. Computed tomography (CT) of the head without the adminis-
tration of contrast material was normal. Hydromorphone, metoclopramide, ondan-
setron, and normal saline were administered intravenously. During the next 2 hours,
the patient reported that numbness extended to involve the left side, and increas-
ing confusion and agitation developed. Approximately 2.5 hours after arrival, she was
transferred to the emergency department at this hospital, arriving 40 minutes later.
The patient had not had fevers, chills, diarrhea, rash, cough, or nasal conges-
tion or discharge. A diagnosis of lupus nephritis had been made 3 years earlier,
when hypertension and proteinuria (1.8 g of protein per 24 hours) developed after
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The New England Journal of Medicine
 case records of the massachusetts gener al hospital
the initiation of oral contraceptives for dysmen-
orrhea and did not resolve after discontinuation of
the medication. A renal biopsy revealed immune-
complex glomerulonephritis. At that time, the
erythrocyte sedimentation rate was 49 mm per
hour; the titer of antinuclear antibody (ANA) was
positive at 1:1280 dilution (reference range, nega-
tive at 1:40 and 1:160 dilutions), with a speckled
pattern; tests for antibodies to double-stranded
DNA were positive at 1:20 dilution (reference
range, negative at 1:10 dilution); tests for anti-
bodies to Ro, La, Sm, and ribonucleoprotein were
negative; and tests of renal function and levels
of complement were normal. Mycophenolate
mofetil and prednisone were administered, with
improvement in proteinuria, and the erythrocyte
sedimentation rate decreased to 13 mm per hour.
At a routine follow-up 2.5 months before admis-
sion, the ANA was positive at 1:40 and 1:160
dilutions, in a speckled pattern, and antibody to
double-stranded DNA was positive at 1:40 dilu-
tion; other laboratory-test results are shown in
Table 1. The dose of prednisone was tapered
gradually over a period of 6 weeks, from 10 mg
daily to 10 mg every other day.
The patient had been born by cesarean sec-
tion after a full-term gestation and was adopted
shortly after birth. She had obesity, dysmenor-
rhea, and a right ovarian simple cyst and had
had tracheomalacia as a toddler. Medications in-
cluded mycophenolate mofetil (1000 mg twice
daily), prednisone (10 mg every other day), enala-
pril (10 mg twice daily), norethindrone (0.35 mg
daily), and ergocalciferol (4000 U daily). She had
no known allergies. She was of African-Ameri-
can ancestry and lived with her adoptive parents
and an adopted sibling. She was a good student
and did not smoke, drink alcohol, or use illicit
drugs. Her biologic mother’s family had had
diabetes mellitus and hypertension.
In the emergency department, the vital signs
and oxygen saturation were normal. On examina-
tion, the patient’s mental status alternated be-
tween somnolent and agitated. She opened her
eyes in response to voice or touch; she did not
make eye contact or respond to questions, she
moaned frequently, and she occasionally called
for her parents. She showed purposeful and sym-
metric limb movements in response to stimuli.
Neurologic examination was limited by her men-
tal status, but no focal abnormalities were de-
tected; the remainder of the physical examina-
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tion was normal. Serum levels of electrolytes,
calcium, phosphorus, magnesium, total protein,
albumin, globulin, amylase, lipase, anticardio-
lipin IgG and IgM antibodies, fibrinogen, and
C-reactive protein were normal, as were tests of
renal function; results of tests for ANA and anti-
bodies to double-stranded DNA, Ro, La, Sm, and
ribonucleoprotein were unchanged, and testing
for lupus anticoagulant and toxicology screening
of the blood and urine were negative; other
laboratory-test results are shown in Table 1.
The ABO blood type was O, Rh-positive, with
negative antibody screening. Urinalysis revealed
red cloudy urine (specific gravity, 1.020; pH, 7.0;
3+ blood and protein; 20 to 50 red cells and 10 to
20 white cells per high-power field; 5 to 10 hya-
line casts and 0 to 2 granular casts per low-
power field; few squamous cells; and mucin).
Agitation precluded CT of the head. The patient
was admitted to the pediatric intensive care unit
(ICU) 5 hours after arrival.
Additional diagnostic testing was performed,
and a management decision was made.
Differ en t i a l Di agnosis
Dr. William D. Binder: I am aware of the diagnosis.
This 16-year-old girl with a history of lupus ne-
phritis presented with a complex array of signs
and symptoms, including a change in mental sta-
tus, anemia, and thrombocytopenia. After the
ABCs — airway, breathing, and circulation —
have been evaluated for stability, a finding of al-
tered mental status requires a rapid and focused
assessment in the emergency department.1
Assessment of altered mental status
Causes of impaired consciousness can be catego-
rized as structural, infectious and inflammatory,
toxic or metabolic, and paroxysmal.2 The medi-
cal history taking and physical examination are
important in defining the cause of altered men-
tal status. Important historical data include the
time course and circumstances of the onset of
symptoms, recent or previous illnesses, and the
use of medications, illicit drugs, or alcohol. Con-
stitutional symptoms (e.g., fever, headache, and
nausea and vomiting) and behavioral changes
are clinically significant and must be elucidated.
In this case, the patient’s hemodynamic and re-
spiratory functions were stable, and the physical
examination showed no focal weakness and in-
2353
 The n e w e ng l a n d j o u r na l of m e dic i n e

termittently comprehensible speech. The neuro- the age and history of this patient and the nor-
logic examination was otherwise limited by her mal CT.
altered mental status. Infectious and inflammatory causes of al-
tered mental status are possible. The patient was
Causes of altered mental status febrile and alternately confused and agitated.
Although this patient was not known to have Patients with systemic lupus erythematosus (SLE)
suffered trauma, structural abnormalities due who are receiving immunosuppressive therapy
to occult trauma must always be considered. are at risk for bacterial and viral infections.3 The
However, the CT scan performed at the other hos- triad of mental-status changes, fever, and neck
pital did not reveal a subdural or epidural hema- stiffness occurs in less than 50% of immuno-
toma or subarachnoid hemorrhage. Although competent persons who have bacterial meningitis
subarachnoid hemorrhage can be missed on CT, and in an even smaller percentage of immuno-
a bleed large enough to cause confusion would compromised patients.4 Vascular and inflamma-
most likely be apparent. Other structural abnor- tory changes in the central nervous system (CNS)
malities such as tumors are unlikely in view of occur in up to 90% of children and adolescent

Table 1. Laboratory Data.*

Reference Range,
Adjusted for Age 6 Wk before Day of Admission, On Admission,
Variable and Sex† Admission Other Hospital This Hospital
Hematocrit (%) 36.0–46.0 39.9 23.2 19.7
Hemoglobin (g/dl) 12.0–16.0 13.9 7.9 6.8
Reticulocytes (%) 0.5–2.5 20.8
White-cell count (per mm3) 4500–13,500 4600 9100 10,500
Differential count (%)
Neutrophils 40–62 71 73 86
Band forms 0–10 0 2 0
Lymphocytes 27–40 23 25 10
Monocytes 4–11 5 0 4
Eosinophils 0–8 1 0 0
Platelet count (per mm3) 150,000–450,000 317,000 16,000 16,000
Mean corpuscular volume (μm3) 78–102 88 88 85
3)
Erythrocyte count (million per mm 4.10–5.10 4.54 2.64 (ref 3.60–5.00) 2.31
Red-cell distribution width (%) 11.5–14.5 12.7 17.7 18.9
Smear description
Anisocytosis None Slight 2+
Polychromasia Normal Occasional 1+
Schistocytes None Occasional 1+
Basophilic stippling Negative Occasional Present
Erythrocyte sedimentation rate (mm/hr) 1–17 15 45
Haptoglobin (mg/dl) 16–199 <6
Activated partial-thromboplastin time (sec) 21.0–33.0 25.9 25.4
Prothrombin time (sec) 10.8–13.4 11.4 14.2
d-Dimer (ng/ml) <500 3508
Fibrinogen (mg/dl) 150–400 368
Glucose (mg/dl) 70–110 84 135
Urea nitrogen (mg/dl) 8–25 10 17
Creatinine (mg/dl) 0.60–1.50 0.78 1.05

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 case records of the massachusetts gener al hospital

Table 1. (Continued.)

Reference Range,
Adjusted for Age 6 Wk before Day of Admission, On Admission,
Variable and Sex† Admission Other Hospital This Hospital
Bilirubin (mg/dl)
Total 0.0–1.0 3.5
Direct 0.0–0.4 0.4
Alkaline phosphatase (U/liter) 15–350 55
Aspartate aminotransferase (U/liter) 9–32 60
Alanine aminotransferase (U/liter) 7–30 15
Lactate dehydrogenase (U/liter) 110–210 1775
C-reactive protein (mg/liter) <8.0 6.2
Complement
Total (U/ml) 63–145 74
C3 (mg/dl) 86–184 130 113
C4 (mg/dl) 20–58 21 18

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogen to millimoles per liter,
multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for bilirubin to micro-
moles per liter, multiply by 17.1. Ref denotes reference range.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are age- and sex-adjusted and are for patients who are not pregnant and do not have medical conditions
that could affect the results. They may therefore not be appropriate for all patients.

patients with SLE.5 The spectrum of neuropsychi-

critical clues to the diagnosis. The patient had
atric disorders associated with SLE includes thrombocytopenia, which can result from a fail-
cerebrovascular disease, cognitive dysfunction,ure of production, abnormal distribution or se-
seizures, and the acute confusional state.5,6 CNS
questration, or destruction of platelets. She did
lupus was a leading consideration in this case.not have splenomegaly, so it is unlikely that there
There is an enormous list of toxic and meta-is sequestration or an abnormal distribution of
bolic reasons for a change in mental status. Inplatelets. Failure of production is possible, but
thrombocytopenia in patients with SLE is more
this patient, we can rule out most inborn errors
commonly caused by platelet destruction.8
of metabolism, although late-onset disorders can
be triggered in some circumstances.7 Complica- The patient also had a normocytic anemia.
tions of diabetes, such as diabetic ketoacidosis,
Anemia, thrombocytopenia, and leukopenia are
were ruled out at the other facility. Other endo-
present in up to 75% of pediatric patients with
crine diseases such as hypothyroidism and hy- SLE.9,10 Anemias may be due to a failure of pro-
duction of red cells, blood loss, or destruction of
perthyroidism are possible but unlikely. Finally,
red cells. Although mycophenolate mofetil may
ingestion of illicit or prescription drugs could
create a stuporous state and must be consideredcause gastroenteritis, this patient did not have
in this 16-year-old patient. evidence of gastrointestinal bleeding. Causes of
Paroxysmal causes of confusion, such as sei-decreased red-cell production include iron defi-
zure, were not witnessed. However, seizures canciency, viral hepatitis, infection with Epstein–
be present, with unusual behaviors and depres- Barr virus, and parvovirus infections, but the
physical examination and the laboratory studies
sion as their only manifestations. In some studies,
are not suggestive of any of these diagnoses. Red-
seizure disorders have been reported in approxi-
mately 50% of pediatric patients with SLE.5,6 cell destruction may be due to either intrinsic
abnormalities of the red cells or extrinsic causes.
Laboratory-test results Data from this patient suggest a pattern of ex-
While we were strongly considering a diagnosis trinsic hemolysis. The blood smear reportedly
of primary CNS lupus, laboratory data provided showed 1+ schistocytes, a finding that is sugges-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 1. Renal-Biopsy Specimen.

Panel A (periodic acid–Schiff) shows globally thickened glomerular basement membranes. Subepithelial, amorphous,
electron-dense deposits are present in the glomerular basement membrane (Panel B, arrows). Immunofluorescence
reveals finely granular deposits of IgG along the glomerular basement membrane (Panel C), and electron microscopy
reveals tubuloreticular structures in the glomerular endothelial cells (Panel D, arrow). These features are typical of
membranous lupus nephritis class V. There was no evidence of thrombotic microangiopathy.

tive of a microangiopathic hemolytic anemia. The and hypertension, no extrarenal symptoms of

elevated lactate dehydrogenase (LDH) and indi- SLE, and normal complement levels. We obtained
rect bilirubin levels were further evidence of renal-biopsy specimens at that time, which would
hemolysis. be informative to review now.
In this patient with fever and changes in men-
tal status, the laboratory findings of microangio- Pathol o gic a l Discussion
pathic hemolytic anemia and thrombocytopenia
were suggestive of a diagnosis of thrombotic Dr. Robert B. Colvin: The renal-biopsy specimen
thrombocytopenic purpura (TTP).11 We asked for (Fig. 1) had more than 20 glomeruli, which
consultations from the neurology, rheumatology, looked normal on light microscopical examina-
hematology, and nephrology services, and the tion except for mildly thickened basement mem-
patient was admitted to the pediatric ICU. branes; on immunofluorescence, there were nu-
merous granular deposits of IgG, IgM, IgA, C3,
Lupus nephritis and C1q along the glomerular basement mem-
Dr. Avram Z. Traum: This teenage girl had present- brane in a haphazard, scattered pattern. These
ed 2 years earlier with hematuria, proteinuria, were better seen by electron microscopy, pene-

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 case records of the massachusetts gener al hospital
trating the basement membrane and surrounded
by spikes of new basement membrane, features
that are typical of membranous glomerulone-
phritis. Another feature, which represented a re-
sponse to interferon-α, was the presence of tubu-
loreticular structures in the endothelium. The
vessels were normal, with no evidence of throm-
botic microangiopathy. This pattern of mem-
branous glomerulonephritis can be seen in many
diseases other than lupus, but the presence of the
tubuloreticular structures and the penetrating
deposits in a so-called full house (the presence of
all three immunoglobulin classes [IgG, IgM, and
IgA] and complement factors C3 and C1q) led us
to conclude that the membranous glomerulone-
phritis was most likely lupus nephritis class V,
according to the International Society of Ne-
phrology and the Renal Pathology Society classi-
fication. Membranous lupus nephritis is a unique
category of lupus nephritis.12 Although classes I
through IV represent escalating degrees of sever-
ity of glomerulonephritis, class V lupus nephritis
does not represent a more severe form than class
IV but, rather, is a distinct diagnosis.
Differ en t i a l Di agnosis
Dr. Traum: After the biopsy findings were reported,
I obtained an ANA titer, which was positive at
1:1280, along with an anti–double-stranded DNA
titer that was positive at a low titer of 1:20, confirm-
ing the diagnosis of class V lupus nephritis. This
form of lupus nephritis is unique, with its own
manifestations, including normal complement lev-
els and the absence of extrarenal disease. Protein-
uria is more prominent than in other types of lupus
nephritis, and nephritic features such as red-cell
casts may be absent. The risk of thrombosis ap-
pears to be higher in membranous nephropathy
than in other subtypes of nephrotic syndrome.13
Because of her hypertension and proteinuria,
this patient was initially treated with mycophen­
olate mofetil and prednisone, with improvement
in her proteinuria and inflammatory markers. I
had been tapering her prednisone to a relatively
low dose (10 mg on alternate days), with close
monitoring of her proteinuria and inflammatory
markers. At the time of this acute presentation,
she had been on a stable dose for some months.
CNS lupus
A systemic lupus flare with cytopenias and CNS
involvement was a serious consideration in this
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case. SLE-related cytopenias can be autoimmune
in nature, and this patient’s elevated indirect hy-
perbilirubinemia and LDH levels were suggestive
of hemolysis, supporting this diagnosis; how-
ever, the antibody screening was negative. Anti­
phospholipid antibodies can be present in pa-
tients with lupus and can lead to a clinical picture
of thrombocytopenia and changes in mental sta-
tus; in this patient, screening for antiphospho-
lipid antibodies had been negative 2 years earlier.
Hypertensive crisis can lead to changes in mental
status and can cause a thrombotic microangiop-
athy with anemia and thrombocytopenia. How-
ever, the patient’s blood pressure was normal at
the time of this presentation.
Thrombotic thrombocytopenic purpura
Laboratory-test results showed 1+ schistocytes, a
finding that is suggestive of a microangiopathic
hemolytic anemia. In thrombotic microangiopa-
thy, an insult to the microvasculature leads to
microthrombus formation with consumption of
platelets, shearing of red cells with hemolysis,
and the laboratory findings of schistocytes,
thrombocytopenia, and anemia. The subsequent
signs and symptoms are due to end-organ ische­
mia from microthrombi, particularly in the brain
and renal glomeruli. Our patient had all these
features, and additional laboratory testing re-
vealed undetectable haptoglobin and an elevated
reticulocyte count, which are further evidence of
hemolysis. The differential diagnosis includes
TTP and the hemolytic–uremic syndrome, both
of which share features of microangiopathic he-
molytic anemia and thrombocytopenia.
TTP is a rare disease14 but is seen more com-
monly in women, blacks, obese persons, and pa-
tients with autoimmune disease, including lu-
pus; this patient had all these risk factors.15,16
TTP is due to a deficiency of ADAMTS 13, a
protease that breaks down large, thrombogenic
von Willebrand factor multimers into mono-
mers.17 The presentation of TTP can be identical
to that of the hemolytic–uremic syndrome. Usu-
ally, however, renal involvement is more promi-
nent in the hemolytic–uremic syndrome. Fever is
absent, and neurologic symptoms are variable.
In diarrhea-associated hemolytic–uremic syn-
drome, which is typically seen in younger chil-
dren, Shiga toxin produced by Escherichia coli
O157:H7 or other related bacteria leads to endo-
thelial injury. Hemolytic–uremic syndrome asso-
ciated with the absence of a diarrheal prodrome
2357
 The n e w e ng l a n d j o u r na l
Figure 2. Representative Peripheral-Blood Smear from Another Patient
with Thrombotic Thrombocytopenic Purpura.
At high magnification, notable findings include schistocytes (arrows) and
a virtual lack of platelets. One platelet can be seen (arrowhead).
can follow other infections or can be due to
genetic causes, such as mutations in genes en-
coding factor H, factor I, or membrane cofactor
protein (MCP).
In this patient, the preexisting diagnosis of
lupus, the mild nature of the renal disease, the
microangiopathic hemolytic anemia, and the
thrombocytopenia, in the absence of a diarrheal
prodrome, make TTP the more likely diagnosis.
The treatment of choice for TTP is plasma ex-
change, so the Blood Transfusion Service was
consulted.
Cl inic a l Di agnosis
Thrombotic thrombocytopenic purpura.
Pathol o gic a l Discussion
Dr. Robert S. Makar: With Dr. Verena Gobel (Pedi-
atric Hematology), we reviewed the peripheral-
blood smear (Fig. 2); this revealed schistocytes
and reticulocytes and virtually no platelets, indi-
cating a microangiopathic hemolytic anemia that
was consistent with a thrombotic microangiopa-
thy. The differential diagnosis of a thrombotic
microangiopathy is broad (Table 2) and includes
many conditions that require distinct therapeutic
interventions. TTP is caused either by congenital
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of m e dic i n e
deficiency of the plasma enzyme ADAMTS 13
(Upshaw–Schülman syndrome),18 or by autoanti-
body inhibitors of ADAMTS 13 that result in a
deficiency of the enzyme.19-23 In patients with id-
iopathic TTP, microvascular hemostasis is disrupt-
ed; plasma exchange is a lifesaving procedure for
these patients,19 because it corrects the perturba-
tion by replacing the ADAMTS 13 enzyme and re-
moving, over the course of several procedures,
the autoantibody inhibitor that is often detected
during the acute illness. Therefore, a clinical di-
agnosis of TTP and treatment with plasma ex-
change is appropriate when there is evidence of a
thrombotic microangiopathy without clinical or
laboratory evidence of an alternative cause. Al-
though this patient had evidence of end-organ
injury, in the form of altered mental status and a
very mild elevation in her serum creatinine level,
neither a neurologic finding nor acute renal fail-
ure is required to make the diagnosis of idio-
pathic TTP and initiate plasma exchange.22,24 In
this patient, a diagnosis of idiopathic TTP was
made and plasma exchange was begun.
Discussion of M a nagemen t
Dr. Makar: Patients with idiopathic TTP used to be
treated with either plasma infusion or plasma ex-
change, but a randomized, controlled trial con-
ducted approximately 20 years ago showed the
superiority of plasma exchange.25 Plasma infu-
sion is appropriate only as a temporary measure
while arrangements are being made for plasma
exchange. Therapeutic plasma exchange requires
excellent venous access to support the blood flow
required by the instrument, at least a 17-gauge
needle for a withdrawal and an 18-gauge intrave-
nous catheter for return. Because most patients
require multiple procedures, a central venous
catheter for apheresis is often required before
plasma exchange can start. Although a recently
published case series found no evidence of harm
from platelet transfusion in patients with TTP,26
prophylactic platelet transfusion before insertion
of the catheter is not recommended.
Patients with TTP undergo daily plasma ex-
change, typically accompanied by glucocorticoids,
until clinical remission (i.e., a normal platelet
count, rising hemoglobin level, and normal or
near-normal LDH level) occurs and persists for
several days.27,28 Plasma exchange is then per-
formed on alternate days or is stopped, and the
 case records of the massachusetts gener al hospital

Table 2. Differential Diagnosis of Thrombotic Microangiopathy.*

Disease Suggestive History or Clinical or Laboratory Data

Disseminated intravascular coagulation Temperature >38.9°C, abnormal PT, PTT, or fibrinogen level
Evans syndrome Positive direct antiglobulin test, spherocytes rather than schistocytes on the
peripheral-blood smear
Antiphospholipid-antibody syndrome Prolonged PTT, positive lupus anticoagulant or anticardiolipin antibodies
Severe vasculitis Positive antinuclear antibody, low complement
Malignant hypertension Blood pressure usually ≥180/120, retinal hemorrhages or papilledema, history
of cocaine or amphetamine use
Disseminated cancer History of metastatic cancer
Drug-related History of gemcitabine, cyclosporine, quinidine, ticlopidine therapy
Pregnancy-related Preeclampsia or eclampsia, HELLP syndrome
Hemolytic–uremic syndrome Oliguria or anuria at presentation, history of recent diarrheal illness
Thrombotic thrombocytopenic purpura Thrombocytopenia and microangiopathic hemolytic anemia without alterna-
tive explanation

* HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count; PT prothrombin time; and PTT partial-
thromboplastin time.

administration of glucocorticoids is tapered. The tide is cleaved, a fluorescent signal is detected

number of postremission exchanges is empirical
and reflects institutional practice. No matter
which strategy is used to discontinue plasma
exchange, vigilant monitoring is required for
evidence of disease exacerbation (recurrence with-
in 30 days after diagnosis) or relapse. Our pa-
tient’s mental status cleared after the first plasma
exchange and her hematologic parameters nor-
malized after six treatments, so we decided to
move to an alternate-day regimen. Unfortunately,
after one exchange was skipped, the platelet
count fell markedly (Fig. 3), the hematocrit fell,
and the LDH level rose, so daily plasma ex-
change was reinstituted.
Although testing for ADAMTS 13 enzyme
activity and inhibitor is not necessary for the
diagnosis of TTP, such testing may provide use-
ful prognostic information for this patient. A se-
vere deficiency of ADAMTS 13 and the presence
of detectable autoantibody inhibitors at diagno-
sis are associated with an increased risk of re-
lapse.22,29 Furthermore, high titers of autoanti-
body inhibitors may predict a delayed response
or refractoriness to plasma exchange.29,30 We
use a fluorescence resonance energy transfer as-
say to measure ADAMTS 13 activity. This method
involves incubating the patient’s plasma with a
fluorogenic von Willebrand factor peptide frag-
ment containing the site where ADAMTS 13
cleaves von Willebrand factor.31 When the pep-
that is proportional to the ADAMTS 13 activity
in the specimen. Several days after we started
treating this patient, results of ADAMTS 13 test-
ing showed less than 5% enzyme activity and a
high titer of autoantibody inhibitors (3.6 Bethesda
units). These results suggested that the patient
might be at increased risk for recurrent disease
after the discontinuation of plasma exchange.
Indeed, although she remained asymptomatic
throughout her treatment course, thrombocyto-
penia and microangiopathic hemolytic anemia
recurred whenever we attempted to withdraw
plasma exchange (Fig. 3).
Rituximab has gained favor as an adjunctive
agent to treat refractory or relapsing TTP.32-34
Clinical trials are required to clarify whether
rituximab should be used in conjunction with
plasma exchange for all patients with TTP or
only for those with refractory or relapsing dis-
ease. For this patient, we suggested a course of
rituximab, which, together with intermittent plas-
ma exchange, resulted in a durable clinical re-
mission.
Dr. Nancy Lee Harris (Pathology): Dr. Traum,
would you tell us how the patient is doing?
Dr. Traum: One year after this episode, the
patient is doing well. Her kidney disease is in
remission, TTP has not recurred, and her plate-
let count, hematocrit, and LDH level are normal.
Her proteinuria is slightly better than before the

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 The n e w e ng l a n d j o u r na l of m e dic i n e

secondary form of the disease is associated with

Rituximab
drugs such as the thienopyridines ticlopidine
TPE
and clopidogrel, both of which appear to elicit
the formation of an anti–ADAMTS 13 autoanti-
40 2000
body, although clopidogrel may also trigger the
disease through a nonimmune mechanism.35 In
Platelet Count (×10−4 per mm3)

1600
30 patients with severe deficiency and an autoanti-
Hematocrit body inhibitor, relapse rates range from 30 to
Hematocrit (%)

LDH (U/liter)
1200
70%.22
20 Platelet
count A Physician: If you suspect TTP, is it ever right
800
to give platelets?
10
400
Dr. Makar: Platelet transfusion may be associ-
ated with acute deterioration or even death from
0
LDH
0
TTP.36-38 For this reason, platelet transfusion is
1 10 20 30 40 50 relatively contraindicated in patients with throm-
Clinical Course (days) botic thrombocytopenic purpura and should be
limited to the treatment of life-threatening
Figure 3. Clinical Course. bleeding.
The graph shows the patient’s platelet count, hematocrit, and lactate dehy-
drogenase (LDH) level during her hospitalization and subsequent outpatient
care. A normal platelet count for a 16-year-old girl is 150,000 to 400,000 per PATHOL O GIC A L DI AGNOSIS
cubic millimeter. Individual therapeutic plasma exchanges (TPE) are denot-
ed by thin arrows, and rituximab infusion by short arrows. Thrombotic thrombocytopenic purpura due to
autoantibodies to ADAMTS 13 in a patient with
episode of TTP. She continues to take mycophen- class V lupus nephritis.
olate mofetil and 10 mg of prednisone per day; This case was discussed at Emergency Medicine Grand Rounds,
in the future, we may try again to wean these November 10, 2009.
No potential conflict of interest relevant to this article was re-
treatments, but not yet. ported.
Dr. Harris: Are there any questions? Disclosure forms provided by the authors are available with
Dr. David F. Brown (Emergency Medicine): Is it the full text of this article at NEJM.org.
We thank Dr. David F. Brown (Emergency Medicine) and Dr.
known what triggers the development of auto- Julie Ingelfinger (Pediatrics) for helping with the organization
antibodies? What is the overall recurrence rate of the conference; Drs. Sholeen Nett, Verena Gobel, and Holly
of TTP? Rothermel (Pediatrics) and Dr. Walter Dzik (Pathology, Blood
Transfusion Service) for helping with the preparation of the
Dr. Makar: What induces the formation of case history; and Dr. Verena Gobel for contributing to the dis-
autoantibodies in idiopathic TTP is unknown. A cussion.

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