You are on page 1of 10

T h e n e w

e ngl a nd

j o u r na l

o f

m e dic i n e

case records of the massachusetts general hospital

Founded by Richard C. Cabot

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

Eric S. Rosenberg, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Christine C. Peters, Assistant Editor

T h e n e w e ngl a nd j o u r na l

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 esen tation of C a se

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.

Copyright © 2010 Massachusetts Medical Society.

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

2352

n engl j med 363;24

nejm.org

december 9, 2010

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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-

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 ti 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-

n engl j med 363;24

nejm.org

december 9, 2010

2353

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

T h e n e w

e ngl a nd

j o u r na l

o f

m e dic i n e

termittently comprehensible speech. The neuro- logic examination was otherwise limited by her altered mental status.

Causes of altered mental status

Although this patient was not known to have suffered trauma, structural abnormalities due to occult trauma must always be considered. However, the CT scan performed at the other hos- pital did not reveal a subdural or epidural hema- toma or subarachnoid hemorrhage. Although subarachnoid hemorrhage can be missed on CT, a bleed large enough to cause confusion would most likely be apparent. Other structural abnor- malities such as tumors are unlikely in view of

the age and history of this patient and the nor- mal CT. Infectious and inflammatory causes of al- tered mental status are possible. The patient was febrile and alternately confused and agitated. Patients with systemic lupus erythematosus (SLE) who are receiving immunosuppressive therapy are at risk for bacterial and viral infections. 3 The triad of mental-status changes, fever, and neck stiffness occurs in less than 50% of immuno- competent persons who have bacterial meningitis and in an even smaller percentage of immuno- compromised patients. 4 Vascular and inflamma- tory changes in the central nervous system (CNS) 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 mm 3 )

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 mm 3 )

150,000–450,000

317,000

16,000

16,000

Mean corpuscular volume (μm 3 )

78–102

88

88

85

Erythrocyte count (million per mm 3 )

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

2354

n engl j med 363;24

nejm.org

december 9, 2010

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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- atric disorders associated with SLE includes cerebrovascular disease, cognitive dysfunction, seizures, and the acute confusional state. 5,6 CNS lupus was a leading consideration in this case. There is an enormous list of toxic and meta- bolic reasons for a change in mental status. In this patient, we can rule out most inborn errors of metabolism, although late-onset disorders can be triggered in some circumstances. 7 Complica- tions of diabetes, such as diabetic ketoacidosis, were ruled out at the other facility. Other endo- crine diseases such as hypothyroidism and hy- perthyroidism are possible but unlikely. Finally, ingestion of illicit or prescription drugs could create a stuporous state and must be considered in this 16-year-old patient. Paroxysmal causes of confusion, such as sei- zure, were not witnessed. However, seizures can be present, with unusual behaviors and depres- sion as their only manifestations. In some studies, seizure disorders have been reported in approxi- mately 50% of pediatric patients with SLE. 5,6

Laboratory-test results

While we were strongly considering a diagnosis of primary CNS lupus, laboratory data provided

critical clues to the diagnosis. The patient had thrombocytopenia, which can result from a fail- ure of production, abnormal distribution or se- questration, or destruction of platelets. She did not have splenomegaly, so it is unlikely that there is sequestration or an abnormal distribution of platelets. Failure of production is possible, but thrombocytopenia in patients with SLE is more commonly caused by platelet destruction. 8 The patient also had a normocytic anemia. Anemia, thrombocytopenia, and leukopenia are present in up to 75% of pediatric patients with SLE. 9,10 Anemias may be due to a failure of pro- duction of red cells, blood loss, or destruction of red cells. Although mycophenolate mofetil may cause gastroenteritis, this patient did not have evidence of gastrointestinal bleeding. Causes of decreased red-cell production include iron defi- ciency, viral hepatitis, infection with Epstein– Barr virus, and parvovirus infections, but the physical examination and the laboratory studies are not suggestive of any of these diagnoses. Red- cell destruction may be due to either intrinsic abnormalities of the red cells or extrinsic causes. Data from this patient suggest a pattern of ex- trinsic hemolysis. The blood smear reportedly showed 1+ schistocytes, a finding that is sugges-

n engl j med 363;24

nejm.org

december 9, 2010

2355

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

2356

T h e n e w

e ngl a nd

j o u r na l

o f

m e dic i n e

A B C D
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 elevated lactate dehydrogenase (LDH) and indi- rect bilirubin levels were further evidence of hemolysis. In this patient with fever and changes in men- tal status, the laboratory findings of microangio- pathic hemolytic anemia and thrombocytopenia were suggestive of a diagnosis of thrombotic thrombocytopenic purpura (TTP). 11 We asked for consultations from the neurology, rheumatology, hematology, and nephrology services, and the patient was admitted to the pediatric ICU.

Lupus nephritis

Dr. Avram Z. Traum: This teenage girl had present- ed 2 years earlier with hematuria, proteinuria,

and hypertension, no extrarenal symptoms of SLE, and normal complement levels. We obtained renal-biopsy specimens at that time, which would be informative to review now.

Pathol o gic a l Discussion

Dr. Robert B. Colvin: The renal-biopsy specimen (Fig. 1) had more than 20 glomeruli, which looked normal on light microscopical examina- tion except for mildly thickened basement mem- branes; on immunofluorescence, there were nu- merous granular deposits of IgG, IgM, IgA, C3, and C1q along the glomerular basement mem- brane in a haphazard, scattered pattern. These were better seen by electron microscopy, pene-

n engl j med 363;24

nejm.org

december 9, 2010

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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 ti 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

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 disease 14 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

n engl j med 363;24

nejm.org

december 9, 2010

2357

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

T h e n e w

e ngl a nd

j o u r na l

o f

m e dic i n e

Figure 2. Representative Peripheral-Blood Smear from Another Patient with Thrombotic Thrombocytopenic Purpura. At high magnification, notable
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.

Clinic 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

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

2358

n engl j med 363;24

nejm.org

december 9, 2010

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

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 Severe vasculitis Malignant hypertension

Prolonged PTT, positive lupus anticoagulant or anticardiolipin antibodies Positive antinuclear antibody, low complement Blood pressure usually ≥180/120, retinal hemorrhages or papilledema, history

Disseminated cancer Drug-related Pregnancy-related Hemolytic–uremic syndrome Thrombotic thrombocytopenic purpura

of cocaine or amphetamine use History of metastatic cancer History of gemcitabine, cyclosporine, quinidine, ticlopidine therapy Preeclampsia or eclampsia, HELLP syndrome Oliguria or anuria at presentation, history of recent diarrheal illness 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 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-

tide is cleaved, a fluorescent signal is detected 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

n engl j med 363;24

nejm.org

december 9, 2010

2359

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

T h e

n e w

e ngl a nd

j o u r na l

o f

m e dic i n e

Rituximab TPE 40 2000 1600 30 Hematocrit 1200 20 Platelet count 800 10 400 LDH 0
Rituximab
TPE
40
2000
1600
30
Hematocrit
1200
20
Platelet
count
800
10
400
LDH
0
0
1
10
20
30
40
50
Clinical Course (days)
Figure 3. Clinical Course.
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
cubic millimeter. Individual therapeutic plasma exchanges (TPE) are denot-
ed by thin arrows, and rituximab infusion by short arrows.
Platelet Count (×10 −4 per mm 3 )
Hematocrit (%)
LDH (U/liter)

episode of TTP. She continues to take mycophen- o late mofetil and 10 mg of prednisone per day; in the future, we may try again to wean these treatments, but not yet. Dr. Harris: Are there any questions? Dr. David F. Brown (Emergency Medicine): Is it known what triggers the development of auto- antibodies? What is the overall recurrence rate of TTP? Dr. Makar: What induces the formation of autoantibodies in idiopathic TTP is unknown. A

secondary form of the disease is associated with

drugs such as the thienopyridines ticlopidine

and clopidogrel, both of which appear to elicit

the formation of an anti–ADAMTS 13 autoanti-

body, although clopidogrel may also trigger the

disease through a nonimmune mechanism. 35 In

patients with severe deficiency and an autoanti-

body inhibitor, relapse rates range from 30 to

70%. 22

A Physician: If you suspect TTP, is it ever right

to give platelets?

Dr. Makar: Platelet transfusion may be associ-

ated with acute deterioration or even death from

TTP. 36-38 For this reason, platelet transfusion is

relatively contraindicated in patients with throm- botic thrombocytopenic purpura and should be limited to the treatment of life-threatening bleeding.

PATHOL O GIC A L DI AGNOSIS

Thrombotic thrombocytopenic purpura due to autoantibodies to ADAMTS 13 in a patient with class V lupus nephritis.

This case was discussed at Emergency Medicine Grand Rounds, November 10, 2009. No potential conflict of interest relevant to this article was re- ported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Dr. David F. Brown (Emergency Medicine) and Dr. Julie Ingelfinger (Pediatrics) for helping with the organization of the conference; Drs. Sholeen Nett, Verena Gobel, and Holly Rothermel (Pediatrics) and Dr. Walter Dzik (Pathology, Blood Transfusion Service) for helping with the preparation of the case history; and Dr. Verena Gobel for contributing to the dis- cussion.

2360

References

  • 1. Goldstein JN, Greer DM. Rapid fo-

cused neurological assessment in the emergency department and ICU. Emerg Med Clin North Am 2009;27:1-16.

  • 2. Lehman RK, Mink J. Altered mental

status. Clin Pediatr Emerg Med 2008;9:68-

  • 6. Greenberg BM. The neurologic mani-

festations of systemic lupus erythemato- sus. Neurologist 2009;15:115-21.

  • 7. Marcus N, Scheuerman O, Hoffer V,

Zilbershot-Fink E, Reiter J, Garty BZ. Stu- por in an adolescent following Yom Kip-

  • 75. pur fast, due to late-onset ornithine trans-

    • 3. Cuchacovich R, Gedalia A. Patho-

physiology and clinical spectrum of infec- tions in systemic lupus erythematosus.

Rheum Dis Clin North Am 2009;35:75-

carbamylase deficiency. Isr Med Assoc J

2008;10:395-6.

  • 8. Ziakas PD, Giannouli S, Zintzaras E,

Tzioufas AG, Voulgarelis M. Lupus throm-

  • 93. bocytopenia: clinical implications and

    • 4. Chávez-Bueno S, McCracken GH Jr.

Bacterial meningitis in children. Pediatr Clin North Am 2005;52:795-810.

  • 5. Muscal E, Brey RL. Neurologic mani-

festations of systemic lupus erythemato- sus in children and adults. Neurol Clin

2010;28:61-73.

prognostic significance. Ann Rheum Dis

2005;64:1366-9.

  • 9. Schmugge M, Revel-Vilk S, Hiraki L,

Rand ML, Blanchette VS, Silverman ED. Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus. J Pediatr 2003;143:666-9.

  • 10. Benseler SM, Silverman ED. Systemic

lupus erythematosus. Rheum Dis Clin North Am 2007;33:471-98.

  • 11. Jaffey PB, Feldman HA. The clinical

spectrum of thrombotic thrombocytope- nic purpura. Emerg Med 2005;37:36-44.

  • 12. Weening JJ, D’Agati VD, Schwartz

MM, et al. The classification of glomeru- lonephritis in systemic lupus erythemato-

sus revisited. Kidney Int 2004;65:521-30.

  • 13. Glassock RJ. Prophylactic anticoagu-

lation in nephrotic syndrome: a clinical

conundrum. J Am Soc Nephrol 2007;18:

2221-5.

  • 14. Terrell DR, Williams LA, Vesely SK,

Lämmle B, Hovinga JA, George JN. The incidence of thrombotic thrombocytope- nic purpura-hemolytic uremic syndrome:

all patients, idiopathic patients, and pa-

n engl j med 363;24

nejm.org

december 9, 2010

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

case records of the massachusetts gener al hospital

tients with severe ADAMTS-13 deficiency. J Thromb Haemost 2005;3:1432-6.

  • 15. Coppo P, Bengoufa D, Veyradier A, et

al. Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal in- volvement. Medicine (Baltimore) 2004;83:

233-44.

  • 16. Vesely SK, George JN, Lammle B, et al.

ADAMTS13 activity in thrombotic throm- bocytopenic purpura–hemolytic uremic

syndrome: relation to presenting features and clinical outcomes in a prospective co- hort of 142 patients. Blood 2003;102:60-8.

  • 17. Tsai HM. The molecular biology of

thrombotic microangiopathy. Kidney Int

2006;70:16-23.

  • 18. Furlan M, Robles R, Solenthaler M,

Wassmer M, Sandoz P, Lammle B. Defi- cient activity of von Willebrand factor- cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997;89:3097-103.

  • 19. Furlan M, Robles R, Galbusera M, et al.

Von Willebrand factor–cleaving protease in thrombotic thrombocytopenic purpu- ra and the hemolytic–uremic syndrome. N Engl J Med 1998;339:1578-84.

  • 20. Furlan M, Robles R, Solenthaler M,

Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytope- nic purpura. Blood 1998;91:2839-46.

  • 21. Tsai HM, Lian EC. Antibodies to von

Willebrand factor–cleaving protease in

acute thrombotic thrombocytopenic pur- pura. N Engl J Med 1998;339:1585-94.

  • 22. Sadler JE. Von Willebrand factor,

ADAMTS13, and thrombotic thrombocy- topenic purpura. Blood 2008;112:11-8.

  • 23. Moake JL. Thrombotic microangiopa-

thies. N Engl J Med 2002;347:589-600.

  • 24. George JN. Thrombotic thrombocyto-

penic purpura. N Engl J Med 2006;354:

1927-35.

  • 25. Rock GA, Shumak KH, Buskard NA,

et al. Comparison of plasma exchange

with plasma infusion in the treatment of

thrombotic thrombocytopenic purpura. N Engl J Med 1991;325:393-7.

  • 26. Swisher KK, Terrell DR, Vesely SK,

Kremer Hovinga JA, Lämmle B, George JN. Clinical outcomes after platelet trans- fusions in patients with thrombotic

thrombocytopenic purpura. Transfusion

2009;49:873-87.

  • 27. Allford SL, Hunt BJ, Rose P, Machin

SJ. Guidelines on the diagnosis and man- agement of the thrombotic microangio- pathic haemolytic anaemias. Br J Haema- tol 2003;120:556-73.

  • 28. George JN. How I treat patients with

thrombotic thrombocytopenic purpura–

hemolytic uremic syndrome. Blood 2000;

96:1223-9.

  • 29. Zheng XL, Kaufman RM, Goodnough

LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease

activity, inhibitor level, and clinical out- come in patients with idiopathic and non- idiopathic thrombotic thrombocytopenic purpura. Blood 2004;103:4043-9.

  • 30. Tsai HM, Li A, Rock G. Inhibitors of

von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura. Clin Lab 2001;47:387-92.

  • 31. Kokame K, Nobe Y, Kokubo Y, Okaya-

ma A, Miyata T. FRETS-VWF73, a first

fluorogenic substrate for ADAMTS13 as- say. Br J Haematol 2005;129:93-100.

  • 32. Chemnitz J, Draube A, Scheid C, et al.

Successful treatment of severe throm-

botic thrombocytopenic purpura with the monoclonal antibody rituximab. Am J He- matol 2002;71:105-8.

  • 33. Galbusera M, Bresin E, Noris M, et al.

Rituximab prevents recurrence of throm- botic thrombocytopenic purpura: a case report. Blood 2005;106:925-8.

  • 34. Zheng X, Pallera AM, Goodnough LT,

Sadler JE, Blinder MA. Remission of chron- ic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab. Ann Intern Med 2003;138:

105-8.

  • 35. Bennett CL, Kim B, Zakarija A, et al.

Two mechanistic pathways for thienopyri- dine-associated thrombotic thrombocyto- penic purpura: a report from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol 2007;50:1138-43.

  • 36. Bell WR, Braine HG, Ness PM, Kickler

TS. Improved survival in thrombotic thrombocytopenic purpura–hemolytic ure- mic syndrome — clinical experience in

108 patients. N Engl J Med 1991;325:398-

403.

  • 37. Harkness DR, Byrnes JJ, Lian EC, Wil-

liams WD, Hensley GT. Hazard of platelet transfusion in thrombotic thrombocyto- penic purpura. JAMA 1981;246:1931-3.

  • 38. Ridolfi RL, Bell WR. Thrombotic

thrombocytopenic purpura: report of 25 cases and review of the literature. Medi- cine (Baltimore) 1981;60:413-28.

Copyright © 2010 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences

Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends, shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens, and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced, averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record.

The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

n engl j med 363;24

nejm.org

december 9, 2010

2361

The New England Journal of Medicine Downloaded from www.nejm.org by RAJIV MEDANKI on December 8, 2010. For personal use only. No other uses without permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.