You are on page 1of 12

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

case records of the massachusetts general hospital


Founded by Richard C. Cabot 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 Alice M. Cort, m.d., Associate Editor 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.

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

2032

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

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

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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 diagnoTable 1. Laboratory Data.* Reference Range, Adults 36.046.0 12.016.0 450011,000 4070 010 2244 411 0 0 0 150,000 400,000 4,000,000 5,200,000 11.514.5 0.52.5 017 161393 0.000.52 <10 16199 70110 0.01.0 0.00.4 4.3 932 730 110210 30160 230404 10200 Negative Negative at 1:10 dilution 59 77 461 4.9 353 1.25 <10 Elevated, by report 53,000 Other Hospital, on Admission 20.0

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-

Variable Hematocrit (%) Hemoglobin (g/dl) White-cell count (per mm3) Differential count (%) Neutrophils Band forms Lymphocytes Monocytes Myelocytes Metamyelocytes Nucleated red cells (per 100 white cells) Platelet count (per mm3) Erythrocyte count (per mm3) Red-cell distribution width (%) Reticulocytes (%) Erythrocyte sedimentation rate (mm/hr) Fibrinogen (mg/dl)
D-Dimer

Other Hospital, Day 2 20.1 7.5 10,300

This Hospital, on Admission 19.4 7.2 27,200 79 8 10 2 1 7

This Hospital, First Admission, Days 79 32.9 11.1 14,500 85 6 5 2 2 1 67,000 3,450,000 20.7 10.3 (manual)

87,000

122,000 2,200,000 22.5 10.7 104

(mg/liter)

Fibrin-degradation products (g/ml) Haptoglobin (mg/dl) Glucose (mg/dl) Bilirubin (mg/dl) Total Direct Indirect Aspartate aminotransferase (U/liter) Alanine aminotransferase (U/liter) Lactate dehydrogenase (U/liter) Iron (g/dl) Total iron-binding capacity (g/dl) Ferritin (ng/ml) EpsteinBarr virus DNA, by PCR Antibodies to double-stranded DNA

<6 140 2.0 0.4 36 52 484 444 176 229 775 Positive 8 IU/ml Negative at 1:10 dilution

<6 112 1.5 0.3 138 349 416

<300

2034

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

case records of the massachuset ts gener al hospital

Table 1. (Continued.) Reference Range, Adults 0.019.99 0.019.99 Negative at 1:20 dilution Negative at 1:20 dilution None detected 015 015 Negative at 1:40 and 1:160 dilutions Nonreactive Nonreactive Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative 0.90 0.90 Negative Nonreactive Nonreactive None detected 31.6 14.9 Positive at 1:40 and 1:160 dilutions, homogeneous pattern Reactive Negative Positive Positive Negative Negative Negative Negative Negative Negative Positive Positive Negative Positive 1.71 0.81 Other Hospital, on Admission Other Hospital, Day 2 3.9 (AI ref 0.00.9) 0.7 (AI ref 0.00.9) This Hospital, on Admission This Hospital, First Admission, Days 79 10.27 8.89 Positive at 1:20 dilution Negative at 1:20 dilution

Variable Antibodies to SSA (Ro) (OD units) Antibodies to SSB (La) (OD units) Antibodies to smooth muscle Antimitochondrial antibodies Cytomegalovirus DNA, by quantitative PCR (copies per ml) Anticardiolipin IgM antibodies (MPL units) Anticardiolipin IgG antibodies (GPL units) Antinuclear antibodies

Hepatitis B surface antibodies Hepatitis B surface antigen Hepatitis B core antibodies Hepatitis A total antibodies Hepatitis A IgM antibodies Hepatitis C antibodies Hepatitis B e antigen Hepatitis B e antibodies Hepatitis B nucleic acid IgM antibodies to EpsteinBarr virus VCA IgG antibodies to EpsteinBarr virus VCA Antibodies to EpsteinBarr virus nuclear antigen Heterophile antibodies Varicella IgG antibodies Mycoplasma pneumoniae IgG antibody index M. pneumoniae IgM antibody index

* 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 symp2035

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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.
Table 2. Selected Causes of Hemolytic Anemia.* Cause Associated with intrinsically normal red cells Autoimmune hemolytic anemia Complement-induced lysis Direct trauma (seen in runners, bongo drummers, patients with burns) Drug-induced immune hemolytic anemia Hemolytic transfusion reactions Hypersplenism Hypotonic lysis Infection (e.g., malaria, babesia, bartonella) Clostridial sepsis Infusion of intravenous immune globulin Microangiopathic hemolytic anemia (e.g., hemolyticuremic syndrome, thrombotic thrombocytopenic purpura, DIC, HELLP syndrome, hypertensive emergency)

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

Major Site of Hemolysis Extravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular Extravascular Intravascular

Findings on Peripheral-Blood Smear and Laboratory Tests Spherocytes, reticulocytes, nucleated red cells, positive direct antiglobulin test Hemoglobinuria, myoglobinuria Spherocytes, positive direct antiglobulin test Spherocytes

Red-cell inclusion bodies Red-cell ghosts 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

Oxidant injury (due to exposure to dapsone, phenazopyridine, aniline dyes) Shearing by prosthetic heart valves Cold-agglutinin disease (in some cases) Paroxysmal cold hemoglobinuria Associated with intrinsically abnormal red cells Hemoglobinopathy (e.g., sickle cell anemia, thalassemias, unstable hemoglobins) Metabolic deficiency (e.g., G6PD deficiency, pyruvate kinase deficiency) Defect in the red-cell membrane Hereditary spherocytosis Paroxysmal nocturnal hemoglobinuria

Extravascular Intravascular Intravascular Intravascular Extravascular Extravascular Schistocytes Red-cell agglutination Erythrophagocytosis Target cells, abnormal hemoglobin electro phoresis, abnormal genetic-test results In G6PD deficiency: bite cells, blister cells, low level of G6PD activity Spherocytes Glycosylphosphatidylinositol-linked proteins on flow cytometry

Extravascular Intravascular

* 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

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

case records of the massachuset ts gener al hospital

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 hapto globin 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).
Autoimmune Hemolytic Anemia

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.
Systemic Lupus Erythematosus

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-

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

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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

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).

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

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-

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

case records of the massachuset ts gener al hospital

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.

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

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.

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 hemato2039

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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

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

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.

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.

2040

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

case records of the massachuset ts gener al hospital

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-

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 CASE ings are consistent with a compensatory marrow reTITLE Revised EMail to cytopenias, with no sponse evidence 4-C of an underlyLine SIZE ing Enon abnormality of the marrow.H/T Pathological ARTIST: mst boneH/T 16p6 conFILL Combo B and C) shows examination of the spleen (Panels gestion, extramedullary hematopoiesis, AUTHOR, 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.
JOB: 36921 ISSUE: 11-21-13

n engl j med 369;21

nejm.org

november 21, 2013

2041

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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
References
1. Selo-Ojeme DO, Bhattacharjee P, Izuwa-

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.

Njoku NF, Kadir RA. Emergency peripartum hysterectomy in a tertiary London hospital. Arch Gynecol Obstet 2005;271:154-9. 2. Jandl JH. Hemolytic anemia. N Engl J Med 1963;268:482-6. 3. Parker CJ. Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria. Hematol Oncol Clin North Am 2009;23:333-46. 4. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician 2004;69:2599-606. 5. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002;69:258-71. 6. Garratty G. Drug-induced immune

hemolytic anemia. Hematology Am Soc Hematol Educ Program 2009:73-9. 7. Klutts JS, Ford BA, Perez NR, Gronowski AM. Evidence-based approach for interpretation of Epstein-Barr virus serological patterns. J Clin Microbiol 2009; 47:3204-10. 8. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2005; 54(RR-16):1-31. [Errata, MMWR Morb Mortal Wkly Rep 2006;55:158-9, 2007;56: 1267.]

9. Corey L, Holmes KK. Genital herpes

simplex virus infections: current concepts in diagnosis, therapy, and prevention. Ann Intern Med 1983;98:973-83. 10. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271-7. 11. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40:1725. 12. Evans RS, Duane RT. Acquired hemolytic anemia; the relation of erythrocyte antibody production to activity of the disease; the significance of thrombocytope-

2042

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

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.

case records of the massachuset ts gener al hospital


nia and leukopenia. Blood 1949;4:1196213. 13. Evans RS, Takahashi K, Duane RT, Payne R, Liu C. Primary thrombocytopenic purpura and acquired hemolytic anemia: evidence for a common etiology. AMA Arch Intern Med 1951;87:48-65. 14. Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009;114:316772. 15. Dameshek W, Rosenthal MC, Schwartz LI. The treatment of acquired hemolytic anemia with adrenocorticotrophic hormone (ACTH). N Engl J Med 1950;244:11727. 16. Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J Pediatr Hematol Oncol 1997;19:433-7. 17. Wang WC. Evans syndrome in childhood: pathophysiology, clinical course, and treatment. Am J Pediatr Hematol Oncol 1988;10:330-8. 18. Allgood JW, Chaplin H Jr. Idiopathic acquired autoimmune hemolytic anemia: a review of forty-seven cases treated from 1955 through 1965. Am J Med 1967;43:25473. 19. Oda H, Honda A, Sugita K, Nakamura A, Nakajima H. High-dose intravenous intact IgG infusion in refractory autoimmune hemolytic anemia (Evans syndrome). J Pediatr 1985;107:744-6. 20. Anderson D, Ali K, Blanchette V, et al. Guidelines on the use of intravenous immune globulin for hematologic conditions. Transfus Med Rev 2007;21:Suppl 1:S9S56. 21. Bussone G, Ribeiro E, Dechartres A, et al. Efficacy and safety of rituximab in adults warm antibody autoimmune haemolytic anemia: retrospective analysis of 27 cases. Am J Hematol 2009;84:153-7. 22. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory Evans syndrome and other immune-mediated hematologic diseases. Am J Hematol 2004;77:303-10. 23. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin Proc 2003; 78:1340-6. 24. Dierickx D, Verhoef G, Van Hoof A, et al. Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study. J Intern Med 2009;266: 484-91. 25. Akpek G, McAneny D, Weintraub L. Comparative response to splenectomy in Coombs-positive autoimmune hemolytic anemia with or without associated disease. Am J Hematol 1999;61:98-102. 26. Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenia purpura. Br J Haematol 2002; 117:712-5. 27. Mak A, Mok CC. Mycophenolate mofetil for refractory haemolytic anemia in systemic lupus erythematosus. Lupus 2005;14:856-8. 28. Kotb R, Pinganaud C, Trichet C, et al. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: a single center preliminary study. Eur J Haematol 2005;75:60-4. 29. Emilia G, Messora C, Longo G, Bertesi M. Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders. Br J Haematol 1996;93:341-4. 30. Shvidel L, Sigler E, Shtalrid M, Berrebi A. Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures. Am J Hematol 2006;81:423-5. 31. Chang DK, Yoo DH, Kim TH, et al. Induction of remission with intravenous immunoglobulin and cyclophosphamide in steroid-resistant Evans syndrome associated with dermatomyositis. Clin Rheumatol 2001;20:63-6. 32. Pignon JM, Poirson E, Rochant H. Danazol in autoimmune haemolytic anaemia. Br J Haematol 1993;83:343-5. 33. Oyama Y, Papadopoulos EB, Miranda M, Traynor AE, Burt RK. Allogeneic stem cell transplantation for Evans syndrome. Bone Marrow Transplant 2001;28:903-5. 34. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:1526-33.
Copyright 2013 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 369;21nejm.orgnovember 21, 2013

2043

The New England Journal of Medicine Downloaded from nejm.org on January 22, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved.