Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 53, No. 6, December 15, 2005, pp 982985
DOI 10.1002/art.21583
2005, American College of Rheumatology
CONTRIBUTION FROM THE FIELD
Frequency of Microangiopathic Hemolytic Anemia
in Patients With Systemic Lupus Erythematosus
Exacerbation: Distinction From Thrombotic
Thrombocytopenic Purpura, Prognosis, and
Outcome
SYLVIA DOLD, RANJU SINGH, HAROON SARWAR, YAMINI MENON, LILIANA CANDIA,
LUIS R. ESPINOZA
Introduction
Hematologic abnormalities such as anemia, thrombocyto-
penia, and leukopenia are common features of systemic
lupus erythematosus (SLE). In SLE, anemia of chronic
disease is the most common type of anemia, followed by
autoimmune hemolytic anemia (1). Thrombotic thrombo-
cytopenic purpura (TTP), which was rst described by
Moschowitz in 1924 (2), is characterized by a classic pen-
tad of severe thrombocytopenia (50,000/l ), microangio-
pathic hemolytic anemia (MAHA), neurologic symptoms,
renal impairment, and fever, and a clinical course charac-
terized by relapses or recurrent episodes. All of these
clinical features can also be seen with SLE exacerbation,
but the pathogenic mechanisms are quite different.
MAHA describes a severe type of hemolytic anemia
characterized by the presence of many contracted, dis-
torted, and fragmented red cells (schistocytes) in periph-
eral blood, and it may occur in association with several
other disorders, including SLE (3). The differential diag-
nosis of MAHA includes TTP; hemolysis, elevated liver
enzymes, and low platelets syndrome; hemolytic uremic
syndrome; disseminated intravascular coagulopathy; an-
tiphospholipid antibody syndrome; and vasculitis, among
others (4). Due to many overlapping features, distinction
Presented in part at the 2003 Annual Scientic Meeting of
the American College of Rheumatology in Orlando, FL.
Sylvia Dold, DO, Ranju Singh, MD, Haroon Sarwar, MD,
Yamini Menon, MD (current address: Ochsner Foundation
Hospital, Jefferson, Louisiana), Liliana Candia, MD, Luis R.
Espinoza, MD: Louisiana State University Medical Center,
New Orleans.
Address correspondence to Luis R. Espinoza, MD, Louisi-
ana State University Health Science Center, 1542 Tulane
Avenue, New Orleans, LA 70112-2822. E-mail: luisrolan@
msn.com.
Submitted for publication February 1, 2005; accepted in
revised form June 30, 2005.
982
AND
between SLE exacerbation and TTP can be difcult. As a
result, patients with SLE exhibiting a TTP-like illness are
often treated with plasmapheresis with or without immu-
nosuppressive agents to avoid the near 100% mortality
rate of untreated TTP (5). Tissue biopsy, particularly gin-
gival biopsy, can help conrm the diagnosis of TTP in
30 50% of the cases (5). The diagnostic vascular lesion
consists of platelet microthrombi (ne granular in appear-
ance) with overlying proliferative endothelial cells that are
positive for periodic acidSchiff and Giemsa stains on
light microscopy. The purpose of the current observational
study was to identify and characterize the clinical features
of patients with SLE with and without MAHA, separate
TTP from SLE exacerbation, and delineate treatment.
Patients and Methods
Study population. The study cohort consisted of 114
consecutive patients who fullled at least 4 of the Ameri-
can College of Rheumatology revised criteria for SLE (6).
After obtaining an Institutional Review Boardapproved
informed consent, patients medical records were retro-
spectively reviewed between January 2001 and July 2001,
and the patients completed a series of questionnaires and
underwent physical examination and serologic testing.
Demographic, clinical, and immunologic data were ob-
tained at the baseline visit and then every 6 months until
completion of the study in October 2003 for those patients
with SLE exhibiting MAHA. The mean SD age was 41
14 years (range 1774 years), 104 were African American
females, 4 were Hispanic females, 2 were African Ameri-
can males, and 4 were white females. The mean SD
disease duration was 6 7 years (range 0 33 years).
Clinical variables evaluated included fever, Raynauds
phenomenon, serositis, arthritis, thrombosis, neurologic
abnormalities, pregnancy loss, and mucocutaneous nd-
ings. For patients with a reported history of hospitaliza-
MAHA: SLE Exacerbation or TTP?
Table 1. Patient characteristics*
SLE without MAHA
Variables
Age, mean/range years
Sex, female/male
Race
African American
White
Hispanic
Disease duration, mean/range years
SLEDAI score, mean/range
Autoantibodies
Anti-Sm
Anti-RNP
Anti-dsDNA
Anticardiolipin
Anti-SSA/SSB
* SLE systemic lupus erythematosus; MAHA microangiopathic hemolytic anemia; SLEDAI
Systemic Lupus Erythematosus Disease Activity Index; anti-dsDNA anti double-stranded DNA.
tion, charts were reviewed to determine what treatments
were implemented during the hospital stay. Laboratory
studies included complete blood count; renal prole; he-
patic prole; urinalysis; antinuclear antibodies by indirect
immunouorescence (IIF); anti double-stranded DNA an-
tibodies by IIF against Crithidia luciliae; anti-Sm; anti-Ro/
SSA; anti-La/SSB; anti-RNP by immunodiffusion; and C3
and C4 serum levels, IgG, IgM, and IgA antiphospholipid
antibodies by enzyme-linked immunosorbent assay. Mark-
ers of hemolysis were documented including elevated re-
ticulocyte count, elevated indirect bilirubin level, elevated
serum lactate dehydrogenase, reduced serum haptoglobin,
a positive Coombs test result, and the presence of schis-
tocytes on peripheral smear. Clinical disease activity at
baseline and during the month preceding the study visit
was measured using the Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI) score. In addition, pa-
tients with SLE were divided into MAHA-positive and
MAHA-negative groups.
Statistical analysis. Two group comparisons of contin-
uous data were assessed using nonparametric tests (chi-
square and Mann-Whitney). Categorical data were com-
pared using Fishers exact test. A GraphPad In Stat
software program (GraphPad Software, San Diego, CA) was
used to perform the analysis.
Results
A total of 114 consecutive patients with SLE were in-
cluded in the study. Fifteen patients (13%) were found to
have laboratory features of MAHA, and all of them had a
negative Coombs test result. All 15 patients with MAHA
had a history of hospitalization for SLE exacerbation, TTP,
or TTP-like illness. Of these, 5 patients exhibited 1 of the
classical features of TTP, 4 patients exhibited 2 features, 2
patients exhibited 3 features, 2 patients exhibited 4 fea-
tures, and 2 patients exhibited all 5 features, as indicated
in Table 1. The 5 patients that exhibited only 1 feature of
TTP had isolated MAHA. Four patients exhibited central
983
SLE with MAHA
(n 99) (n 15) P
40/1575 35/2057 0.0120
95/4 14/1
92 14
3 1
4 0
9.5/135 5.8/012
6.4/056 15.3/035 0.0006
15 5 0.0149
24 7 0.0065
37 8
18 2
31 8
nervous system (CNS) involvement (2 with coma and 2
with mental confusion). All patients exhibited thrombocy-
topenia (100,000/l) and hemolytic anemia; however,
none had platelet counts 50,000 l or hemoglobin 8
gm/dl (data not shown). Low levels of anticardiolipin an-
tibodies (mostly IgA and IgG) were seen in similar fre-
quency in both groups (data not shown). In this subset of
patients, age 35 years, presence of Sm antibodies, and
presence RNP antibodies (P 0.0120, P 0.0149, and P
0.0065, respectively) were associated with higher inci-
dence of MAHA. SLEDAI scores were signicantly higher
(P 0.0006) in patients exhibiting features of MAHA
(Table 1).
During hospitalization, all 15 patients with MAHA
showed a favorable clinical response to pulse methylpred-
nisolone either alone or in combination with other thera-
pies. Seven of 15 patients responded to methylpred-
nisolone alone, 4 of 15 responded to methylprednisolone
in combination with plasmapheresis, 2 of 15 responded to
methylprednisolone in combination with immunosup-
pressive therapy, and 2 of 15 responded to methylpred-
nisolone in combination with both plasmapheresis and
immunosuppressive therapy (Table 2). The favorable re-
sponse was evidenced by improvement in abnormal clin-
ical ndings, disappearance of schistocytes on peripheral
smear, and improvement in all laboratory abnormalities
including erythrocyte sedimentation rate and hemolysis
parameters. The mortality rate among these patients was
zero. At the 3-year followup, none of the patients with SLE
and MAHA exhibited a relapse.
Discussion
The association of TTP with SLE is rare and appears to be
more common in children than in adults (7). In adults, SLE
develops before the onset of TTP in most cases (73%); in
15% of patients, especially in children, SLE and TTP
occur concomitantly, and in 12% TTP precedes the diag-
nosis of SLE (8). In our patients, SLE was present 112
years before the onset of TTP in all cases, the degree of
 984

Table 2. Characteristics of hospitalized patients*

Intervention
Features of TTP Other
Disease SLEDAI High-dose immunosuppressive
Age/sex duration, years score MAHA Thrombocytopenia Neuro Renal Fever corticosteroid Plasmapheresis therapy

32/F 12 10
27/F 4 8
37/F 9 0
44/F 12 10
53/F 7 9
51/F 7 5
57/F 8 17
24/F 6 26
25/F 1 20
35/F 6 23
24/F 3 35
34/F 1 18
20/F 1 19
29/F 3 15
30/F 5 12

* TTP thrombotic thrombocytopenic purpura; SLEDAI Systemic Lupus Erythematosus Disease Activity Index; MAHA microangiopathic hemolytic anemia; neuro neurologic; yes;
no.
Intravenous immunoglobulin.
Dold et al
MAHA: SLE Exacerbation or TTP?
thrombocytopenia was moderate, and none of the patients
exhibited a platelet count 50,000/l. Also, the patients exacerbation, these clinical associations will remain a
clinical manifestations were present to a variable degree
prior to their exacerbation. More importantly, no patient
experienced a relapse during the 3-year followup.
In classic TTP, most patients exhibit the complete pen-
tad of clinical features; 70% display some evidence of
renal disease; and 85% present the triad of MAHA,
thrombocytopenic purpura, and neurologic involvement.
In contrast, most of our patients (73%) exhibited 3 clin-
ical manifestations suggestive of TTP (9). These ndings
suggest a true SLE exacerbation rather than de novo TTP.
Although MAHA has been described as an uncommon
occurrence in SLE (3,4), we found a 13% incidence in an
unselected group of patients, all African American fe-
males, that was associated with higher SLEDAI scores,
younger age, and anti-Sm and anti-RNP antibodies. Of
interest, the presence of both anti-Sm and anti-RNP anti-
bodies occurs more frequently in African American pa-
tients with SLE, and rising titers of Sm antibodies have
been associated with disease ares and/or more active SLE
(10 12). The occurrence of MAHA in patients with SLE
should not be that surprising in view of the endothelial
cell and/or vascular damage seen in SLE secondary to
immune complex deposition; autoantibodies; platelet ab-
normalities; and disorders of brinolysis, presence of hy-
pertension, and also possible presence of antiphospho-
lipid antibodies, all of which can be seen with SLE
exacerbation (13). The specic role of antiphospholipid
antibodies requires further study, although in this study
population their frequency was similar in both groups
with or without MAHA (14,15).
Total plasma exchange or plasmapheresis is the stan-
dard treatment for TTP (16). On the contrary, the rst line
therapeutic modality of SLE exacerbation is high-dose cor-
ticosteroids with or without immunosuppressive therapy;
furthermore, plasmapheresis is not benecial in managing
severe SLE nephritis (17). A TTP-like presentation, as seen
in our SLE population, is usually treated with urgent plas-
mapheresis. However, this procedure was only used in
less than half of our entire patient cohort (40%), speci-
cally in patients with neurologic involvement, i.e., coma (2
patients) and mental confusion (2 patients). All 15 patients
received high doses of intravenous steroids for 3 days
followed by 60 mg of prednisone by mouth. Only 4 pa-
tients received other immunosuppressive therapy. The
outcome, however, remained the same in all patients irre-
spective of the treatment given.
The present study shows that MAHA may occur in SLE
exacerbation with or without all of the classic features of
TTP, and that MAHA carries a better prognosis. In most
cases, clinical and laboratory response to high-dose corti-
costeroids with or without other immunosuppressive ther-
apy is favorable, and plasmapheresis is usually not indi-
cated. At times, however, overlapping features, i.e., severe
CNS involvement, make TTP indistinguishable from SLE
exacerbation, and this may require the use of plasmaphere-
sis. Until a denite, prospective, control study of the as-
sociation of SLE with TTP is performed, or a denite test
985
becomes available to differentiate MAHA, TTP, and SLE
challenge.
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