Evans syndrome: a study of six cases with

review of literature
Kajal Kiran Dhingra1, Deepali Jain1, Shramana Mandal1, Nita Khurana1,
Tejinder Singh1 and Naresh Gupta2
1

Department of Pathology and 2Department of Medicine, Maulana Azad Medical College and Lok
Nayak Hospital, Bahadur Shah Zafar Marg, New Delhi 110002, India
Evans syndrome is an uncommon condition characterised by simultaneous or sequential
development of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA)
with a positive direct antiglobulin test (DAT) in the absence of a known underlying aetiology. The
great majority of patients with Evans syndrome have a chronic relapsing course despite
treatment, which is associated with significant morbidity and mortality. We reviewed the clinical
and laboratory features of six patients with Evans syndrome. All patients had thrombocytopenia,
bleeding symptoms and haemolytic anaemia with positive direct Coombs test at presentation. We
discuss the aetiopathogenic, clinical, therapeutic and natural history of Evans syndrome.
Keywords: Evans, thrombocytopenia, haemolytic, anemia, autoimmune

Introduction
In 1951, Evans and colleagues described a group of
patients whose clinical course was characterised by
immune thrombocytopenia and autoimmune haemolytic anaemia that varied in course and duration with
frequent spontaneous remissions and exacerbations.
The combination of direct Coombs positive haemolytic anaemia and immune thrombocytopenia without any obvious underlying aetiology defines patients
with Evans syndrome.1 Since the incidence is
unknown and there is paucity of literature regarding
this syndrome from Indian population, we studied six
patients of Evans syndrome along with their detailed
clinical and laboratory features and the outcome.2,3

Materials and method

This study was conducted in department of
Pathology, Maulana Azad Medical College and
associated Lok Nayak Hospital and included six
new patients of Evans syndrome diagnosed from
January 2006 to December 2007.The diagnosis was
made on the basis of medical history, physical

examination and detailed laboratory features.

Clinical features recorded were signs of thrombocytopenia including purpura, petechiae, ecchymoses,
mucosal bleeds and signs of anaemia such as pallor,
fatigue and light-headedness. The presence of jaundice indicated haemolysis. Laboratory investigation
included biochemical parameters for evidence of
haemolysis such as direct and indirect hyperbilirubinemia, serum LDH and haptoglobin, urinalysis for
bilirubin. Complete hemogram with a peripheral
smear examination was carried out along with a
reticulocyte count. Bone marrow examination was
carried out to rule out other causes of bicytopenias.
Direct and indirect Coombs test was also performed.
Serology was carried out for Cytomegalovirus, HIV,
hepatitis A, B, C and Epstein Barr virus infection.
Tests for anti-nuclear, anti-double stranded DNA
antibodies along with lupus anticoagulant and anticardiolipin antibodies were carried out to rule out an
underlying lupus erythematosus. The clinical and
laboratory data were tabulated (Tables 1 and 2).

Results and observations

Correspondence to: Deepali Jain, Department of Pathology, Maulana
Azad Medical College, New Delhi 110002, India
Email: deepalijain76@gmail.com

356

W. S. Maney & Son Ltd 2008

Received 10 March 2008; accepted 25 April 2008
DOI 10.1179/102453308X343518

The patients ages ranged from 9 to 30 years with a

mean of 24.83 years; four patients were females and

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Dhingra et al.

Evans syndrome: a study of six cases

Figure 1 Peripheral smear showing spherocytic red cells,

diminished platelets with giant forms (Giemsa,
6400)

Figure 2 Bone marrow aspirate smears showing normoblastic erythroid hyperplasia, with spherocytes
in the background (Giemsa, 6400)

two were males. Clinically symptoms of bleeding were

seen in four cases; however, all patients had
thrombocytopenia with a mean platelet count of 50
6 109/l. There was no evidence of coincidental or
precipitating infections or immune disorders. Pallor
was present in all cases and mean haemoglobin was
5.05 g%. Jaundice was seen in two of the patients
with a mean indirect bilirubin of 5.5 mg%. The LDH
was increased (mean: 424 U/l) and haptoglobin levels
were reduced (mean: 7/dl). Urinalysis showed darkyellow urine and was negative for bilirubin. All
patients had a positive direct Coombs test for warm
type reactive anti-IgG and anti-C3d at the time of
presentation. Peripheral smear showed anisopoikilo-

cytosis with the presence of spherocytes, polychromatophils and nucleated red cells (range: 732
nucleated RBCs/100 leukocytes) and diminished
platelets with giant forms (Fig. 1). There was
reticulocytosis (mean corrected reticulocyte count:
23.66%) in all the cases. The total and differential
leukocyte count was normal. Haemoglobin electrophoresis showed a normal AA pattern. Bone marrow
aspirate smears in all six cases showed hypercellular
marrow with moderate erythroid hyperplasia
(Fig. 2). Myelopoiesis was normal and there was
megakaryocytic hyperplasia including clusters at
places with presence of immature megakaryocytes
(Fig. 3). In all cases, the serology was negative for
CMV, HIV, hepatitis A, B, and C and Epstein Barr
virus infection. Anti-nuclear and anti-double stranded
DNA antibodies were also negative in all cases.
Based on Coombs positive spherocytic haemolytic
anaemia and thrombocytopenia with reactive marrow changes, a diagnosis of Evans syndrome was
made.
All the patients were started on steroid therapy
and intravenous immunoglobulin, only one of our

Table 1 Clinical manifestations of 6 patients with Evans

syndrome
CASE

Age (years)
Sex
Purpura / Petechiae/Ecchymoses
Mucosal bleeding
Pallor

23
M
2
z
z

27
F
z
z
z

9
F
z
z
z

50
F
z
2
z

10
M
z
2
z

30
F
2
z
z

Table 2 Laboratory features of patients with Evans syndrome

CASE

Hemoglobin (gm%)
TLC (per mm3)
Platelets (per mm3)
Reticulocyte count
Peripheral blood smears
Nucleated RBCs (/100 WBC)
Spherocytes
Antiglobulin test (Coombs)
Antiplatelet antibodies
Viral serology
Anti-nuclear and anti- double stranded DNA antibodies

5.3
11 200
56104
15%
NCNC
10
z
z
z
2
2

6.2
5600
36104
11%
MicHC
7
z
z
z
2
2

5.0
7200
56104
33%
MicHC
27
z
z
z
2
2

6.5
8900
66104
38%
MicHC
32
2
z
2
2
2

7.3
9500
76104
25%
NCNC
18
z
z
z
2
2

4.5
8600
46104
20%
MicHC
12
z
z
z
2
2

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Evans syndrome: a study of six cases

Figure 3 Bone marrow aspirate smears showing megakaryocytic hyperplasia with hypolobated and
dwarf forms (Giemsa, 6400)

patients has achieved remission and the rest of them

continue to have cytopenias.

Discussion
Robert Evans first described an association between
idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia in 1951. Since the syndrome is rare and sporadically reported, exact
frequency is difficult to determine.1 Pirofsky estimated the minimal annual incidence of immune
haemolytic anaemia of one case in 80,000 US
residents.2 No study has quoted the incidence in
India and there are very few reports of Evans
syndrome from the Indian subcontinent.3 The six
cases we have studied presented to a tertiary care
setting in a span of 2 years. Familial occurrence is
extremely rare4 and we found no family history in
any of our cases.
Evans syndrome is predominantly a disease of
paediatric age group though it has been reported in
older individuals at a much lower frequency.5 In a
1997 survey by American haematologists, the median
reported age at diagnosis was 7.7 years (range: 0.2
26.6 years). The age of presentation in our study
ranged from 9 to 30 years with the mean age of 24
.83 years which is higher than that observed in
Western literature.6 Only one of our case was in the
paediatric age group (case 3), the rest were adults. No
gender predilection is known though autoimmune
haemolytic anaemia affects boys more frequently
than girls in a ratio of 1.4 : 1. Among adults, Evans
syndrome is known to affects women more often than
men.7 In our experience, there were four females and
two males with a F/M ratio of 2 : 1.

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Evans syndrome presents either with features

of thrombocytopenia such as purpura, petechiae,
ecchymoses and mucosal bleeds in form of menorrhagia, haematuria and gastric bleed or with features
of anaemia such as pallor, fatigue and lightheadedness. Rarely concurrent symptoms of both
autoimmune haemolytic anaemia and autoimmune
thrombocytopenia may be seen at presentation
which is known as the mixed type Evans syndrome.8
Four of our patients at presentation had clinical
evidence of bleeding indicating significantly
lowered platelet count. The mean platelet count was
50 6 109/l. Pallor and weakness were seen in all our
patients. The haemoglobin was low in all the cases
with a mean of 5.05 g%. Thus, features of concurrent
autoimmune haemolytic anaemia and thrombocytopenia (mixed type) were seen in four patients.
Biochemical parameters including serum bilirubin,
LDH and serum haptoglobin indicated features of
haemolysis.
Peripheral blood smears showed microcytic hypochromic picture in four cases and normocytic red cells
in two cases. Along with this, there was anisocytosis,
poikilocytosis and nucleated red cells and polychromatophils indicating accelerated erythropoeitic
response from the bone marrow. Spherocytes were
seen in all cases and in fact pointed to a suspected
autoimmune aetiology of haemolysis guiding further
investigations. Reticulocyte count was elevated with a
mean reticulocyte index of 23.66%. Platelets were
diminished in all the six cases with the presence of
giant platelets indicative of peripheral destruction
and accelerated thrombopoeisis, hence a probable
immune mediated destruction.
A bone marrow aspiration is often necessary
because it rules out aplastic anaemia or an infiltrative
disorder. It is indicated when patients initially present
with pancytopenia, however, it is not essential in
classic cases of Evans syndrome when patients
present with autoimmune haemolytic anaemia or
immune thrombocytopenia. Marrow shows mild to
moderate erythroid hyperplasia although occasionally there may be hypoplasia. Normal to increased
numbers of megakaryocytes are present and confirm
that increased destruction of platelets in the peripheral blood is the cause of thrombocytopenia.9 In all
our cases, the bone marrow aspirate showed hypercellular marrow with moderate erythroid hyperplasia. The erythroid reaction was normoblastic in
five cases and megaloblastic in one case probably
due to a coexisting vitamin B12/Folate deficiency.
Myelopoiesis was unremarkable. In all the six cases,

Dhingra et al.

there was megakaryocytic hyperplasia with the

presence of dwarf, hypolobated and immature forms
along with megakaryocytes in clusters.
A fully developed Evans syndrome should be
associated with a Coombs positive haemolytic
anaemia (confirming antibodies against red cells)
which is essential for definitive diagnosis.9 Coombs
test was performed in all the cases after preliminary
biochemical and haematological investigation and a
positive Coombs test formed the mainstay of
diagnosis. Similarly for confirming the immune
mediated thrombocytopenia, antiplatelet antibodies
to platelets were tested. Five out of six patients had
positive antiplatelets antibodies.
Concomitant conditions of immune dysfunction
have often been reported in cases of Evans syndrome,
suggesting a common pathogenetic mechanism. Since
Evans syndrome is a diagnosis of exclusion, confounding disorders such as viral infections, rheumatologic diseases, diabetes mellitus, HIV, organ
transplantation and malignancies which also present
with autoimmune cytopenias, must be ruled out.10,11
Zuelzer et al. suggested that patients with Evans
syndrome have a generalised immune dysregulation
characterised by generalised lymphadenopathy and
abnormal serum immunoglobulins.12 Serology for
viral infections including HIV which could also cause
autoimmune haemolytic anaemia and thrombocytopenia was negative both for IgG and IgM antibodies.
Antinuclear antibody as well as other tests to rule out
an autoimmune disorder was negative in all our cases
ruling out systemic autoimmune disorders that could
present with symptoms of Evans syndrome.13 One of
our patients had diabetes mellitus. There was no solid
or haematological malignancy in any of our cases.
None of the six patients had a history of immunosuppressive condition.
Drug induced Evans syndrome has been reported
to occur with diclofenac and ramipril. The early
recognition of this condition and the prompt
discontinuation of therapy with the drug can be
life-saving. In our study, none of the patients had a
history of preceding medication.14
The aetiology of Evans syndrome remains speculative. An underlying deficiency in humoral or cellmediated immunity may be the causative factor in
Evans syndrome. The occurrence of isolated episodes
of thrombocytopenia and haemolytic anaemia and
the results of in vitro studies have suggested that noncross reacting autoantibodies are targeted at different
antigenic determinants on red cells and platelets.11
Research shows that most patients with Evans

Evans syndrome: a study of six cases

syndrome have decreased levels of serum IgG, IgM

and IgA and decreased in vitro synthesis of IgG
and/or IgM.5 Quantitative abnormalities in T-cells
and immunoglobulins are common.15 Qualitative
abnormalities in form of decreased T-helper and
increased T-suppressor lymphocyte populations have
also been speculated. T- and B-cell function tests for
quantitative immunoglobulins can be carried out to
evaluate for hypogammaglobulinemia and perturbations in T-cell numbers.16 These were not studied in
our institution.
In a national survey, it was found that approximately 2025% of children with autoimmune haemolytic anaemia develop immune thrombocytopenia but
evolution into Evans syndrome is relatively uncommon in patients with ITP.17 Contrary to these data,
Dash et al. confirmed a spectrum like relationship
between primary thrombocytopenia and haemolytic
anaemia in pediatric patients as also observed by
Evans et al. in adults. They observed evidence of
subclinical haemolysis in pediatric ITP patients using
serum haptoglobin measurement and hypothesised
the concept of attenuated form of Evans syndrome.
This also emphasises the significance of obtaining a
Coombs test in all patients newly diagnosed with ITP
and during their follow-up.5
Although rare, Evans syndrome should be suspected and investigated for in patients presenting
with autoimmune haemolytic anaemia or autoimmune thrombocytopenia concurrently or sequentially. Patients of either of these disorders
individually should therefore be thoroughly investigated for the other so as not to miss a diagnosis of
Evans syndrome.
Corticosteroids and/or intravenous immunoglobulins are the first-line therapy, to which most patients
respond; however, relapses are frequent. The secondline therapy includes immunosuppressive drugs.
Danazol and cyclophosphamide may be necessary
because of recurrent anaemia and thrombocytopenia.
Recently, some patients have been treated with
rituximab.18 Splenectomy may also be considered
although long-term remissions are less frequent than
in uncomplicated ITP. For severe and refractory
cases, stem cell transplantation (SCT) offers the only
chance of long-term cure.19
Evans syndrome generally has a chronic course
and is characterised by frequent relapses and remissions.20 The clinical course may be complicated by
frequent exacerbations and outcome is poor in
Evans syndrome patients when compared with
patients of isolated ITP or AIHA.21 We have a short

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Evans syndrome: a study of six cases

follow-up of 12 years in our specialised weekly

haematology outpatient clinic. Only one of our
patients has achieved remission and the rest of them
continue to have clinically evident anaemia and
thrombocytopenia despite steroid and immunosuppressive therapy. Long-term follow-up is also mandatory since there is a substantial risk for
development of other autoimmune problems and
hypogammaglobulinemia.5

2
3

6
7
8

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Evans RS, Takahash K, Duane RT, Payne R, Liu C. Primary

thrombocytopenic purpura and acquired haemolytic anemia: evidence
for a common etiology. AMA Arch Intern Med 1951; 87: 4865.
Pirofsky B. Clinical aspects of autoimmune hemolytic anemia.
Semin Hematol 1976; 13: 251265.
Dash S, Marwaha R, Trehan A. Attenuated form of Evans
syndrome among paediatric ITP patients. Indian Pediatr 2006; 43:
340343.
McLeod AG, Pai M, Carter RF, Squire J, Barr RD. Familial
Evans syndrome: a report of an affected sibship. J Pediatr Hematol
Oncol 1999; 21: 244247.
Wang WC. Evans syndrome in childhood: pathophysiology,
clinical course, and treatment. Am J Pediatr Hematol Oncol
1988; 10: 330338.
Prasad M, Gang C, Winfred W. Evans syndrome: results of
a national survey. Am J Pediatr Hematol Oncol 1997; 19: 433437.
Pui CH, Wilimas J, Wang W. Evans syndrome in childhood. Eur J
Haematol 2006; 76: 526530.
Park CY, Chung CH. A Patient with mixed type Evans syndrome:
efficacy of rituximab treatment. Korean Med Sci 2006; 21: 1115
1116.

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11

12

13

14

References
1

2008

VOL

13

NO

15

16

17

18

19

20

21

Savasan S, Warrier I, Ravindranath I. The spectrum of Evans

syndrome. Arch Dis Child 1997; 77: 245248.
Martino R, Muniz-Diaz E, Arilla M. Combined autoimmune
cytopenias. Haematologica 1995; 80: 305310.
Miller BA, Schultz Beardsley D. Autoimmune pancytopenia of
childhood associated with multisystem disease manifestations.
J Pediatr 1983; 103: 877878.
Zuelzer WW, Mastrangelo R, Stulberg CS, Poulik MD, Pageb RH,
Thompson RI. Autoimmune hemolytic anemia. Natural history
and viral-immunologic interactions in childhood. Am J Med 1970;
49: 8093.
Avcin T, Jazbec J, Kuhar M, Zupancic M, Rozman B. Evans
syndrome associated with antiphospholipid antibodies. J Pediatr
Hematol Oncol 2003; 25: 755756.
Keung YK, Mallarino MC, Cobos E. Drug-induced evans
syndrome. Ann Intern Med 1998; 128: 327
Kakaiya RM, Sherman LA, Miller WV, Katz AJ. Nature of
platelet antibody in Evans syndrome: a case report. Ann Clin Lab
Sci 1981; 11: 511515.
Teachey DT, Manno CS, Axsom KM et al. Unmasking Evans
syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood 2005; 105:
24432448.
Scaradavou A, Bussel J. Evans syndrome. Results of a pilot study
utilizing a multiagent treatment protocol. J Pediatr Hematol Oncol
1995; 17: 290295.
Raetz E, Zecca M, Nobili B et al. Rituximab for the treatment of
refractory autoimmune hemolytic anemia in children. Blood 2003;
101: 38573861.
Beatty PG, Adams RH. Treatment of severe Evans syndrome with
an allogenic cord blood transplant. Bone Marrow Transplant 1997;
20: 427429.
Silverstein MN, Heck FJ. Acquired hemolytic anemia and
associated thrombocytopenic purpura: with special reference to
Evans syndrome. Mayo Clin Proc 1962; 37: 122128.
Ng SC. Evans syndrome: a report on 12 patients. Clin Lab Hematol
1992; 14: 189193.