EVANS SYNDROME
Senior Tawarta Keliat, Andri Iskandar Mardia,
Henny Syahrini Lubis, Savita Handayani, Dairion Gatot, Guntur Ginting
Division Of Hematology & Oncology, Department Of Internal Medicine,
Unversity of North Sumatera / H. Adam Malik Central Hospital
ABSTRAK
Evans syndrome is a rare autoimmune disorder characterized by simultaneous or
sequential presence of a positive anti-globulin test, autoimmune hemolytic anemia
(AIHA) and immune thrombocytopenia (ITP). It is characterized by frequent
exacerbations and remissions within a chronic course.
We reported a 38-years-old female that came to us on 20th September 2014 with
progressive pallor, icteric, passage of tea-coloured urine and generalized weakness with
history of repeated transfusion. Her laboratory examinations revealed a hyperchromatic
anemia, thrombocytopenia, with leucocytosis. Features of hemolysis showed by profound
elevated of reticulocyte and increase of bilirubin and lactate dehydrogenase (LDH). A
definitive diagnosis of Evans syndrome subsequently determined by positive result of
coomb’s test and after having excluded other possible causes.
Patient has received high dosed intravenous steroid therapy as the first line
therapy and cyclosprorin as well as vincristin for the second line. However during the
monitoring, the clinical condition was worsened. The improvement of hemoglobin as well
as platelet were not satisfactory. Patient died after seven days of treatment after
1. INTRODUCTION
Combination of autoimmune haemolytic anaemia and idiopathic thrombocytopenic
purpura is rare. It was first described by Evans and his associates (1951). The patients may
be affected by low levels of all three types of blood cells at one time, or may only have
problems with one or two of them. The specific cause for Evans syndrome is unknown and it
has been speculated that for every case the cause may be different.1,2
There have been no genetic links identified. The course of Evans syndrome varies by
case. The patient may be symptomatic of whatever blood levels are down. If the red blood
cells are down, the problems complained of may be weakness, fatigue, shortness of breath
and the usual things associated with anemia. With low platelets, they are susceptible to
bleeding and major bruising from minor bumps and cuts. With low white blood cells, the
patient has increased susceptibility to infections and difficulty in fighting these infections.
The patient may have problems with one, two or all three of these blood lines, at one time.
The laboratory findings, including those on bone marrow aspirate and study, are compatible
with haemolytic anaemia. Idiopathic thrombocytopenia with the presence of antiplatelet
antibodies was also diagnosed. Serological evidence of autoimmune haemolytic anaemia
(AIHA) is generally obtained by a direct Coomb’s test (DCT). With few exceptions, a
positive DCT is indicative for the presence of autoantibodies, however, DCT negative AIHA
is suspected to constitute up to 5% of all AIHAs. Immune mediated haemolysis can be
confirmed by fluorescent activated cell sorter (FACS) analysis using anti-human IgG or IgM
immunoglobulin.2,3,4
In the United States, Evans syndrome is uncommon but not rare; its exact frequency is
unknown. Familial occurence is rare. In a report from Malaysia by Ng, Evans syndrome was
diagnosed in 12 of 220 adults patients with immune trhrombocytopenia and 102 with
AIHA.5,6 Evans syndrome occurs in individuals of all ages. In a 1997 survey of North American pediatric hematologist, the median reported age at diagnosis was 7.7 years (range
0.2-26.6 years). This late presentation age may indicate that the disease was undiagnosed
until the second presentation of cytopenia, which usually occured months to years after the
first presentation. Evans syndrome in adults has been anecdotally reported. No sexual
predilection is known in Evans syndrome. AIHA affects boys more frequently than girls, in
ratio of 1.4:1. Among adults, however, AIHA affect women more often than men. In a study
2. CASE REPORT
A 38-years-old female presented to us on 20th December 2014 with progressive pallor, jaundice, passage of tea-coloured urine and generalized weakness. She had all of this
symptoms since 2 years ago without bleeding and fever history. At that time, some units of
blood was transfused and she was diagnosed to had hemolytic anemia, but there was no
sufficient medical data at that time of diagnosis. This patient was previously treated with
epoetin alfa, and some food suplements. All medications were stopped since this 3 months as
the disease progress worsen and then she came to us. Ten unit of red blood cell were
transfused in other hospital 3 months ago. There was no history of chronic contact with
chemical material, fever history was unclear. She reported several times of black liquid stool
for about two days which volume 100-200 cc a day.
On physical examination she was found severely pale, subfebrile, tachycardia with
moderate volume pressure, tachypnea, but her blood pressure was found normal and stable,
yellowish icteric, jaundice, spenomegaly matched to schuffner II, striae alba on her abdomen,
pale and cold on extremities, several hematomas on both upper extremities, markly on the site
of blood puncture. No lymphadenopathy was found. Also there was no blood or black stool
on digital rectal examination
Her complete blood examination detected severe anemia (hemoglobin 2,3 g/dL) with
MCV 137,7 fl; MCH 43,4pg; MCHC 31,5 g%, low erythrocyte count (0,53 x 106 /mm3), leucocytosis (21.940/mm3) with normal differential count, reduced platelet count (19.000/mm3). Peripheral blood morphology revealed a polychromatic anemia, anisocytosis, and moderate amount of nucleated red blood cells. Hemostatic panel showed an elevated of
prothrombine time (38,3 sec [R 2,59]), INR 2,5 (but later decreased to 1,41 after treatment),
normal aPTT and TT. Fibrinogen was at borderline level (139 mg/dL) with D-Dimer was
moderately increased (2244 ng/mL) but found increased on several days to >5000 ng/mL.
Bleeding time was found prolonged (10-12 sec). Other laboratory finding include high level
of LDH (1696 IU/L), albumin 2,9, slightly increase of liver enzymes (SGOT 101 U/L ; SGPT
286 U/L), normal gamma-GT (40 U/L) and ALP 74 U/L. Iron profiles showed an increased
of ferritin ( >2000 ng/mL ; SI 187 mg/mL ; TIBC 195 µg/mL) with profound increased of
reticulocyte count (51,61%). Renal function test and electrolyte was found at normal range at
that time.
The Diagnosis of Evans syndrome was then made after laboratory finding detected a
positive direct anti-globulin tes (coomb’s test) and after excluding other possible etiologies
HBsAg (-) ; Anti HCV (-) ; IgM Anti HAV (-), and peripheral blood examination of malaria
was negative. Chest X-ray was normal while ultrasonogram of whole abdomen revealed
hepatosplenomegaly without focal lession and congestion.
As the treatment for this patient, we started an intravenous injection of
methylprednisolon 250 mg bid for three days, and as it’s dose reduced to 125 mg bid on
fourth day, cyclosporin 100mg bid were the added. Vincristine injection 2mg a week for three
weeks were then planned to be given because unfavorable clinical response. We also gave
antibiotic Ceftazidime 1 g every 8 hours and ranitidin intravenous every 12 hours for
prophylactic purpose. Supportive medication were given as transfussion with red blood cell,
single donor platelet and fresh frozen plasma.
After several days of treatment, the patients’s clinical conditon seen worsening.
Tachypnea, icteric, jaundice and weakness became more prominent. The level of
conciousness and hemodynamis changed with fluctuation.
The increasing of patient’s hemoglobin is not as expected by the transfusion procedure. The level of Hb only increase to 4,1 g/dL and dropped again 3 days later to 3,7
g/dL. The platelet also showed similiar manner or even worse. Five days after platelet
transfusion, the number of platelet was only 6000/mm3. Leucocyte count did not change much, but the neutrophil percentage was increasing, however there were still no evidence for
infection.
After seven days of hospitalization, her clinical condition suddenly deteriorates. She
experienced several times of seizure, then unconsciousness and coma. Patient died a few
hours after appearing seizure.
3. DISCUSSION
Evans syndrome is the coexistence of simultaneous or sequential direct
coombs-positive autoimmune hemolytic anemia (AIHA) in conjunction with immune-mediated
thrombocytopenia, with no known underlying etiology. In the initial description by Evans et
al in 1951, the anemia and thrombocytopenia varied with respect to time of onset, course, and
duration.5 Although Evans syndrome seems to be a disorder of immune regulation, the exact pathophysiology is unknown, and the underlying etiology is unclear. Autoantibodies targeting
different antigenic determinants on red blood cells (RBCs) and platelets are assumed to cause
isolated episodes of hemolytic anemia and thrombocytopenia, respectively. The cytopenia
that occur with Evans syndrome may be related to T-cell abnormalities; decreases in helper T
than half (58%) of the patients with Evans syndrome had evidence of lymphoid hyperactivity.
Teachey et al demonstrated that more than half (58%) of the patients with Evans syndrome
might have autoimmune lymphoproliferative syndrome (ALPS). Programmed cell death
(apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell sufrace
protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and
defective expression of either Fas or Fas ligand results in marked overaccumulation of mature
lymphocytes and autoimmune disease in mice. Some study results suggest that defective
lumphocyte apoptosis caused by mutations of Fas gene can result in severe ALPS in humans.
Teachey et al suggests that there may be some overlap between Evans syndrome and ALPS.5 The typical clinical course are chronic and relapsing, and therapy is generally
progressive and poor.5 Patients may present with AIHA or ITP either separately or concomitantly. Neutropenia occurs in up to 55% of patients at presentation or pancytopenia
(14% in a national survey of 42 patients). The development of the second cytopenia may
occur months to years after the first immune cytopenia and may delay diagnosis. Clinical
presentation includes the usual features of haemolytic anaemia: pallor, lethargy, jaundice,
heart failure in severe cases; and thrombocytopenia: petechiae, bruising, mucocutaneous
bleeding. Examination may reveal lymphadenopathy, hepatomegaly and/or splenomegaly.
The lymphadenopathy and organomegaly may be chronic or intermittent and in some cases
may only be apparent during episodes of acute exacerbation.7,8,9
In this case, hemolytic anemia and thrombocytopenia were came simultaneously.
History of anemia with previous transfusion, history of bleeding, livid bruises on the skin,
icteric, jaundice, general weakness, tea-coloured urine, splenomegaly, pale and cold on the
acral of extremities, met the clinical criteria of Evan syndrome.
A full blood count will confirm the presence of cytopenias and a blood film should be
examined for features of AIHA (polychromasia, spherocytes) and to exclude other underlying
diagnoses (malignancies, microangiopathic haemolytic anaemia, congenital haemolytic and
thrombocytopenic conditions). Features of haemolysis should be sought including a raised
reticulocyte count, unconjugated hyperbilirubinaemia and decreased haptoglobins. The direct
antiglobulin test (DAT) is almost invariably positive (although often weakly so), even in the
absence of haemolytic anaemia, and may be positive for IgG and/or complement (C3). The
indirect antiglobulin test may also be positive. other autoimmune conditions, particularly
systemic lupus erythematosis (SLE), should be sought by measuring antinuclear antibody
(ANA), double-stranded DNA (dsDNA) and rheumatoid factor. The most important
flow cytometry is essential in all cases of Evans syndrome. The presence of double negative
(CD4)/CD8), CD3+, TCRab+) T cells has been found to be the most sensitive first-line
screening test for ALPS (and allows differentiation from cases of Evans syndrome).
Autoantibody testing for platelets and granulocytes may be positive but a negative result does
not exclude the diagnosis and routine testing at presentation may not be helpful.7 Bone marrow investigation may be of use in evaluation of Evans syndrome where it is necessary to
exclude infiltrative processes in patients who present with pancytopenia. Otherwise it is not
usually helpful as the findings are non-specific and may be normal or show trilineage
increased cellularity.7,9
In this case, cytopenia came as severe anemia and thrombocytopenia. The peripheral
blood film show polychromatic anemia. No malignant cell was found on her blood. Features
of hemolysis showed by profound elevated of reticulocyte and increase of bilirubin and
lactate dehydrogenase (LDH). A definitive diagnosis of Evans syndrome subsequently
determined by positive result of coomb’s test and after having excluded other possible causes
like systemic lupus erythematosis, malaria, viral infection, malignancies, etc. Unfortunately,
we did not performe several important laboratory examination such as serum haptoglobin,
flow cytometry and total immunoglobulins which could have made a better diagnosis due to
limitation of aour facilities. Bone marrow study in this case was deemed not necessary
because little likelihood of aplastic anemia or infiltrative process diseases.
The management of Evans syndrome remains a challenge. The syndrome is
characterised by periods of remission and exacerbation and response to treatment varies even
within the same individual. Most patients require treatment although occasional spontaneous
remissions have been recorded. Indications for treatment have not been established by
evidence-based studies. However, it is usual and reasonable to treat symptomatic patients
with low counts; as with ITP, not all asymptomatic patients with low counts require treatment
and the decision to treat has to be taken on a case-by-case basis.7
First-line therapy, The most commonly used first-line therapy is corticosteroids and/or intravenous immunoglobulin (IVIG). In the acute setting, blood and/or platelet
transfusions may also be required to alleviate symptoms although their use should be
minimised (fig 1). Corticosteroids Despite the lack of controlled trials demonstrating their
effectiveness, corticosteroids remain the mainstay of treatment for control of the acute,
symptomatic cytopenias with good initial results. The dose of prednisolone used has
generally varied from 1 mg/kg/d to 4 mg/kg/d although a good initial response to megadose
mg/kg/d, 1 week each) has also been reported. Intravenous immunoglobulin For those
patients for whom steroids are ineffective or who require unacceptably high doses to remain
in remission or in whom toxicity results, the most commonly used first-line therapy is IVIG.
Various doses have also been suggested, most commonly 0,4 g/kg/d for 4 d, with some
authors recommending higher doses (up to 5 g/kg) to improve response in AIHA.7
Second-line therapy, These include immunosuppressive agents [cyclosporin, mycophenolate mofetil (MMF) and danazol], the monoclonal antibody (rituximab,
alemtuzumab), chemotherapy (vincristine, cyclophosphamide) and other uncommonly used
modalities (azathioprine, antilymphocyte globulin, 6-thioguanin, tacrolimus, anti-D and
plasmapharesis). Splenectomy may also be considered a second-line treatment.7
Third-line therapy. The majority of patients will respond to first or second-line therapy, at least for many years. However, for patients with severe, relapsing disease despite
second-line therapy, other options will have to be considered. The main third-line options are
cyclophosphamide, alemtuzumab or stem cell transplantation (SCT).7
In this case, we gave a high dose of intravenous methylprednisolone (250mg bid) for
three days, and further reduced to 125mg bid in line with the addition of cyclosporin 100mg
bid. Vincristine injection 2 mg a week for three weeks were then planned to be given because
unfavorable clinical response. We also gave antibiotic ceftazidime 1 g every 8 hours and
ranitidin intravenous every 12 hours for prophylactic purpose. Supportive medication were
given as transfussion with red blood cell, single donor platelet and fresh frozen plasma.
Long-term survival data are limited. In patients followed for a median range of 3-8
None of these patients developed any malignancy.2 Reccurences of thrombocytopenia and anemia are common, as are episodes of hemorrhage and seious infections. In a national
survey by mathew et al, reccurences of thrombocytopenia were documented in 60% of Evans
syndrome patients; the number of reported episodes was 1-20. AIHA recurred in 31% of
patients; the number of episodes ranged from 1-8. Neutropenia recurred in 15% of patients.
In this case, patient has received first line therapy (methylprednisolon), second line
therapy (cyclosporin) and supportive treatment. However during the monitoring, the clinical
condition was worsened. The improvement of hemoglobin as well as platelet were not
satisfactory. Patient died after seven days of treatment after previously having several
seizures and then fell into coma and death.
CONCLUSION
Evan’s Syndrome is a rare chronic, relapsing and refractory disease but sometimes may present acutely with mortality rate is up to 36%. In patients presenting as immune
thrombocytopenia and anemia with haemolytic component, DAT is mandatory.7,10 Despite the fact that Evans syndrome is a condition which is not easily treated, but trials with
combinations of multi-agent therapy should remain continued, especially for new agents and
modalitis such as monoclonal antibody and splenectomy. For severe and refractory cases,
hematopoietic stem cell transplantation offers the only chance for cure, with limited data
showing that allogeneic hematopoietic stem cell transplantation may be superior to
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