Concurrent Autoimmune Hemolytic Anemia in Thalassemia

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Case Report
Concurrent Autoimmune Hemolytic Anemia in Thalassemia
S Jayanthi
investigated for the cause of intravascular hemolysis and
was given an empirical course of antimalarials and
Hemolysis is chronic and extra vascular in most inherited
broad-spectrum antibiotics. She was then referred to us
hemoglobinopathies1. Occurrence of acute hemolysis in
for further evaluation. Parental screening for thalassemia
congenital hemolytic anemia is rare. Increased frequency
was negative. Hemogram showed hemoglobin of 4 gm/
of transfusion requirement in an otherwise stable,
dl, TLC, DC and platelets were normal. Peripheral film
transfusion dependent hemolytic anemia should alert
showed evidence of hemolysis, but no spherocytosis or
the physician for another cause. A case of concurrent
schistocytes were noted. Complete urine examination
autoimmune hemolytic anemia in a child with
showed mild albminuria and microscopy was normal.
thalassemia is presented.
Urine was positive for hemoglobin by dipstick test.
Electrolytes and renal function tests were normal. Liver
function tests showed a total bilirubin of 9.8 mg/dl with
A two-year old female child was referred to us for
evaluation of recurrent life threatening anemia. She was
conjugated fraction of 5 cm/dl, SGOT was 100 u/l, SGPT
95 U/L, alkaline phosphatase 252IU/l. Smear for
diagnosed to have thalassemia and was on regular
malarial parasites was negative. Coagulogram was
transfusions once in 4 weeks from the age of 6 months.
She was admitted elsewhere for pallor, anasarca and
normal. HIV serology was nonreactive. Sickling test was
negative. Serum ceruloplasmin was 24.8 mg/dl and K F
shortness of breath of one month duration. She was
ring was absent. Direct Coomb’s test was positive. Anti
found to have pallor, hemolytic facies, and anasarca.
The cardiovascular system revealed a functional
nuclear antibodies were negative. Warm antibodies were
absent, cold agglutinins were positive. Osmotic fragility
murmur, chest examination showed bilateral basal
test showed decreased (2-8oC) red cell osmotic fragility.
crepitations and abdominal examination revealed
Urine for hemosiderin was positive. Sucrose lysis tests
moderate hepatosplenomegaly. A diagnosis of
and Ham’s tests were negative. In view of increasing
thalassemia with congestive cardiac failure was made.
transfusion requirement, intravascular hemolysis, DCT
Investigation showed Hemoglobin of 3 gm/dl, total
positivity steroids (prednisolone 2 mg/kg) were started.
leukocyte count 10,000 cells/mm3, differential count was
The hemolysis stopped, hemoglobin was stabilized in 3
normal. Red blood cells showed anisocytosis,
days and increased to 10.9 gm/dl in ten days. She was
microcytosis hypochromia polychromasia, with many
continued on steroids and folic acid. After remaining
tear drop cells, nucleated cells. Leucocytes and platelets
stable for 3 months, hemoglobin started dropping again.
were normal. After two aliquots of packed red cells,
Hemoglobin electrophoresis performed after these three
hemoglobin was 5 gm/dl. She was transfused again.
months showed an Hb A 13.5%, Hb A 2.9%, Hb F 83.6%
The child started having fever, was passing cola colored
suggesting thalasemia. G6PD status was normal. Bone
urine and was found to be icteric after two days. A repeat
marrow examination revealed erythroid hyperplasia
10 ml/kg aliquot of packed cells was given, but the
with increased marrow iron stores suggesting hemolytic
hematocrit failed to raise. The child received a total of
anemia. DNA analysis of the child and parents was
fifteen packed cell transfusions every alternate day to
done. The patient was found to be homozygous for IVS
maintain a hemoglobin at a bare minimum of 5 gm/dl.
1-5(G-C) mutation and both the parents were carriers for
Meanwhile she continued to have evidence of intra
the same mutation. So, an underlying thalassemia was
vascular hemolysis (drop in heamotocrit, icterus, cola
proven beyond doubt and the recent increased
colored urine) every time she was transfused. She was
Department of Pediatrics, Nizam’s Institute of Medical Sciences, Hyderabad 500 082.
Clin. Proc. NIMS l 17 : 2; April 2005

transfusion requirement leading to intravascular
with intravascular hemolysis1. Membrane abnormalities
hemolysis was attributed to an “acquired autoimmune
from sickling and oxidative damage, along with impaired
hemolytic anemia” as Coombs test was positive and she
deformability of sickle cells would lead to hemolysis
responded to steroids dramatically. Now that the
with some intravascular component. Alloimmune
transient “acquired hemolytic anemia” is treated with
hemolytic anemia is mainly due to mismatched blood
steroids she was able to sustain hemoglobin of 10 gm/
transfusion resulting in a catastrophic reaction. Delayed
dl for 3 months and then the hemoglobin started to fall
hemolytic reactions due to minor group incompatibility
revealing the basic disorder. At the end of 4 months
occur three to ten days after a transfusion and usually
hemoglobin dropped to 5gm/dl (in spite of steroids).
caused by low titer antibodies to minor red cell antigens
Since there was no evidence of intravascular hemolysis
leading to extra vascular hemolysis. Compared with
and Coomb’s test was negative, her steroids were tapered
acute transfusion reaction the onset and progression are
off. She is currently requiring transfusion once in 4 weeks.
more gradual6.
So, a diagnosis of “concurrent autoimmune hemolytic
Anemia, reticulocytosis, microspherocytes on peripheral
anemia in thalassemia” was made.
smear and a positive direct Coomb’s test would prompt
the diagnosis of autoimmune hemolytic anemia 1. It is
again subdivided into Warm and Cold hemolytic
Thalassemias are a heterogeneous group of heritable
anemias according to their maximal binding
hypochromic anemias of varying degrees of severity.
temperature. Warm antibodies (IgG) attach to the red
Defective hemoglobin synthesis leads to ineffective
cell surface, which are ingested by macrophages of spleen
erythropoiesis and extravascular hemolysis that is
leaving microspherocytes. Thus these cells are trapped
chronic. Thalassemia major is a transfusion dependent
in splenic sinusoids and removed from circulation. Cold
state with moderate hepatosplenomegaly. Increased
antibodies (IgM) bind to red cell membrane, activate
transfusion requirement, acute anemia and intravascular
complement and deposit C3 on the cell surface. These
hemolysis should arouse a suspicion of an alternate
C3 coated red cells are cleared by macrophages of liver
diagnosis. As the patient is transfused on most occasions
(extra vascular hemolysis). Less frequently, the complete
before being referred, the opportunity to get a pre
complement cascade (C5-C9) is activated resulting in
transfusional hemoglobin electrophoresis done is lost.
insertion of membrane attack complex on the red cell
Immune mediated destruction of red blood cells may
surface leading to intravascular hemolysis 6 .The clinical
result from either autoimmune or alloimmune
pattern of autoimmune hemolytic anemia in children is
antibodies. Likewise they are classified as autoimmune,
predominantly acute, transient type lasting for 3-
alloimmune and drug induced hemolytic anemias.
6months in 70-80% of cases. Corticosteroids are the
Autoimmune hemolytic anemia could be either
mainstay of therapy in severe transfusion dependent
idiopathic, secondary to an underlying disorder like
states. Treatment should be continued until the rate of
infection, other autoimmune states, immunodeficiency
hemolysis decreases, and then the dose is gradually
syndromes and malignancy2,3,4,5. Inherited
reduced and tapered off .The acute variant of idiopathic
hemoglobinopathies are not included as associated
autoimmune hemolytic anemia in childhood varies in
disorders of autoimmune hemolytic anemia. However,
severity but is self-limited. Chronic hemolysis develops
congenital dyserythropoietic anemia and
in 30% of patients with an underlying secondary
myelodysplastic syndromes are reported to have been
associated with concurrent occurrence of autoimmune
hemolytic anemia7,9. There are reports of sinus
In conclusion, this case has some interesting findings.
histiocytosis with massive lymphadenopathy and
Concurrent occurrence of autoimmune hemolytic anemia
disseminated childhood tuberculosis complicated by
in thalassemia has not been reported so far .As the initial
concurrent occurrence of autoimmune hemolytic
parental screening was negative, the fact that the child
anemia8,10. Their concurrent occurrence could be a
has transfusion dependent thalassemia was difficult to
chance association. But, to a clinician it would lead to
believe. After initial stabilization of hemoglobin for 3
confusion. It is more important to differentiate as
months with steroids the course of the disease prompted
management is different in both cases. Secondary causes
us to make the final diagnosis.
of failure to build up hemoglobin after transfusion like
malaria, Clostridium welchii sepsis, mismatched
transfusion reaction, G6PD deficiency states should be
Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic
considered. Intravascular hemolysis, spontaneous or
anemia. Am Fam Physician 2004; 69(11): 2599-2606.
induced is commonly seen with G6PD deficiency. Among
Tabbara IA. Hemolytic anemias. Diagnosis and
the hemoglobinopathies, sickle cell anemia is associated
management. Med Clin North Am 1992; 76(3):649-668.
Clin. Proc. NIMS l 17 : 2; April 2005

Concurrent Autoimmune Hemolytic Anemia in Thalassemia
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Pruss A, Salama A, Ahrens N, Hansen A, Kiesewetter H,
10. Kiran PS, Sowdi VP, Shetty SB, Venugopal U,
Koscielny J, et al. Immune hemolysis-serological and
Parameshwariah S, Dias E, et al. Sinus histiocytosis with
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Address for Correspondence: Dr. S. Jayanthi, Assistant Professor, Department of Pediatrics, Nizam’s Institute of Medical Sciences,
Hyderabad 500 082.

Clin. Proc. NIMS l 17 : 2; April 2005