Thalassemia Patients and Friends
Discussion Forums => Thalassemia-related Issues => Topic started by: Andy Battaglia on February 13, 2009, 07:00:26 AM
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In this case the transfused blood seems to set off a hemolysis that kills both transfused blood cells and the red blood cells that were already in the patient, leading to a lower Hb level after being transfused. This case was treated successfully with the chemotherapy drug, cyclophosphamide (cytoxan). The risk of the chemo drug is outweighed by the danger of continued hyperhemolysis.
http://www.ajts.org/article.asp?issn=0973-6247;year=2009;volume=3;issue=1;spage=26;epage=27;aulast=Morawakage
Hyperhemolysis in a patient with
β-thalassemia major
R. Lakmali Morawakage, B. J. C. Perera1, P. D. N. Dias1, S. K. Wijewardana1
Abstract:
A case of hyperhemolysis in a 2-year-old boy with β thalassemia major was noted. After several transfusions, he
developed hyperhemolysis with a positive (C3d only) direct antiglobulin test (DAT) and no clinically significant RBC allo or
auto-antibodies. (There was a weak cold antibody, showing a narrow thermal range). Because there was no significant
improvement with steroid and immunoglobulin infusions, cyclophosphamide therapy was tried with notable success.
Key words:
β- thalassemia, direct antiglobulin test, hyperhemolysis, transfusion
Introduction
The term hyperhemolysis is applied when the
post-transfusion hemoglobin (Hb) level is less than
the pre-transfusion level, suggesting destruction
of both the patients own red blood cells (RBCs)
and the transfused RBCs. The mechanism of
hyperhemolysis is not well understood although it
has been well described in patients with sickle cell
disease. Transfusion of antigen-negative cross-match
compatible RBCs does not prevent hyperhemolysis.
Serologic studies of post-transfusion and follow-up
samples may show a negative or positive (complement
only) direct antiglobulin test and usually no RBC
antibodies, leaving the hemolysis unexplained (i.e.,
there is no evidence of red cell antigen + antibodymediated
immune destruction). In a mild form, the
option is to stop transfusion to avoid exacerbating the
hemolysis. In severe forms, further transfusions have
been given successfully only with concurrent IVIg
and IV steroid therapy. Recurrent hyperhemolysis
is fortunately rare and is unpredictable.
Awareness of the potential for recurrent
hyperhemolysis is important because, where possible,
alternative therapy should be sought and transfusion
should be avoided. For patients with past history
of recurrent hyperhemolysis, if transfusions are
required, use of concurrent IVIg and steroids should
be considered. Note, however, that because infusion
of IVIg has been associated with renal toxicity,
thrombosis and estimated 0.6% risk of stroke, its use
should be selective.
Case Report
A two-year-old Sri Lankan Tamil boy, diagnosed
with β thalassemia major 6 months ago, was
transferred to the tertiary care hospital for children
for the management of severe anemia. His hemoglobin
on arrival was 3.1 g/dl, even though he had received
600 ml of RBC transfusions on two consecutive days,
Þ ve days ago. Six months earlier, when he was Þ rst
diagnosed with β thalassemia, he was started on
monthly RBC transfusions that lasted three months,
and then the transfusion interval was gradually
reduced to every few days due to very low pretransfusion
hemoglobin levels.
At the time of transfer, the patient was severely
pale and deeply icteric with a large spleen (8 cm) and
liver (3 cm) but there were no signs of heart failure.
The diagnosis of β thalassemia major was conÞ rmed
by high performance liquid chromatography
(HPLC). Both parents were diagnosed as having the
thalassemia trait. Transfusions with leukoreduced
red cells matched for Rh and Kell antigens were
given at 4-6 day intervals. The patient developed
fever on and off but his clinical condition generally
remained the same with high total serum bilirubin
of 137 μmol/l with indirect serum bilirubin of 115
μmol/l. Coagulation screen, renal function tests
and serum proteins were normal, and there was no
evidence of G6PD deÞ ciency or malarial infection. A
blood culture was negative. A bone marrow biopsy
showed a poorly managed major hemoglobinopathy
with increased iron stores and no evidence of any
storage diseases.
Serological investigations confirmed his blood
group as O R1R1 with a phenotype of K-, k+, Fya+,
Fyb+, Jka+, Jkb-, Lea-, Leb+, MMss. There was a weak
cold autoantibody reactive only in undiluted serum
in NISS below 20oC. The DAT was positive (2+) with
C3d only. Unexpected antibodies were not detected
in any of the serum samples. An eluate could not be
done due to the low Hb level.
Despite transfusion with cross-match compatible,
leukoreduced and phenotype-selected blood in doses
[Downloaded free from http://www.ajts.org on Thursday, February 12, 2009]
Asian J Transf Sci - Vol 3, Issue 1, January 2009 27
of 20 ml/kg, the patient continued to hemolyze. Oral prednisolone
and azothioprin were given with no apparent improvement.
Azothioprin was stopped due to elevated liver enzymes and the
discovery of free ß uid in the abdomen. Addition of intravenous
immunoglobulin at 0.4 g/kg/day for 7 days showed no therapeutic
beneÞ t. High doses of cyclophosphamide therapy at 50 mg/kg were
given in two doses, three days apart. During the cyclophosphamide
therapy, the size of the spleen reduced to 4 cm, and the DAT became
negative for C3d. A weakly reactive DAT with anti-IgG was noted,
possibly attributable to immunoglobulin therapy. While receiving
initial cyclophosphamide therapy, the patient developed a lower
respiratory tract infection with positive radiological Þ ndings that was
successfully treated with intravenous antibiotics. After the second
dose of cyclophosphamide, the patient became more lethargic with
Hb level of 2.7 g/dl. Transfusion of Rh and Kell phenotype-matched
RBCs was given in a dose of 20 ml/kg. His post-transfusion Hb was 6
g/dl with no evidence of hyperhemolysis and an obviously improved
clinical condition. Hemoglobin was around 6 g/dl for about three
weeks and was followed by regular monthly transfusions.
Discussion
A case of hyperhemolysis causing severe anemia in a patient with
β thalasemia major, who continued to hemolyze despite use of
leukoreduced and phenotype-matched transfusions was reported.
He had no demonstrable clinically signiÞ cant RBC antibodies at any
time but showed a positive DAT with C3d only which disappeared
after immunosuppressive therapy with cyclophosphamide. The exact
pathogenesis of hyperhemolysis is complex and poorly understood.
It involves destruction of both transfused and autologous RBCs.
Hyperhemolysis was Þ rst recognized in patients with sickle cell
disease.[1-3] It is rarely reported in thalassemic patients.[4] Some
theories that have been proposed based on observations principally
of sickle cell patients who are chronically transfused include
suppression of erythropoiesis, hyperactive macrophages causing
bystander hemolysis, defective regulation of complement, and
antibodies below the limit of detection of current serologic method,
IgA antibodies or possibly HLA antigen-antibody reactions. In sickle
cell disease patients, hyperhemolysis is commonly associated with
reticulocytopenia, which may reß ect suppression of erythropoiesis.
[2] However, responses to steroids suggest something more than
erythropoiesis suppression may be involved in its pathogenesis.
In the absence of RBC antibody-mediated hemolysis, hyperactive
macrophages could be responsible for destruction of the patients
own red cells as well as the transfused cross-match compatible
cells.[3]
The RBCs of patients with sickle cell anemia have defective
regulation of the complement membrane attack complex.[5] This
defect may make sickle cells more susceptible to bystander
hemolysis in which immune complexes cause lysis of bystander,
antigen negative red cells.[1,2,6,7] In this case there is no detectable
alloantibody. Red cell destruction can occur by antibody-dependent
cell mediated cytotoxicity (ADCC) with levels of antibody that
are below the serological detection threshold. Cell mediated lysis
independent of antibody may occur for red cell antigens in the
absence of detectable antibody.[8-10] Some red cells express HLA
antigens and HLA antibodies and can cause red cell hemolysis.[11,12]
Hemolysis due to HLA antigen and antibody reaction by hyperactive
macrophages and bystander hemolysis of HLA antigen negative
transfused cells could be another possible mechanism of red cell
lysis with no detectable red cell alloantibody. [13] Incomplete IgA
antibodies can produce hemolysis with negative Þ ndings using
common serological techniques.[14] 51Chromium-labelled red blood
cell survival studies, if available, should be considered whenever
an unexplained hemolytic transfusion reaction occurs, or when an
expected red blood cell alloantibody cannot be demonstrated by in
vitro laboratory studies.[15]
This patients dramatic response to cyclophosphamide suggests
that cyclophosphamide can be used in patients with hyperhemolysis
where transfusion is unavoidable due to other associated medical
conditions.
References
1. Garratt y G. Severe reactions associated with transfusion of patients
with sickle cell disease. Transfusion 1997;37:351-61.
2. Petz LD, Calhoun L, Shulman LA, Johnson C, Herron RM. The
sickle cell haemolytic transfusion reaction syndrome. Transfusion
1997;37:382-92.
3. Win N, Yeghen T, Needs M, Chen FE, Okpala I. Use of intravenous
immunoglobulin and intravenous methylprednisolone in
hyperhaemolysis syndrome in sickle cell disease. Haematology
2004;9:433-6.
4. Grainger JD, Marker Y, McManus A, Wynn R. Refractory hyperhaemolysis
in a patient with B-thalasaemia major. Transfus Med
2001;11:55-7.
5. Test ST, Woolworth VS. Defective regulation of complement by the
sickle erythrocyte: Evidence for a defect in control on membrane
att ack complex formation. Blood 1994;83:842-52.
6. Sirchia, G, Morelati F, Rubulla P. The sickle cell haemolytic transfusion
reaction syndrome. Transfusion 1997;37:1098-9.
7. King KE, Shirly RS, Lankiewicz MW, Young-Ramsaran J, Ness PM.
Delayed hemolytic transfusion reactions in sickle cell disease: Simultaneous
destruction of recipients red cells. Transfusion 1997;37:376-
81.
8. van der HART, Engelfriet CP, Prins HK, van Loghem J. A haemolytic
transfusion reaction without demonstrable antibodies in vitro. Vox
Sang 1963;8:363-70.
9. Baldwin ML, Barrasso C, Ness PM, Garratt y G. A clinically signiÞ -
cant erythrocyte antibody detectable only by 51Cr survival studies.
Transfusion 1983;37:357-61.
10. Gilsanz F, De La Serna J, Molto L, Alvarez-Mon M. Haemolytic
anaemia in chronic large granular lymphocytic leukemia of natural
killer cells: Cytotoxicity of natural killer cells against autologous red
cells is associated with haemolysis. Transfusion 1996;36:463-6.
11. Benson K, Agosti SJ, Latoni-Benedett i GE, Lepare GF. Acute and
delayed haemolytic transfusion reactions secondary to HLA alloimmunization.
Transfusion 2003;43:753-7.
12. Panzer S, Matyr WR, Graninger W, Puchler K, Hocker P, Lechner
K. Haemolytic transfusion reactions due to HLA antibodies: A
prospective study combining red cell serology with investigations
of chromium-51-labelled red cell kinetics. Lancet 1987;28:474-8.
13. Win N, Doughty H, Telfer P, Wild BJ, Pearson TC. Hyperhaemolytic
transfusion reaction. Transfusion 2001;41:323-8.
14. Greenberg MS, Jandl JH. The selective destruction of transfused
compatible red cells in patients with splenomegaly. J Lab Clin Med
1975;49:233-45.
15. Davey RJ, Gustafson M, Holland PV. Accelerated immune red cell
destruction in the absence of serologically detectable alloantibodies.
Transfusion 1980;20:348-53.
pdf file attached
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Thanks for the info Andy,this is scary stuff,i hope it won't happen to anyone ever,but being informed is good.
Zaini.