Cerebrovascular accident in b-thalassemia major (b-TM) and

b-thalassemia intermedia (b-TI)

Mehran Karimi,1 Maryam Khanlari,1 and Eliezer A. Rachmilewitz2*
Chronic hypercoagulable state expressed clinically by thromboembolic events has been described in thalassemia. One of the affected organs is the brain where symptomatic and asymptomatic damage has been
reported. The present report describes seven cases who presented with the signs of cerebrovascular accident (CVA), ve ischemic and two with hemorrhage. Two of them died. All patients were splenectomized,
ve received regular blood transfusions, and their ferritin levels were between 1,200 and 3,000 mg %. In
addition, four patients had congestive heart failure and atrial brillation, and three had Bronze diabetes,
The recommendation on the basis of the results is that well-designed clinical trials are indicated to monitor
asymptomatic brain damage by magnetic resonance imaging in splenectomized patients over the age of
20 years, who are not regularly transfused and have a high risk to develop thromboembolic events. In this
subset of patients, anticoagulant and/or antiplatelet therapy should be considered. Moreover, treatment of
additional complications resulting from iron overload, which may contribute to the etiology of CVA such as
cardiac failure and arrhythmia with or without bronze diabetes, is mandatory. Am. J. Hematol. 83:7779,
C 2007 Wiley-Liss, Inc.
2008. V

Introduction
The standard of care of thalassemic patients, which is
adequate transfusion program together with an effective
iron chelation, has recently improved, resulting in close to
doubling of the average life expectancy [1].
Consequently, more complications are being recognized
including a chronic hypercoagulable state with an increase
in thromboembolic events involving major organs such as
the brain [2]. Asymptomatic cerebrovascular accident (CVA)
and asymptomatic brain damage were reported, inversely
correlated with hemoglobin (Hb) levels and increased with
age [3]. We describe seven cases who presented with the
signs CVA to the Shiraz University of Medical Sciences
Hospital in southwest Iran. The implications of specic contributing factors to the etiology of CVA will be discussed.
Patients and Methods
Between 1991 and 2004, seven patients (ve b-thalassemia major
(TM) and two b-thalassemia intermedia (TI)) out of 1,200 patients
(1,080 TM and 120 TI) presented with signs of thrombotic or hemorrhagic stroke. The pertinent clinical and laboratory data are summarized in Table I.
Patients 1 and 2 were homozygous for the mutation IVSII-I (G ? A),
which is common in the south of Iran [4]. In the other ve patients the
diagnosis was made on the basis of Hb electrophoresis and family history.
All the patients were splenectomized at the time when the CVA was
diagnosed. Five of them were regularly transfused every 2030 days
starting from 1 to 3 years. They received an average number of 18
packed RBC transfusions per year and their average Hb levels was
7.5 g/%. In the two patients with TI who were not or regularly transfused, the average Hb level was 8.0 g/%. The mean platelet count in
the patients with TM and TI was 450 and 550 per mm3, respectively.
All the patients were irregularly chelated with deferioxamine administered subcutaneously, 45 nights per week, and their mean ferritin levels were between 1,500 and 3,000 mg/% (Table I). Their prothrombin
time and partial thromboplastin time were within normal range. Cardiac
examination consisted of physical examination, electrocardiogram,
echocardiogram, and chest X-ray. The clinical diagnosis of CVA was
conrmed by brain CT (computerized tomography model of General
Electric American Max 640) or MRI (Magnetic Resonance Imaging
Model of Philips Germany Gyroscan Intra).

Patients
Patient 1 was a 14-year-old girl with TM, splenectomized at 6 years,
and transfusion dependent from infancy. She developed insulin-dependent diabetes mellitus 12 months and congestive heart failure 4 months
prior to admission because of fever and periorbital edema. The major
ndings on admission were S3 gallop, atrial brillation, and hepatomegaly of 18 cm. Her sugar blood level was >300 mg/%. There was a
decrease in sensorium and deep tendon reexes on the right side of
her body. CT scan of the brain disclosed hypodense areas in the left
frontal lobe, which was diagnostic for CVA. Her condition gradually
deteriorated and she developed meningitis and mucormycosis in addition to the CVA and died 35 days after the onset of admission.
Patient 2 was a 10-year-old boy with TM, splenectomized at 5 years
and transfusion-dependent from infancy. He was admitted with severe
headache, left periorbital edema, and impaired consciousness. He had
no fever and all the cultures were negative, ruling out the possibility of
infection. He already had CVA in the past year resulting from left parietal infarction. The major ndings were decrease in all deep tendon
reexes mainly on the right side. MRI of the brain revealed left parietal
infarction and multiple bilateral enhancing lesions. There was also
thrombosis in the left common carotid artery as well as thrombosis in
the left lower extremities. The patient died 14 days after admission,
with evidence of multiple thrombosis in lower extremities and lung. Autopsy was not performed.
Patient 3 is a 24-year-old woman with transfusion-dependent TM,
splenectomized when she was 19 years old, and hospitalized because
of nausea, vomiting, and decrease in the level of consciousness. She
developed insulin-dependent diabetes mellitus 5 years and congestive

1
Department of Pediatrics, Thrombosis and Hemostasis Unit, Hematology
Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Hematology, The Edith Wolfson Medical
Center, Holon, Israel

*Correspondence to: E.A. Rachmilewitz, M.D., Hematology Department, The

Edith Wolfson Medical Center, Holon, Israel.
E-mail: tovaagam10@hotmail. com
Received for publication 3 August 2006; Revised 27 December 2006; Accepted
24 January 2007
Am. J. Hematol. 83:7779, 2008.
Published online 15 August 2007 in Wiley InterScience (www.interscience.
wiley.com).
DOI: 10.1002/ajh.20938

C 2007 Wiley-Liss, Inc.

V

American Journal of Hematology

77

http://www3.interscience.wiley.com/cgi-bin/jhome/35105

TABLE I. Pertinent Clinical and Laboratory Findings in Seven Patients with TI and TM Who Developed CVA
Type of thalassemia/Gender

b-TM, F Ex.

b-TM, M Ex.

b-TM, F

b-TM, F

b-TM, M

b-TI, F

b-TI, M

Age at onset of CVA (years)

Type of CVA
Congestive heart failure
Atrial brillation
Diabetes mellitus
Splenectomy
Hemoglobin (g/dl)
Platelet 3 103
Prothrombin/sec
Serum ferritin (mg %)

14
Ischemic
1
1
1
1
8.1
716
20
2,500

10
Ischemic
2
1
2
1
8
970
15
2,900

24
ICH
1
1
1
1
10.7
470
24
2,800

23
Ischemic
2
1
1
1
7.9
700
16
1,800

12
Ischemic
1
1
2
1
9.0
630
15.5
3,000

40
SAH
2
2
2
1
6.5
530
18
1200

4
Ischemic
1
1
2
1
5.7
560
14.5
1,300

b-TM, b-Thalassemia major; b-TI, b-Thalassemia intermedia; Ex., expired; F, female; M, male; ICH, intra cranial hemorrhage; SAH, subarachnoid
hemorrhage

heart failure 2 years prior to admission. Physical examination revealed

decrease in all tendon reexes, hepatomegaly of 19 cm, and harsh systolic murmur over the apex of the heart. Echocardiography disclosed
left ventricular failure. MRI of the brain demonstrated intrathalamic infarction. Diffusion weighted imaging was not performed. She was
treated with warfarin for 6 months and at present with deferioxamine
and insulin.
Patient 4 is a 24-year-old woman with transfusion-dependent TM
from infancy, splenectomized when she was 6 year old. She developed
insulin-dependent diabetes 6 years prior to admission because of
decrease in consciousness. Physical examination disclosed right facial
palsy and left hemiplegia. CT of the brain demonstrated left (Fig. 1)
and right parietal infarctions. She also had atrial brillation. She was
treated with warfarin for 4 months and today she is treated with deferioxamine and insulin.
Patient 5 is a 12-year-old boy with TM, is transfusion dependent
from infancy, and was splenectomized 2 years prior to admission
because of headache and right side hemiplegia. Asystolic murmur was
heard all over the heart and decrease in the reexes in the right side of
the body. ECG showed atrial brillation and left ventricular hypertrophy
and echocardiogram revealed dilated cardiomyopathy and decreased
left ventricular function. Brain CT showed infarctions in two places in
the left hemisphere. He was treated with heparin and at present is without any physical disability.
Patient 6 is a 40-year-old lady with TI, irregularly transfused, and
splenectomized 4 years prior to admission because of severe headache. CT of the brain showed the presence of subarachnoid hemorrhage. She was treated with nimodipine (calcium channel blocker), dihydropyridine for cerebral vasospasm after subarachnoid hemorrhage,
and her present condition is stable.
Patient 7 is a 4-year-old boy, diagnosed as TI who received only two
blood transfusions, splenectomized 1 year prior to admission because
of decrease in the level of consciousness shortly after receiving blood
transfusion. Physical examination revealed diastolic murmur over the
apex of the heart and hepatomegaly with a span of 17 cm. Echocardiography revealed cardiac dilatation, mild systolic dysfunction, left ventricular hypertrophy, and atrial brillation. Brain CT showed right front
parietal ischemic infarction. He was treated with nimodipine, and at
present his condition is without any physical disability.

Discussion
The existence of lifelong chronic hypercoagulable state
has been established in thalassemia [2] and it seems that
the incidence of thromboembolic phenomena is higher in
patients with b TI who underwent splenectomy and/or are
not regularly transfused [5]. In a recent study conducted in
the Mediterranean area on 6,670 patient with TM and
2,190 with TI, 61 (0.9%) with TM and 85 (4%) with TI at a
mean age of 30 13 years, had a history of thrombotic
event [6]. The underlying mechanism is due to abnormal
exposure of phosphatidylserine (PS) on the outer layer of
the RBC membrane following oxidative denaturation of the
membrane lipids [7]. The abnormal external exposure of

78

Figure 1. Part of a CT scan of Patient 4 showing a 45

cm hypodense area with central hemorrhage and mass
effect in the area of the left middle cerebral artery. [Color
gure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

PS provides a docking site for prothrombinase complex

and factor X, initiating conversion of factor X to Xa and
subsequent conversion of prothrombin to thrombin. This in
turn is correlated with the expression of platelet activation
markers and to vascular damage. The increased number of
the activated platelets after splenectomy obviously increase
their contribution to the pathophysiology of the hypercoagulable state [8]. Consequently, thromboembolic complications
have been identied in several organs including the brain.
The incidence of CVA with clinical signs and symptoms
was less than 5% [2]. However, asymptomatic brain damage including ischemic lesions was found by MRI in 37%
out of 41 patients. Precipitating factors are splenectomy,
low Hb levels, and increasing age [3].
In the present group of patients there were additional risk
factors probably resulting from iron overload in major
organs such as heart and pancreas documented by
increased serum ferritin levels, most probably due to inadequate iron chelation. Patients: 1, 4, 5, and 7 developed
atrial brillation on top of congestive heart failure and
impaired left ventricular contractility. These cardiac abnormalities substantially increase the risk of thromboembolic
CVA [9]. Another complication present in patients 1, 3, and

American Journal of Hematology DOI 10.1002/ajh

4 was diabetes mellitus, dened as bronze diabetes [10]

due to iron accumulation in the pancreas. The association
between diabetes and vascular damage including in the
brain, is a well known entity [11].
Patient 7 who was irregularly transfused developed an ischemic infarction after receiving blood transfusion. Hypertension, convulsion, and cerebral hemorrhage were described in patients after receiving blood transfusion [12,13],
but this patient received only two transfusions, and had cardiac failure and arrhythmia, which are more likely etiological
factors for his CVA.
However, the present data are still insufcient to draw
any practical conclusions on whom and when MRI of the
brain should be performed to diagnose and monitor vascular damage before the appearance of clinical signs and
symptoms, since only one study addressing this issue has
been reported so far (3). Moreover, at this point there are
no clear-cut recommendations who might benet from antiplatelet aggregation and/or anticoagulant therapy.
The only way to answer these questions in a meaningful
way, is by collecting more data about the incidence of
asymptomatic brain damage and by performing wellcontrolled clinical trials comparing the incidence and the
outcome of thromboembolic phenomena with or without
prophylactic anti platelet and/or anticoagulants in patients
with the risk factors that have been described above. Until
then a decision to monitor MRI of the brain and consequently about treatment can be made only in a subset of
patients with risk factors such as age above 20 years, postsplenectomy, inadequate blood transfusion program, and
obviously in those who has a history of thromboembolic
events. A short course of treatment can be considered prior
and after surgical procedures and/or during pregnancy.
One of the ultimate practical conclusions learnt from the
present study is that specic treatment of documented
risk factors resulting from iron overload in the heart and pan-

American Journal of Hematology DOI 10.1002/ajh

creas, who eventually developed cardiac failure and arrhythmia, with or even without bronze diabetes, is mandatory.
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