European Journal of Neurology 2011, 18: 1426–1428

doi:10.1111/j.1468-1331.2011.03431.x

SHORT COMMUNICATION

Etiology and treatment of ischaemic stroke in patients with
b-thalassemia major
S. Vassilopoulou, E. Anagnostou, G. Paraskevas and K. Spengos
First Department of Neurology, University of Athens Medical School, Eginition Hospital, Athens, Greece

Keywords:

atrial fibrillation, cardiac
siderosis, dilative
cardiomyopathy, stroke,
thrombolysis, b-thalassemia major
Received 31 January 2011
Accepted 8 April 2011

Background and purpose: Although hypercoagulability-induced thromboembolism is
generally accepted as cause of cerebral ischaemia in thalassemic patients, cardiogenic
embolism has been recently suggested as another possible stroke etiology.
Methods: We present four adult b-thalassemia major patients with manifest cardiac
involvement who suffered territorial strokes.
Results: In the presence of siderotoxic cardiomyopathy and arrhythmia, we assumed
cardiogenic embolism as etiology of stroke and initiated oral anticoagulation as preventive medication. Two of our patients were the first b-thalassemia major patients
who underwent successful thrombolysis with rtPA.
Conclusions: Cardioembolism seems to be the cause of stroke in cases of b-thalassemia
major. Thrombolysis can be applied in the setting of acute brain ischaemia in such
high risk patients.

Introduction
Thalassemia is an inherited hemoglobinopathy caused
by a deficient globin chain synthesis leading to hemolytic anemia. Regular blood transfusions and effective
iron chelation regimes have significantly prolonged
survival in homozygous carriers of b-globin defects,
who develop b-thalassemia major (b-TM), thus allowing the manifestation of a wide spectrum of serious
complications as more patients reach adulthood. Heart
disease is the leading cause of death [1,2]. Chronic iron
overload in b-TM causes toxic dilated cardiomyopathy,
resulting in heart failure and arrhythmia, mostly atrial
fibrillation (AF) [3,4]. The existence of a chronic
hypercoagulable state is solidly established and
considered as another important cause of morbidity
and mortality because of thromboembolic complications that affect several organs including the brain [5,6].
Ischaemic stroke has been reported in 0.25–0.46% of
patients with b-TM in different endemic countries and
is considered as a rare complication [6–8].

Clinical cases
We report on four cases of hemispheric ischaemic
strokes in patients with b-TM. All patients had manifest
cardiac disease, either myocardial siderosis or arrhythCorrespondence: Konstantinos Spengos, First Department of
Neurology, University of Athens Medical School, Eginition Hospital,
Vas. Sofias 72, 11528 Athens, Greece (tel.: +30 210 7289290;
fax: +30 210 7216474; e-mail: konstantinos.spengos@gmail.com).

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mia and signs of dilative cardiomyopathy. They were all
on antiarrhythmic drugs, but no one received prophylactic anticoagulation. Details about patientsÕ history,
demographics, and other relevant findings are presented
in Table 1 and Fig. 1.
A 32-year-old woman (patient 1) with known severe
myocardial siderosis accompanied by permanent AF
and dilative cardiomyopathy presented with a residual
left-sided hemiparesis (modified Rankin Scale – mRSscore = 3) 3 months after suffering right middle cerebral artery (MCA) infarction. Within the preceding
4 months before ictus, she had presented transient
episodes of aphasia and cortical blindness. Based on the
history of transient ischaemic attacks in different arterial beds, the acute onset of a severe stroke syndrome,
the typical territorial infarction, and the prominent
cardiac involvement, we assumed cardioembolism as
cause of stroke and initiated oral anticoagulation as
secondary preventive medication. Under warfarin, the
patient remains free of any cerebrovascular events for
2 years.
A 34-year-old man (patient 2) with also known
siderotoxic dilative cardiomyopathy and paroxysmal
AF suffered left hemispheric stroke because of a partial
MCA infarction. He improved significantly and left
hospital on clopidogrel (mRS-score = 1). Eight
months later, the patient reported a short lasting episode of homonymous hemianopsia on the left, which
suggested transient ischaemia in the right posterior
cerebral artery territory. The occurrence of signs of
acute ischaemia in different vascular territories at different time points in the presence of left atrial dilatation

Ó 2011 The Author(s)
European Journal of Neurology Ó 2011 EFNS

Ischaemic stroke in b-thalassemia major

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Table 1 PatientsÕ history and relevant findings
Patient 1
Basic Demographics
Gender
Female
Age
32
Disease-related history
Splenectomy
Yes
Chelation therapy
Yes
Regular transfusions
Yes
Cardiac involvement
Cardiac hemosiderosisa
Severe
T2* (msec)a
18
R2* (/s)a
544.8
Atrial fibrillation
Permanent
Other arrhythmia
No
Left atrium diameterb
48 mm
Ejection fractionb
50%
Taken medication at stroke onset
Antiarrhythmics
Verapamil, Propafenone
Antiplatelets
No
Anticoagulants
No
a

Patient 2

Patient 3

Patient 4

Male
34

Female
43

Male
41

Yes
Yes
Yes

Yes
Yes
Yes

Yes
Yes
Yes

Severe
3.3
303.0
Paroxysmal
No
40.5 mm
50%

No
30.0
33.3
Permanent
No
48 mm
60%

Moderate
16.4
64.9
No
Ventricular tachycardia
52 mm
45%

Amiodarone, Betaxolol
No
No

Amiodarone, Metoprolol
No
No

Digoxin
Aspirin
No

Established by means of cardiac MRI.
Assessed by transthoracic echocardiography.

b

and paroxysmal AF indicates again cardiogenic embolism as cause of stroke. Under oral anticoagulation, the
patient remains now free of any cerebrovascular event
for a year.
A 43-year-old woman (patient 3) with no cardiac
siderosis but known permanent AF presented acute leftside hemiplegia. She was immediately transferred to our
hospital where a NIHSS score of 13 was documented. A
dense MCA sign on the right side was demonstrated on
CT. Intravenous thrombolysis with alteplase was initiated 90 min after symptom onset. A territorial MCA
infarction was finally visualized on MRI, whereas MCA
recanalization was demonstrated by means of transcranial Doppler. She was discharged 12 days later after
having regained independence (NIHSS-score = 3;
mRS-score = 2). Based on the above-mentioned facts
and the absence of any vascular lesions, we diagnosed
cardioembolic stroke on the grounds of AF and initiated oral anticoagulation. Six months later, the patient
remains free of any cerebrovascular events and shows a
minimal residuum (mRS-score = 1).
A 41-year-old man (patient 4) with a similar disease
history and moderate heart siderosis presented rightside hemiplegia and global aphasia while being hospitalized for an episode of ventricular tachycardia. A
dense MCA sign on the left side was visualized on CT.
He was then transferred to our stroke unit with a
NIHSS score of 24. Thrombolytic treatment was initiated at the end of the 4.5-hour time window [9]. He
improved significantly and regained mobility within a
few days (NIHSS-score = 9; mRS-score = 3).

Discussion
This work adds to the limited series of reported stroke
cases among patients with b-TM [6,7]. Moreover, it
presents the first two cases of b-TM patients with acute
ischaemic stroke who were treated successfully with
intravenous thrombolysis within the established time
window of 4.5 h [9].
In a recent study in the Mediterranean area, thrombotic events and ischaemic strokes have been reported
in 0.9% and 0.25% of patients with b-TM, respectively
[7]. In an Iranian study, stroke was documented in
0.46% [6]. It should be noted that four of these five
patients suffered large hemispheric infarcts involving
the cortex and that three of them had also AF and
cardiomyopathy. This constellation strongly indicated
an underlying cardioembolic mechanism rather than a
hypercoagulability-associated etiology for these probably territorial infarcts and raised important questions
regarding stroke pathogenesis and prevention among
these high-risk patients [6,8]. The specific clinical and
imaging findings, the cardiologic features, and the
preventive effect of oral anticoagulation in our case
series clearly support this hypothesis, which suggests
cardiogenic embolism as cause of severe stroke in
patients with b-TM and seriously question the etiopathogenic relevance of the permanent hypercoagulable
state that characterizes all thalasemias [5,10]. While
patients with b-TM seem to suffer large hemispheric
territorial infarcts in the presence of AF and cardiomyopathy [6,7], patients with sickle b-thalassemia and

Ó 2011 The Author(s)
European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 18, 1426–1428

1428

S. Vassilopoulou et al.

means of echocardiography, it should be acknowledged
that our argumentation regarding stroke etiology
remains assumptive, although it seems plausible and
most likely to be true. Only prospective registries and
large trials in patients with b-TM can provide solid
evidence for the etiologic mechanism of stroke as well
as the best diagnostic and therapeutic management of
this highly sensitive and young population.

References

Figure 1 Admission CT scans reveal a dense MCA sign (arrows)
indicative of an acute vessel occlusion in patients 3 and 4, whereas
follow-up imaging studies demonstrate typical territorial infarcts
indicative of an embolic stroke mechanism in all cases.

b-thalassemia intermedia present asymptomatic
ischaemic lesions that are smaller and affect deeper
structures while sparing the cortex [11–14]. These
obvious differences indicate different pathogenetic
mechanisms. Accordingly, b-TM patients with AF and
dilative cardiomyopathy should be considered as being
at higher risk. Preventive anticoagulation and extensive
cardiologic evaluation at younger ages might be justified [4]. Finally, the multiple organ damage and morbidity of patients with b-TM should not prohibit the
application of thrombolysis in cases of acute ischaemic
stroke. However, owing to the fact that we did not
demonstrate a definite cardiac source of embolism by

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Ó 2011 The Author(s)
European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 18, 1426–1428