to suggest a diagnosis of hemolytic uremic syndrome, but she did

have an elevated ADAMTS13 inhibitor level and an unmeasurable

ADAMTS13 activity, which confirmed a diagnosis of acquired TTP.

The absence of other underlying disorders such as cancer, systemic

lupus erythematosus, or pregnancy, indicate that our patient’s TTP

was idiopathic.

Treatment for TTP usually involves plasma exchange, which

presumably works by removing ADAMTS13 inhibitors and

replacing someADAMTS13 enzyme [5].While efficacious, plasma

exchange is not without risk and has been associated with numerous

complications. The Oklahoma Blood Institute treated 206 patients

with plasma exchange from June 25, 1996 to June 25, 2005 and

57 (28%) had a major complication. Major complications included

systemic infection, catheter thrombosis (sometimes requiring

catheter replacement and/or systemic anticoagulation), hypotension

requiring dopamine infusion, and hypoxia requiring mechanical

ventilation. There were five deaths and a number of patients had

minor complications such as urticaria, dyspnea that responded to

oxygen given via nasal canula, and hypotension that responded to

intravenous fluids [6–8]. Even the line placement itself can have

serious complications including pneumothorax, hydrothrorax,

cardiac tamponade, hemothorax, and death [9].

This report demonstrates that some children with acquired TTP

may not require treatment. Since TTP is often fatal, further research

should be conducted to determine risk factors that can predict

outcomewith orwithout treatment so that other affected patients can

avoid potential side effects from treatment. Close observation with

frequent blood counts such as was the case with our patient may be

sufficient.

REFERENCES

1. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura:

Report of 16 cases and review of the literature.Medicine (Baltimore)

1966;45:139–159.

2. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma

exchange with plasma infusion in the treatment of thrombotic

thrombocytopenic purpura. Canadian Apheresis Study Group. N

Engl J Med 1991;325:393–397.

3. Horton TM, Stone JD, Yee D, et al. Case series of thrombotic

thrombocytopenic purpura in children and adolescents. J Pediatr

Hematol Oncol 2003;25:336–339.

4. Schneppenheim R, Budde U, Hassenpflug W, et al. Severe

ADAMTS-13 deficiency in childhood. Semin Hematol 2004;41:

83–89.

5. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;

347:589–600.

6. Howard MA, Williams LA, Terrell DR, et al. Complications of

plasma exchange in patients treated for clinically suspected

thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

Transfusion 2006;46:154–156.

7. Rizvi MA, Vesely SK, George JN, et al. Complications of plasma

exchange in 71 consecutive patients treated for clinically suspected

thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome.

Transfusion 2000;40:896–901.

8. McMinn JR, Thomas IA, Terrell DR, et al. Complications of plasma

exchange in thrombotic thrombocytopenic purpura-hemolytic

uremic syndrome: A study of 78 additional patients. Transfusion

2003;43:415–416.

9. Bagwell CE, Salzburg AM, Sonnino RE, et al. Potentially lethal

complications of central venous catheter placement. J Pediatr Surg

2000;35:709–713.

Reversal of Iron-Induced Dilated Cardiomyopathy During TherapyWith Deferasirox in Beta-Thalassemia

Omar Trad, MD,1* Mohamed A. Hamdan, MD,2 Altaf Jamil, MD,1 Muhammad F. Khanani, MD,1

M. Kashif Ishaqi, MD,1 Aisha Shamsi, MD,1 and Mohamed Hayek, MD1

A 15-year-old male with b-thalassemia major developeddilated cardiomyopathy secondary to iron-overload (Z-scores ofleft ventricle (LV) dimensions >3, ejection fraction (EF) 33%).Treatment with deferoxamine was unsuccessful, presumably dueto poor compliance. After 15 months of using deferasirox (DFX),

LV end-diastolic dimension normalized (Z-scores <2), and EFimproved to 58%. We conclude that treatment with DFX resultedin a reversal of iron-induced cardiomyopathy. Pediatr Blood Cancer2009;52:426–428. � 2008 Wiley-Liss, Inc.

Key words: cardiomyopathy; deferasirox; pediatrics; thalassemia

——————Abbreviations: EF, ejection fraction; LVED, left ventricle end-diastolic

dimension; LVSD, left ventricle end-systolic dimension.

1Division of Hematology/Oncology, Department of Pediatrics, Tawam

Hospital-in-Affiliation with Johns Hopkins Medicine, Al Ain, United

Arab Emirates; 2Division of Cardiology, Department of Pediatrics,

Tawam Hospital-in-Affiliation with Johns Hopkins Medicine, Al Ain,

United Arab Emirates

——————Statement of ethics: This case report was written in compliance with

the regulations of the Human Research and Ethics Committee at

Tawam Hospital-in-Affiliation with Johns Hopkins Medicine, Al Ain,

United Arab Emirates. Data regarding the patient’s clinical status were

collected by chart review. Patient’s confidentiality was maintained

during data collection and manuscript preparation.

*Correspondence to: Omar Trad, Tawam Hospital-in-Affiliation With

Johns Hopkins Medicine, P.O. Box 15258, Al Ain, United Arab

Emirates. E-mail: oatrad@hotmail.com

Received 22 June 2008; Accepted 3 September 2008

� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21795Published online 4 November 2008 in Wiley InterScience(www.interscience.wiley.com)

426 Brief Reports

INTRODUCTION

Cardiac complications secondary to hemosiderosis are the

leading causes of death in b-thalassemia major [1]. Although

cardiac morbidity and mortality have recently decreased after

the introduction of angiotensin-converting-enzyme inhibitors and

b-blockers, the mainstay of therapy of cardiac hemosiderosis

remains iron-chelating agents [1]. We present a patient with

b-thalassemia major who developed dilated cardiomyopathy

(DCM) secondary to cardiac hemosiderosis, which improved only

after DFX treatment.

CASE REPORT

A 15-year-old Pakistani male with b-thalassemia major was

maintained on regular blood transfusions (about 15 ml/kg every

3–4 weeks). He took folic acid and penicillin prophylaxis. Poor

compliance to subcutaneous deferoxamine resulted in elevated

serum ferritin levels (11–13,000 mg/L). He developed insulin-

dependant diabetes mellitus at age 11 years. He was hospitalized

after presentingwith congestive heart failure secondary toDCM.He

was started on digoxin, furosemide, lisinopril, and carvedilol.

Initial LVend-diastolic dimension was 6.6 cm (Z-score 4.5), and LV

end-systolic dimension was 5.1 cm (Z-score 5.3). Despite maximal

therapy, LV EF decreased from 45% to 41% over 9 months (Fig. 1).

He developed atrial flutter requiring electrical cardioversion and the

addition of amiodarone and warfarin. Despite adequate control of

arrhythmia, LV dilation increased and EF declined to 33%.

Therefore, deferoxamine was stopped and a trial of oral DFX

(30 mg/kg/day once daily) was initiated to enhance patient’s

compliance with chelation therapy. Over 15 months, serum ferritin

decreased from 12,457 upon initiation of DFX to 1,736 mg/L, andLV dimensions and systolic function improved significantly. LV

end-diastolic dimension decreased to 5.1 cm (Z-score: 2.0), LV-end

systolic dimension decreased to 3.6 cm (Z-score: 2.5), and EF

increased to 58% (Fig. 1). There was no modification in the dosage

of other medications or blood transfusion requirements throughout

that period (Z-score, number of standard deviations above or

below the mean (normal Z-score: �2 to þ2 corresponding to

2.5th percentile to 97.5% percentile limits). Z-score values are

adapted from Ref. [2]).

DISCUSSION

Iron-chelation with deferoxamine improves survival, and

reverses cardiac dysfunction [1,3]. However, nearly half of the

patients are non-compliant with this therapy because of the

discomfort and demanding nature of the regimen [4]. In 2005,

the United States Food and Drug Administration approved DFX

(ICL670, Exjade1, Novartis Pharmaceuticals, East Hanover, NJ),

an oral chelating agent, for the treatment of iron-overload in patients

older than 2 years of age [5,6]. DFX has good oral bioavailability

and a half-life of 8–16 hr allowing once-daily administration, thus

improving compliance [6]. Its metabolism and elimination as well

as that of its iron-chelation effect, are primarily by hepatic

glucuronidation followed by hepatobiliary excretion into the

feces [6]. It has been studied in over 500 adult and pediatric

patients with transfusion-related iron-overload. Phase III trial

results showed equivalent efficacy of DFX (20–30 mg/kg/day) to

subcutaneous deferoxamine (>35 mg/kg/day, administered 5 days

per week) [5].

Our patient was maintained on a hyper-transfusion regimen, but

failed to comply with deferoxamine chelation. His serum ferritin

was extremely high, resulting in several hemosideric complications,

including cardiac dysfunction. When it became available, he was

switched toDFX that resulted in improved compliance, lower serum

ferritin and improved cardiac function (Fig. 1). Galanello et al. [7]

showed excellent compliance with DFX in 40 patients with TM

between 2 and 17 years of age, with acceptable side effect profile.

Over 48 weeks, DFX decreased mean serum ferritin concentration

to less than 3,000 mg/L [7]. In our patient, serum ferritin decreased

from around 12,500 to less than 2,000 mg/L over 15 months.

Prevention of cardiac mortality is a most important beneficial

effect of iron-chelation therapy. The development of orally effective

iron-chelators such as deferiprone and DFX is intended to improve

compliance and decrease morbidity. In animal studies, both

deferiprone and DFX show comparable reduction in cardiac iron

content by 19–20.5% [8]. Although deferiprone results in increased

cardiac mass and myocyte hypertrophy, the clinical significance of

such effect is unknown [8]. DFX has the ability to penetrate

cell membranes; thus, its effects on the cardiac muscle may be

significantly enhanced [8]. Hershko et al. [9] showed that DFX

reduced cardiac muscle iron stores by 46% within 24 hr of its use.

This results in less myocyte damage, less dilation, and improved

contractility. Glickstein et al. [10] demonstrated in vitro improve-

ment of cardiac muscle contractility within 1 hr of using DFX

chelation. Moreover, the chelating activity of DFX was retained

throughout 24 hr, compared to deferoxamine, which only lasted for

12 hr [10].

Although we are encouraged by the reversibility of cardiomy-

opathy we have observed over a 15-month period, we have no direct

measure of the cardiac iron stores, for example, T2* (gradient echo)

magnetic resonance image. Larger trials are required to study the

effect of DFX on cardiac hemosiderosis, in relation to the long-term

morbidity and mortality.

REFERENCES

1. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of

deferoxamine in preventing complications of iron overload in

patients with Thalassemia major. N Engl J Med 1994;331:567–

573.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Serum ferritin and left ventricle ejection fraction before and

during deferasirox therapy.

Brief Reports 427

2. Pettersen MD, Du W, Skeens ME, et al. Regression

equations for calculation of Z scores of cardiac structures in a

large Cohort of healthy infants, children, and adolescents: An

echocardiographic study. J Am Soc Echocardiogr 2008;21:922–

934.

3. Politi A, Sticca M, Galli M. Reversal of haemochromatotic

cardiomyopathy in beta Thalassemia by chelation therapy. Br

Heart J 1995;73:486–487.

4. Taher A, Gattermann N. New trends in iron chelation: Impacting

outcomes. Semin Hematol 2007;44:S21–S25.

5. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of

deferasirox (ICL670), a once-daily oral iron chelator, in patients

with beta-Thalassemia. Blood 2006;107:3455–3462.

6. Stumpf JL. Deferasirox. Am J Health Syst Pharm 2007;64:606–

616.

7. Galanello R, Pig A, Forni GL, et al. Phase II clinical evaluation of

deferasirox, a once-daily oral chelating agent, in pediatric patients

with beta-Thalassemia major. Haematologica 2006;91:1343–

1351.

8. Wood JC, Otto-Duessel M, Gonzalez I, et al. Deferasirox and

deferiprone remove cardiac iron in the iron-overloaded gerbil.

Transl Res 2006;148:272–280.

9. Hershko C, Konijn AM, Nick HP, et al. ICL670A: A new synthetic

oral chelator: Evaluation in hyper transfused rats with selective

radioiron probes of hepatocellular and reticuloendothelial iron

stores and in iron-loaded rat heart cells in culture. Blood 2001;

97:1115–1122.

10. Glickstein H, El RB, Link G, et al. Action of chelators in iron-

loaded cardiac cells: Accessibility to intracellular labile iron and

functional consequences. Blood 2006;108:3195–3203.

Pediatr Blood Cancer DOI 10.1002/pbc

428 Brief Reports