Blood, 15 August 2002, Vol. 100, No. 4, pp. 1516-1517
CORRESPONDENCE
To the editor:
Long-term treatment with oral sildenafil in a thalassemic
patient with pulmonary hypertension
Pulmonary hypertension (PHT), defined as Doppler peak systolic
tricuspid gradient (TG) higher than 30 mmHg, develops in a high
percentage of patients with 
-thalassemia (10% in thalassemia major
and greater than 50% in thalassemia intermedia [TI]). Recent studies
correlate PHT with age and high cardiac output. In patients with TI,
whether or not transfusion dependent, PHT is the main cause for
congestive heart failure.1 We report the case of a
thalassemic patient with secondary PHT who has been successfully treated with sildenafil, a selective and potent inhibitor of
cGMP-specific phosphodiesterase (PDE5) that promotes smooth muscle
relaxation in lung vasculature.2
A 34-year-old male with -thalassemia intermedia, splenectomized at
the age of 18, started regular transfusion and iron chelation therapy
in our center at the age of 32. Echocardiography showed a steady
increase of pulmonary artery pressure (PAP) with right ventricular
enlargement and moderate tricuspid valve regurgitation (TG systolic 56 mmHg, mean 42 mmHg). Left ventricular systolic function was preserved.
Patient symptoms included reduced tolerance to exercise, dyspnea during
light physical exertion, and thoracic constriction. There were no signs
of iron overload. Pulmonary scintigraphy with 99 Tc demonstrated
numerous defects in perfusion capacity of the right lung. Spirometry
revealed medium-grade ventilation impairment with a restrictive pattern
(Inspiratory Vital Capacity [IVC] = 2.66 L, 57% of the normal
value, Forced Expiratory Volume L/s [FEV1] = 1.96 L, 52% of the
normal value). Treatment was started with calcium antagonists but had
to be quickly interrupted due to severe side effects. Based on the
potential role suggested for sildenafil in the management of
PHT,3 sildenafil, 25 mg 2 times per day, was administered
for 1 month and progressively increased to 50 mg 2 times per day. After
15 months of therapy, right ventricular dimension and mean TG were back
to normal (TG systolic 40 ± 3 mmHg, mean 25 mmHg;
P < .03). Respiratory function tests showed only a mildly
restrictive ventilation pattern (IVC = 3.54 L, 76% of the normal
value, FEVI = 3.03 L, 81% of the normal value). Systemic artery
pressure was normal, and the patient's conditions had improved. The
drug was well tolerated except for transient episodes of nasal mucosa
congestion. Different to what has previously been described in a
patient with sickle cell trait treated with sildenafil, no priapism or
erectile dysfunction was observed in our patient.4
The etiology of PHT in thalassemic patients remains
unclear.5 Obstruction of pulmonary arteries by thrombotic
events has been observed in autopsies of patients with
-thalassemia/HbE disease.6 In fact, perfusion pulmonary
scintigraphy with Tc99 of our patient shows multiple areas of perfusion
impairment in pulmonary microcirculation (data not shown). Recent
studies have demonstrated the importance of the procoagulant activity
exerted by erythroblasts and damaged erythrocytes that have lost normal asymmetric distribution of membrane phospholipids.5,7 A
higher risk has been attributed to splenectomized TI patients,
especially those who are not transfusion-dependent. The low hemoglobin
levels in untransfused patients leads to compensatory erythroblast
hyperplasia and elevated levels of erythroblasts in
circulation.7 This suggests that therapeutic strategies
directed toward reduction of the raised pulmonary pressure should be
combined with adequate transfusional support and iron chelation
therapy8 in order to reduce hypoxic stimulus on the
pulmonary vessels.
In vitro study has shown that the activation of soluble guanylate
cyclase-cGMP-dependent protein kinase pathway is associated with the
induction of 
-globin gene expression.9 This suggests that sildenafil is also capable of improving erythropoiesis in thalassemia patients. Since our patient is transfusion-dependent, it
was not possible to correlate any improvement in erythropoiesis to
treatment with sildenafil.
Previous experience has shown that calcium antagonists are effective in
only 30% of patients with PHT10 and that prostacyclin analogs are expensive and difficult to manage. The selective
antihypertensive effect, the minimal risk of side effects, and the
option of oral administration make sildenafil an attractive alternative
to conventional therapy for PHT. Further investigation is required to
establish whether the decrease in PHT achieved by sildenafil has the
potential to lower the risk of congestive heart failure in thalassemia patients.
Roberto Littera, Giorgio La
Nasa, Giorgio Derchi, Maria D. Cappellini, Christy Y. P. Chang, and Licinio Contu
Correspondence: Roberto Littera, Centro Trapianti, Osp. R. Binaghi, Via Is. Guadazzonis N. 3, 09126 Cagliari, Italy; e-mail:
litter{at}tiscalinet.it.
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