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American Journal of Hematology 77:45–49 (2004)
Follow-Up of Sickle Cell Disease Patients With
Priapism Treated by Hydroxyurea
Sara T.O. Saad,* Camila Lajolo, Simone Gilli, José Francisco C. Marques, Jr.,
Carmen S. Lima, Fernando F. Costa, and Valder R. Arruda
Hematology and Hemotherapy Center of the State University of Campinas, Campinas, São Paulo, Brazil
Hydroxyurea is one of the most successfully used therapies for sickle cell disease.
Results of many clinical trials point to hydroxyurea administration for patients with
frequent painful crises and acute chest syndrome. Priapism is one of the complications
that could be prevented by hydroxyurea, but there are few reports demonstrating the
results. Since November 1993, hydroxyurea has been used in our clinic for preventing
priapism in patients with stuttering or major attacks who are still capable of achieving
intercourse on demand. Five patients were enrolled in the study, and 4 cases benefited
by this treatment. After the initial treatment for the acute attack, all five patients developed stuttering priapism. Hydroxyurea was then introduced at the initial dose of
10 mg/kg, and as the hydroxyurea dosage increased, the number or length of priapism
episodes decreased. One to two months after the maximal dose (20–35 mg/kg) was
introduced, the episodes disappeared. In two patients, we were forced to administer over
30 mg hydroxyurea/kg to abort the episodes, and, in another patient, 25 mg/kg was
necessary. All patients present normal sexual activity. Hydroxyurea was discontinued
in two patients, but stuttering priapism reappeared. Hydroxyurea was then re-introduced,
and priapism disappeared. One patient, using 20 mg hydroxyurea/kg, had a 6-year
remission of priapism after hydroxyurea administration; however, he experienced stuttering priapism, 1 month before a major attack, that progressed to impotence. During that
month, he did not seek medical attention. In conclusion, the data here presented suggests that hydroxyurea may prevent priapism attacks in sickle cell disease, probably at
higher doses than usually prescribed for painful crisis prevention. Am. J. Hematol.
77:45–49, 2004. ª 2004 Wiley-Liss, Inc.
Key words: sickle cell; priapism; hydroxyurea
INTRODUCTION
Sickle cell disease (SCD) is a common hemoglobinopathy that affects 1/1,000 newborns in southeastern Brazil [1] and over 20,000 individuals in Brazil.
Sickle cell disease is characterized by multiple-organ
infarction following the blockade of capillaries by the
interaction of sickle erythrocytes, leukocytes, platelets, and plasma proteins [2–4]. Apparently, no organ
is exempted from these changes. Priapism, for example, is another complication resulting from sickle cell,
as the corpora cavernosa of the penis are blood reservoirs prone to localized stasis, sickling, and obstruction of venous drainage [5,6]. The prevalence of
this complication could be higher than previously
described [7,8], as patients do not report short episodes or do not associate the symptoms with sickle
ª 2004 Wiley-Liss, Inc.
disease [9–11], suggesting that better education of
these patients is necessary.
The clinical manifestation of priapism appears commonly as stuttering and major attacks [5–7,12,13].
Contract grant sponsor: CAPES; Contract grant sponsor: CNPq;
Contract grant number: 5232299/95-8; Contract grant sponsor:
FAPESP
*Correspondence to: Sara Saad, Hemocentro Campinas, Campinas,
São Paulo, Brazil, CEP 13083-970, CP 6198.
E-mail: [email protected]
Received for publication 16 October 2003; Accepted 29 March
2004
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.20142
46
Saad et al.
Stuttering priapism usually lasts less than 3 hr and is
recurrent, and major attacks exceed 24 hr. Impotence
and psychological problems are devastating complications of priapism.
Treatment for acute attacks includes hydration,
sedation, aspiration, and irrigation with a-adrenergic
agonist, exchange transfusion [5,6,14,15]. Sometimes,
aspiration of the corpora or shunt cavernosus-spongiosum becomes necessary; however, most patients
progress to impotency, in part because procedures
are performed too late [16,17]. Success of surgical
treatment seems to be related to early treatment
(less than 48 hr) [18,19].
Several different strategies have been used in the
treatment of recurrent priapism, such as self-administration of etilefrine or phenylephrine and [14,20–25]
antiandrogens, but side effects including hypertension,
sexual disfunction, etc., are expected. Chronic transfusion has also been reported to be successful for preventing priapism, but allo-immunization, infection,
and hemochromatosis are undesirable side effects.
In addition, the efficiency of this treatment is controversial [26,27], and exchange transfusion has been
associated with neurologic events [28–30].
Hydroxyurea is one of the most successfully used
therapies for sickle cell disease: it elevates levels of
fetal hemoglobin (HbF), lowers levels of leukocytes,
platelets, and reticulocytes, and consequently reduces
endothelial adhesion [31–34]. Indeed, hydroxyurea
increases red cell hydration and may produce nitric
oxide in the plasma of SCD patients following oxidation by heme [35], which also corroborates for a
reduction in vasoocclusive events. Results of many
clinical trials point to hydroxyurea administration
for patients with frequent painful crises and acute
chest syndrome. Priapism is one of the complications
that could be prevented by hydroxyurea, as suggested
by some authors [5,36], but there are few reports
demonstrating the results.
Since November 1993, hydroxyurea has been used
in our clinic for preventing priapism in patients with
stuttering or major attacks who are still capable of
achieving intercourse on demand. Five patients were
enrolled in the study, and 4 cases benefited from this
treatment. We report our experience in treating these
patients during the last ten years.
PATIENTS AND METHODS
We treated five patients suffering from priapism
with hydroxyurea (4 SS, 1 Sb0), seen at the University
of Campinas Hospital, aging from age 13 to 35 years
old at the time of the first episode (Table I). The
protocol was approved by the Local Ethical Committee, and informed consent was obtained from all
patients. Three patients (numbers 2, 3, and 5) were
suffering from stuttering priapism, and one of them
(patient 5) progressed to major crises 10 months afterward. The other two patients (numbers 1 and 4)
presented initially with a major attack successfully
treated, but 2 and 3 years after these attacks, respectively, stuttering priapism appeared. Urethritis was
probably the cause of the major attack in patient 4,
and in the others, no obvious cause was identified.
Initial treatment of all patients included sedation with
morphine, oral and intravenous hydration using
hypotonic solutions (2–3 vol of 5% dextrose/1 vol
of 0.9% NaCl) and sometimes warmth. As these procedures did not result in detumescence during the 4 hr
that followed, the patients were submitted to automated or manual red cell exchanges maintaining HbS
under 30% and hemoglobin level around 10 g/dL. All
but Patient 1 had a transitory resolution of the priapism. None developed cerebrovascular accident.
Cavernosa aspiration followed by irrigation with saline and adrenaline was performed on Patient 1, 8 hr
after the onset of symptoms and, as this procedure
was not successful, shunt cavernosus-spongiosum was
also carried out 36 hr after the onset of symptoms.
However, a few months or years after this initial
episode, all patients experienced stuttering priapism.
Table I presents the data of these patients.
RESULTS
After the initial treatment of priapism, all five
patients developed stuttering priapism. Following
our hydroxyurea protocol [37], the initial dose of
TABLE I. Patients Data at the Moment of the First Episode of Priapism and Initial Treatment for Priapism*
Patient no.
1
2
3
4
5
Genotype
0
Sb
SS
SS
SS
SS
Age (years)
Hb (g/dL)
MCV (fL)
HbF (%)
Priapism pattern
Etiology
ET
I/A
Shunt
13
35
20
16
17
7.8
7.7
7.6
6.7
4.8
69
89
82
91
97
4.5
2.5
4.1
9.1
6.3
MC>ST
ST
ST
MC>ST
ST>MC
Unknown
Unknown
Unknown
urethritis
Unknown
yes
yes
yes
yes
yes
yes
no
no
no
no
Yes
No
No
No
No
*Abbreviations: ET, exchange transfusion; I/A, irrigation with saline and adrenaline; shunt, cavernosus-spongiosum; MC, major crisis; ST,
stuttering priapism.
SCD Patients With Priapism Treated by Hydroxyurea
hydroxyurea was 10 mg/kg/day, given once a day,
and was increased by 5 mg/kg/day every 8 weeks
until the patient presented no priapism at all. Toxicity
was defined by the presence of at least one of the
following characteristics: neutrophils < 2 109/L,
platelets < 100 109/L, reticulocytes < 50 109/L,
a 20% decrease in hemoglobin concentration, a 50%
increase in serum creatinine, or a 100% increase in
hepatic transaminases (AST and ALT). Patients were
seen in the outpatient clinic every 1–2 weeks up to at
least 4 months, when they became asymptomatic and
the maximal drug dose was reached. After this time,
they returned every 8 weeks.
As the hydroxyurea dosage increased, the number
or length of priapism episodes decreased. One to
2 months after the maximal dose was introduced
(Table II), the episodes disappeared. In two patients,
we were forced to administer over 30 mg hydroxyurea/kg to abort the episodes, and in another, the
necessary dose was 25 mg/kg. All patients had normal
sexual activity, that is, they were capable of achieving
intercourse on demand. Before treatment with hydroxyurea, all patients were informed regarding the side
effects of the drug, including azoospermia and oligospermia. Semen analysis was not performed regularly
unless the patient had the wish or intention of becoming a father. In every visit to the clinic, the patients
were seen by one of the three physicians responsible
for the hydroxyurea protocol, they were questioned
about the presence of priapism attacks or stuttering
priapism, and specific files were filled out in order to
guarantee the fidelity of all information.
Hydroxyurea was discontinued in two patients due
to oligospermia and leg ulcer, respectively. The first
(Patient 4) was asymptomatic for 2 years while using
30 mg hydroxyurea/kg; stuttering priapism reappeared
3 months after hydroxyurea discontinuation, and he
opted for re-introduction of hydroxyurea despite still
presenting oligospermia. The same dose of hydroxyurea that he was using before (30 mg/kg) was prescribed, and the priapism symptoms disappeared 5
weeks afterward. He has been asymptomatic since
47
then (2 years). The last patient (number 3) had been
asymptomatic for 3 years using hydroxyurea, but as
leg ulcer appeared and healing was difficult, hydroxyurea was discontinued. Stuttering priapism symptoms returned 1 year later, and hydroxyurea was reintroduced. Priapism disappeared 2 months afterward.
One year later, the patient was still asymptomatic,
without leg ulcers or priapism but decided to discontinue hydroxyurea. Stuttering priapism returned 8
months afterward, and this patient is now under
hydroxyurea treatment and is asymptomatic.
Patient 2 had a 6-year remission of priapism after
hydroxyurea administration; however, he began to
experience stuttering priapism (2–3 times a week lasting less than 30 min), 1 month before a major attack.
At that time, he was taking 20 mg hydroxyurea/kg.
He did not come to us during the stuttering priapism
because he believed that the episodes were not
important and could wait until consultation. He came
to us during the major attack that lasted 6 hr. He
underwent sedation, hydration, and sildenafil treatment [38] without success. He was then submitted to
exchange transfusion and cavernosa aspiration followed by irrigation with saline and adrenaline,
which was performed 12 hr after the beginning of
the symptoms. Finally, 48 hr after the beginning of
the symptoms, he had a shunt cavernosus-spongiosum. Doppler analysis revealed very low flow. Complete detumescence occurred 1 month after this
episode, and the patient is now impotent.
DISCUSSION
Priapism has been recognized as a sickle cell disease
complication since 1934 [39], most cases were only
reported after 1962. Based on hospital admission
data, the prevalence of priapism was estimated in
2–6% [8], but direct questioning revealed that the
incidence is higher, reaching 35–38% [7,9]. Conservative and surgical measures have been used for priapism treatment and for preventing new episodes
an analogue of gonadotropin-releasing hormone,
TABLE II. Follow-UP of Patients With Priapism Using Hydroxyurea*
Hydroxyurea dose
to abort symptoms
Hb (g/dL)
MCV (fL)
HbF (%)
Follow-Up
1
2
3
35 mg/kg
20 mg/kg
20 mg/kg
8.3
10.4
8.4
87
111
93
13.5
7.8
9.1
4
31 mg/kg
8.9
109
19.2
5
25 mg/kg
6.8
110
20.0
Asymptomatic for 3 years, normal sexual activity
Asymptomatic for 6 years, then ST for 1 month MC, and impotency
Asymptomatic alternating with ST for 9 years, depending on
hydroxyurea administration; normal sexual activity
Asymptomatic for 4 years (symptoms reappeared when hydroxyurea
was discontinued); normal sexual activity
Asymptomatic for 10 years; normal sexual activity
Patient
*Normal sexual activity, achieve intercourse on demand; ST, stuttering priapism.
48
Saad et al.
stilboestrol has been included [14,20,24]; however,
these drugs can cause feminization and loss of libido.
Recently, etilefrine has been used with success and
without side effects [20–23,25].
There are no evidence-based guidelines for the prevention of recurrent priapism in patients with SCA,
as none of the reported therapeutic interventions have
been compared in a randomized fashion. The use of
hydroxyurea has been proposed by many authors
aiming to prevent priapism attacks and has been
successfully tested by Al Ja’ma and Al Dabbous
[36]. In our study, the use of hydroxyurea for priapism prevention was successfully used in five SCD
patients; however, it is important to point out that
the dose that was required to stop priapism was
higher than that normally used in our clinic for frequent painful crisis treatment, which is usually lower
than 20 mg/kg [37]. It is important to observe that, in
two patients, there was a strong relationship between
appearance of priapism symptoms and discontinuation of hydroxyurea and vice-versa. Therefore, we
observed that as hydroxyurea dosage increased, the
number or length of priapism episodes decreased.
Thus, in spite of the fact that priapism occurs in all
temporal patterns, including stuttering going into
prolonged spells, long spells leading to stuttering,
and years between episodes in sickle cell disease, in
our patients a clear effect resulting from hydroxyurea
administration was observed against the possibility of
a random occurrence of fewer episodes of recurrent
priapism while receiving this medication.
As described by Al Ja’ma and Al Dabbous [36], the
action of hydroxyurea was quickly observed, and
there was a relationship between hydroxyurea discontinuation and priapism recrudescence. In that report,
the authors used 1.5 g of hydroxyurea. It is possible
that this dose could be higher than 25 mg/kg based on
the weight of our male sickle cell patients, usually
between 55 and 65 kg.
Finally, one of our patients developed impotency 6
years after he was asymptomatic while using hydroxyurea. However, the major crises that culminated in
impotency were preceded by stuttering episodes during the period of 1 month, but he did not seek medical
attention, suggesting that this patient was not wellinformed about the severity of priapism symptoms.
We will never know if an increase in the hydroxyurea
dosage could have prevented the devastating complication that occurred in this patient. This alerts us to
the importance of asking about priapism attacks in
every consultation and of informing the patient, as
thoroughly as possible, about the consequences of
these symptoms.
In conclusion, the data presented here suggest that
hydroxyurea may prevent priapism attacks in sickle
cell disease, probably at higher doses than usually
prescribed for painful crisis prevention.
ACKNOWLEDGMENT
We thank Dr. Nancy Olivieri for encouraging the
presentation of these results.
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