Acute priapism associated with the use of sildenafil in a patient with sickle cell trait

To the editor:

Acute priapism associated with the use of sildenafil in a patient with sickle cell trait

Sildenafil, an oral agent that has proven effective for the treatment of erectile dysfunction (ED), enables a natural erectile response to sexual stimulation by enhancing the relaxant effect of nitric oxide (NO) on the corpora cavernosa. Normal penile erection may involve the release of NO from nonadrenergic, noncholinergic nerves and possibly endothelial cells of the cavernosal bodies. NO activates guanylate cyclase, resulting in increased synthesis of cyclic guanosine monophosphate (cGMP), which induces corpus cavernosal smooth muscle relaxation, increased blood flow to the penis, increased intracavernosal pressure, and penile erection. Sildenafil is a potent inhibitor of cGMP-specific phosphodiesterase (PDE) type 5, which is the predominant PDE isozyme responsible for the degradation of cGMP in the corpora cavernosa. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE type 5 by sildenafil causes increased concentrations of cGMP in the corpora cavernosa. Sexual stimulation is required for sildenafil to produce its beneficial pharmacological effects on erectile function.1 

With the use of sildenafil, the most commonly reported adverse events were headache, flushing, dyspepsia, rhinitis, and color perception disturbances that were all mild to moderate in nature. No cases of priapism were reported with the use of sildenafil in clinically controlled trials.1,2 Patients who have conditions that may predispose them to priapism such as sickle cell anemia, multiple myeloma, or leukemia are, however, advised to use sildenafil with caution.3 We report here a case of priapism in a patient with sickle cell trait associated with the use of sildenafil.

The patient is a 39-year-old male with sickle cell trait (AS) and a past medical history that includes a subarachnoid cyst involving the optic chiasma diagnosed in 1994 and Bell's Palsy/Ramsay Hunt syndrome in 1997. The patient suffered head trauma from a motor vehicle accident in 1998. The patient had sought urologic evaluation for erectile dysfunction (ED) and was prescribed sildenafil. After taking a dose of 50 mg, he had an erection within 15 minutes that was sustained even after ejaculation. His erection became sustained and painful for about 6 hours. The patient immediately noticed a loss of morning erection followed by gradual worsening of his ED, with complete loss of erection 3 months later.

Physical examination was not contributory. Laboratory evaluation showed: WBC 4.90; Hb 15.1 g/dL; Hct 44.4%; MCV 88.6 fl; Platelet 216/nL. Hormonal determinations revealed: FSH 3.0 mIU/mL (nl 1-8); LH 3.6 mIU/mL (nl 2-12); serum prolactin 14.3 μcg/L (nl 3.00-19.0); testosterone 304 ng/dL (nl 262-1593). Hemoglobin (Hb) electrophoresis, isoelectric focusing, and globin separation by denaturing high performance liquid chromatography (HPLC) were consistent with sickle cell trait. Use of those three different methods should detect mutations with charge differences. Red cell separation by isopycnic density gradient that can detect alterations in mean corpuscular hemoglobin concentration (MCHC) that would predispose toward polymer formation5 was consistent with sickle cell trait. Mass spectroscopy can detect electrophoretically silent mutations of Hb. In this case, it revealed only the presence of globin chains with molecular weights corresponding to α, β^A, and β^S, as would be expected in sickle cell trait. We therefore conclude that the patient has sickle trait and has no detectable globin or red cell-based predisposition for polymer formation beyond that which is expected in sickle trait.

Priapism as a complication of sickle cell anemia is a well-known phenomenon, but has not been associated with sickle cell trait. The lifetime incidence of priapism in patients with sickle cell anemia was found to be about 45% in homozygous patients (HbSS) in a Jamaican study.4 Sickle cell disease is a condition with very varied phenotypic expression in patients with the same genetic defect.6 

Patients with sickle cell trait are spared the major complications associated with sickle cell anemia, but a subset of AS individuals develop minor complications such as hyposthenuria (loss of ability of the kidneys to concentrate urine), splenic infarcts when exposed to hypoxic conditions or at high altitudes, and papillary necrosis.7 In addition, AS individuals are at risk for the rare occurrence of renal basal tubular carcinoma.8 The possibility thus exists that patients with sickle cell trait that suffer these complications might have gene modifiers (epistatic genes) that increase the risk for these pleiotropic phenotypic traits.

The effects of sildenafil lead to prolonged relaxation of smooth muscles in the corpora cavernosa and hence restoration of the natural erectile response to sexual stimulation. Nevertheless, the associated stagnation of blood within the corpora cavernosa results in local hypoxia, and in SS individuals the degree of deoxygenation may be sufficient to lead to erythrocytic rigidity and sickling, which can lead to priapism.9 To our knowledge, this complication has not been reported in AS individuals. The susceptibility of a patient with sickle trait to this condition might also depend on the effects of inherited modifier genes, which are yet to be identified.

Physicians should be aware of the possibility of sildenafil causing priapism in patients with sickle cell trait, although we do not know the incidence rate of this event. In the meantime, the manufacturers should advise against the use of this drug in sickle trait individuals until more data are obtained.