23.9 Priapism and Sickle Cell Disease

23.9Priapism and Sickle Cell Disease

23.9.1 Introduction

•Priapism is defined as a prolonged sustained erection, often accompanied by pain and swelling, and not associated with sexual desire.

•Priapism is one of the serious complications of sickle cell disease (SCD) and if left untreated, irreversible fibrosis and impotency may occur (Figs. 23.6 and 23.7).

•The exact incidence of priapism in patients with sickle cell disease is not known but it was thought to be present in 5–10 % of the patients.

•In patients with SCD, the probability of having at least one episode of priapism by age 20 was reported to be 89 %.

•Approximately 27% of patients with SCD reported having at least one episode of priapism.

•The mean age of patients when they had their first episode was 12 years, and the majority of episodes were nocturnal.

•The frequency of priapism in adults ranges from 30 to 45 %.

•There also appears to be bimodal peak frequencies for patients 5- to 13-years old and 21to 29-years old.

•Although the mechanism that causes low-flow priapism in patients with SCD is not fully understood, it may be caused by the sickling of red blood cells in the sinusoids of the corpora cavernosa during normal erection. This sickling leads to venous stasis, resulting in decreased local oxygen tension and pH, which further potentiate stasis, sickling, and secondary priapism.

•This type of priapism is considered a medical and surgical emergency because, if it is left untreated, irreversible cellular damage and fibrosis may occur, resulting in long term impotence.

•There are two types of priapism:

–Low flow priapism (Ischemic priapism)

–High flow priapism (Nonischemic priapism)

•Low-flow priapism tends to be much more common in patients with SCD.

•High-flow priapism is thought to be secondary to unregulated arterial inflow, leading to prolonged but painless erection. It is more commonly associated with penile trauma, but it has been reported in patients with SCD.

•High-flow priapism tends to require arterial embolization or ligation to produce detumescence, while low-flow priapism tends to respond to pharmacologic agents and or surgery.

•Priapism in patients with SCD can be acute, lasting for hours or days, or stuttering, occurring in an intermittent pattern, lasting for a few minutes to up to 3 h and generally resolving on its own.

23.9.2 Epidemiology

•Priapism has been described at nearly all ages, from infancy through old age.

•A bimodal distribution has been noted, with peaks at 5–10 years and 20–50 years.

•Internationally, the overall incidence of priapism is 1.5 cases per 100,000 person-years.

•In men older than 40 years, the incidence increases to 2.9 cases per 100,000 person-years.

•Cases in younger groups are more often associated with SCD, while those in older groups tend to be secondary to pharmacologic agents.

•The rate of priapism in adults with SCD is as high as 89 %.

•In one study, 38–42 % of adult patients with SCD reported at least one episode of priapism.

•The rate of priapism among children with SCD is as high as 27 %.

•Approximately two thirds of all pediatric patients who have priapism also have SCD.

•Priapism of the clitoris has been reported but is extremely rare.

23.9.3 Classification

•Priapism is prolonged painful erection of the penis often starting in the early hours of the morning.

•Priapism develops when there is excess arterial inflow to the penis or when there is persistent venous outflow obstruction to the penis.

•Two types of priapism exist based on blood flow patterns in the penis:

Fig. 23.8 A clinical photograph showing low flow priapism in a child with sickle cell disease

–Low-flow priapism:

•This occurs when there is decreased outflow from penile veins, leading to venous hemostasis.

•Intracavernosal blood sampling reveals acidosis and decreased oxygen tension.

•Although the mechanism that causes low-flow priapism is not fully understood, it may be caused by the sickling of red blood cells in the sinusoids of the corpora cavernosa during normal erection.

•This sickling leads to venous stasis, resulting in decreased local oxygen tension and pH, which further potentiate stasis, sickling, and secondary priapism.

•This type of priapism is considered a medical emergency because, if it is left untreated, irreversible cellular damage and fibrosis may occur, resulting in impotence.

•Low-flow priapism tends to be much more common in patients with SCD (Fig. 23.8).

–High-flow priapism:

•This is thought to be secondary to unregulated arterial inflow, leading to prolonged but painless erection.

•It is more commonly associated with penile trauma, but it has been reported in patients with SCD.

•Diagnosis can often be made by simple observation (erect, painless, brightly colored penis) and aspiration of bright red cavernosal blood.

•Since this type of priapism is associated with the presence of a large amount of oxygenated blood, fibrosis and cellular damage do not occur, and treatment can occur on an elective rather than emergent basis.

•It is important to distinguish between highand low-flow priapism, because treatment strategies differ depending on the type of priapism present.

•High-flow priapism tends to require arterial embolization or ligation to produce detumescence, while low-flow priapism tends to respond to pharmacologic agents.

•Priapism in patients with SCD is also classified into two types based on onset:

–Acute severe priapism:

•This lasts longer than 4 h and can result in impotence.

–Stuttering priapism:

•This occurs in an intermittent pattern, lasting for a few minutes to up to 3 h

•Generally it resolve on its own

•It is often recurrent and may precede a severe attack

•Stuttering or recurrent priapism may occur in patients with sickle cell trait or disease.

•Usually self-limiting in nature, over time such episodes may lead to erectile dysfunction.

23.9.4 Pathophysiology

•Anatomically, the penis is composed of two corpora cavernosa and one corpus spongiosum.

•The two corpora cavernosa are made up of smooth muscles and covered in a tunica albuginea. This is made up of two layers, an inner layer that supports the cavernous tissue and an outer layer that runs longitudinally from the glans to insert onto the pubic rami.

•The inner and outer layers of the tunica albuginea are connected by emissary veins.

•The corpus spongiosum on the other hand has no tunica albuginea, and therefore, serves as an arteriovenous fistula with less rigidity than the corpora cavernosa. The urethra runs within the corpus spongiosum.

•Normally, erection results from corporal smooth muscle relaxation secondary to the release of neurotransmitters.

•The principal neurotransmitter for erection is nitric oxide (NO), which is released by both nerve terminals and endothelial cells. The NO then diffuses into both trabecular cells and arterial smooth muscle cells. This activates guanylate cyclase, which catalyzes the formation of cGMP from GTP, and results in a cascade that decreases intracellular calcium and opens potassium channels to cause smooth muscle relaxation.

•This result in increased blood flow and filling of the corpora cavernosa sinusoids with blood and ultimate compression of venous outflow and trapping of blood.

•Alternative pathways generate cAMP, which enhances this effect.

•Detumescence follows degradation of cGMP and cAMP. cGMP is degraded by phosphodi- esterase-5 (PDE5).

•Typically, in priapism, the corpora cavernosa are tense, congested and tender to palpation while the glans and corpus spongiosum are usually soft and uninvolved.

•Stasis and low blood flow rates within the sinusoids of the erectile tissue make the penis a site at high risk for developing a venoocclusive crisis in patients with SCD.

•SCD is genetically determined by a mutation in the β-globin chain of hemoglobin.

•It results from a single change of one amino acid, valine for glutamic acid in the sixth position of the beta chain of hemoglobin.

•This results in a change in hemoglobin from hemoglobin A to hemoglobin S which is known to be associated with increased mortality and morbidity including pulmonary hypertension, cerebral vascular accidents, lower extremity ulcerations, osteonecrosis, painful

crises, and priapism among other less common clinical problems.

•Classically, in priapism, the primary mechanism is thought to be obstruction of venous drainage resulting in viscous, hypoxic blood leading to interstitial edema and fibrosis of the corpora cavernosa, ultimately resulting in impotence.

•It was shown that the length of time of ischemia directly correlates with the likelihood of return of erectile function, and therefore, ischemic priapism is considered a urologic emergency.

•It was shown that all patients with ischemic priapism episodes of greater than 12 h duration had reduction in erectile function and no patients with priapism lasting greater than 36 h had return of spontaneous erectile function.

•Priapism in sickle cell patients has been classically attributed to vaso-occlusion episodes.

•The deformed sickled red blood cells leads to vasooclusion which is precipitated to by hypoxemia and acidosis in the corpora cavernosa (caused by vasoconstriction, hypovolemia or stasis in the corpora cavernosa during physiologic erection).

•This cause microvascular obstruction, in a vicious cycle: red cells sickling causes vascular obstruction and secondary ischemia, which promotes new red cells sickling.

•This however is not the case and currently, the more accepted theory is the inflammatory theory which is based on the mediating function of the vascular endothelium in the microcirculation.

•In patients with SCA, several factors contribute to the development of priapism including anatomic factors and a low-flow state.

•Recently however it was shown that nitric oxide (NO) plays an important role in the pathogenesis of priapism in these patients.

•SCD is characterized by hemolysis, the extent of this is variable.

•The hemolysis leads to the release of the highly oxidative group heme and causes degradation of the cellular membrane, releasing hemoglobin and arginase into the extracellular environment. This is more exacerbated in those with functional asplenia (autosplenectomy) or surgical asplenia following splenectomy.

•Free hemoglobin oxidizes into methemoglobin, liberating heme groups and ferrous ions.

•Freed arginase in the extracellular environment consumes L-arginine, a substrate for the endothelial synthesis of nitric oxide.

•Nitric oxide is directly consumed in the oxidation of hemoglobin to methemoglobin and in the neutralization of heme groups and ferrous ions.

•The oxidative lesion, direct consumption and deficit of nitric oxide synthesis cause endothelial activation, release of inflammatory and thrombogenic factors and a tendency to vasoconstriction.

•Permanent vascular injuries occur over the long term, perhaps fostered by chronic tissue hypoxemia and the synthesis of vasoproliferative substances.

•Secondary or simultaneous sinusoidal blockage by deformed red blood cells in the microcirculation and worsening of the local process of hemolysis may occur.

•RBC hemolysis result in the release of cellfree plasma hemoglobin which scavenges available NO.

•The absence of NO leads to:

–Increased vascular tone

–Platelet activation

–Up regulation of vascular adhesion molecules.

•Reduced levels of NO have been implicated in the pathogenesis of pulmonary hypertension, priapism and leg ulcers in patients with SCA.

•NO is an important smooth muscle relaxant and a potent vasodilator. It mediates this