Priapism in sickle cell anemia: emerging mechanistic understanding and better preventative strategies

Abstract

Sickle cell anemia is a common and disabling disorder profoundly affecting mortality as well as quality of life. Up to 35% of men with sickle cell disease are affected by painful, prolonged erections termed ischemic priapism. A priapic episode may result in fibrosis and permanent erectile dysfunction. The severity of sickle cell disease manifestations is variable dependent on a number of contributing genetic factors; however, priapism tends to cluster with other severe vascular complications including pulmonary hypertension, leg ulceration, and overall risk of death. The mechanisms underlying priapism in sickle cell disease have begun to be elucidated including hemolysis-mediated dysregulation of the nitric oxide signaling pathway and dysregulation of adenosine-mediated vasodilation. A better understanding of these mechanisms is leading toward novel preventative strategies. This paper will focus on the mechanisms underlying development of ischemic priapism in sickle cell disease, current acute and preventative treatment strategies, and future directions for improved management of this disorder.

Figure 1

Abnormal nitric oxide signaling leads to priapism in SCD. NO can be readily scavenged by free hemoglobin and deactivated by conversion to nitrate. This is normally prevented by compartmentalization of hemoglobin in red cells and a cell free zone adjacent to the endothelium ((a), first panel adapted from Liao [9] and Rother et al. [23]). In SCD, chronic hemolysis leads to higher levels of free hemoglobin and decreased NO availability. This results in decreased basal levels of its downstream effector, cGMP, and decreased PDE5, which degrades cGMP. Following cavernosal nerve stimulation in SCD (b), normal levels of cGMP are achieved as NO is released from nerve terminals. However, PDE5 levels remain low, leading to prolonged cGMP activity and prolonged erection. This can be prevented by long-term treatment with sildenafil ((b), second panel). Inhibition of PDE5 by sildenafil results in increased cGMP, which then increases basal PDE5 levels through normal feedback mechanisms [13, 14].