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Blood First Edition Paper, prepublished online March 25, 2015; DOI 10.1182/blood-2014-09-551887

Title: How I treat priapism Authors: Uzoma A. Anele,1 Brian V. Le,1 Linda M. S. Resar,2,3,4 and Arthur L. Burnett1 Affiliations: 1 The James Buchanan Brady Urological Institute and Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD 20817 2 Division of Hematology, Department of Medicine, 3Department of Oncology, and 4Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 20817 Correspondence: Arthur L. Burnett, MD, MBA Address: The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287-2101, USA Phone: 410-614-3986 Fax: 410-614-3695 Email: [email protected] Additional Author Emails: Uzoma A. Anele [email protected] Brian V. Le [email protected] Linda M. S. Resar [email protected] Conflict of Interest: The authors declare that they have no conflicts of interest.


Word Count: 3,741/4,000

1 Copyright © 2015 American Society of Hematology

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Abstract Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic variant, is often associated with devastating complications, notably erectile dysfunction. Because priapism demonstrates high prevalence in patients with hematological disorders, most commonly sickle cell disease (SCD), there is significant concern for its sequelae in this affected population. Thus, timely diagnosis and management are critical for the prevention or at least reduction of cavernosal tissue ischemia and potential damage consequent to each episode. Current guidelines and management strategies focus primarily on reactive treatments. However, an increasing understanding of the molecular pathophysiology of SCD-associated priapism has led to the identification of new potential therapeutic targets. Future agents are being developed and explored for use in the prevention of priapism.

Introduction Priapism is an uncommon pathologic condition involving prolonged penile erection in the absence of sexual arousal or desire.1,2 The term is derived from Priapus, a Greek god of fertility renowned for his large phallus.3,4 Incidence rates of 1.5 per 100,000 person-years have been estimated among the general population.5 The ischemic sub-type is common in sickle cell disease (SCD) with prevalence rates of up to 40%.6,7 In fact, SCD is an etiologic factor in approximately 23% of adult and 63% of pediatric cases.8 Several previous cohort studies have demonstrated high prevalence rates ranging from 27.5% to 42% in SCD, with up to 89% estimated to experience priapism by 20 years of age.6,7,9 Ischemic priapism is associated with devastating complications including erectile tissue necrosis and fibrosis.1,2 When episodes are unremitting, increasingly invasive options are employed in an attempt to prevent worsening tissue damage and preserve erectile function, or simply provide palliative care when erectile function can no longer be preserved. Here, we present an algorithm for identifying and managing ischemic priapism in SCD as well as the rationale behind various treatments.


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Case R. J. was a 22 year old African American man who presented to the emergency room (ER) with a painful erection lasting approximately 6 hours. He had been in his usual state of health until he finished mowing the lawn and noticed gradual development of an erection. He tried over-the-counter analgesics and masturbation without improvement. He reported previous episodes requiring several ER visits in the past few months, which resolved spontaneously with supplemental oxygen. There was no penile or pelvic trauma, although he reported a family history of SCD. On examination, he had a tender, engorged phallus. There was no hematoma, mucosal pallor or scleral icterus; remaining examination was unremarkable. He received supplemental oxygen and morphine for pain. Corporal aspiration and blood-gas analysis were consistent with ischemia. Further corporal aspiration and irrigation were performed without improvement. Phenylephrine injections ultimately led to penile detumescence. Hemoglobin variant analysis using high performance liquid chromatography showed hemoglobin SS. He was then monitored overnight until discharged the next day.

Nitric Oxide Role in Normal Erection Physiology Penile erection involves a complex coordination of vasorelaxing and vasoconstricting signals from parasympathetic and sympathetic inputs10, respectively, in order to control blood flow within the penis and allow for its engorgement.11 In its basal state, vascular and smooth muscle tone is maintained by vasoconstrictive factors10, allowing the penis to remain in a flaccid state for nearly 23 hours each day.12 Inhibition of this contractile state can occur with genital stimulation, psychosexual excitement, or rapideye movement sleep.13 Upon stimulation, penile erection is facilitated by smooth muscle relaxation, allowing for increased arterial blood flow and trabecular cavernosal tissue distension.14 This distension reduces venous outflow, thus permitting and sustaining penile engorgement.15 Recent investigations into molecular mechanisms underlying penile erection have revealed nitric oxide (NO) signaling as a critical component in normal erections.16,17 Erectile stimulation involves vascular and neurogenic pathways regulated by endothelial and neuronal isoforms of the NO synthase (NOS) enzyme, the primary mediator


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of NO synthesis. Upon activation, endothelial NOS (eNOS) and neuronal NOS (nNOS) utilize L-arginine to generate NO, which diffuses locally into smooth muscle cells to initiate vasodilation through activation of the downstream cyclic guanosine monophosphate (cGMP) pathway (Figure 1).13,18 Termination of the erectile response occurs when phosphodiesterase type 5 (PDE5) hydrolyzes cGMP, inactivating the second messenger nucleotide19 and returning the penis to its flaccid state (Figure 1).

Priapism Classification and Etiology Ischemic Priapism Ischemic priapism, also known as low-flow or veno-occlusive priapism, comprises over 95% of presentations20 and is the variant most commonly observed in patients with SCD. Ischemic priapism is associated with decreased or absent cavernous blood flow, corporal rigidity, and pain.2 It represents a compartment-like syndrome characterized by increased pressure within the enclosed cavernosal space and compressed circulation.21 Consequently, ischemic priapism is a medical emergency with potentially profound sequelae if left untreated. Histopathologic studies show time-dependent erectile tissue damage22 with irreversible corporal damage occurring in episodes lasting >6 hours (major priapism).23 Thus, patients are advised to seek immediate medical care with major episodes.2 Beyond 24 hours, tissue necrosis and fibroblast proliferation result22,24 and can lead to erectile dysfunction (ED), with estimated rates as high as 90% from episodes lasting >24 hours.20 Priapism can also lead to significant psychological and social sequelae.25 Diverse etiologies for priapism have been described, including neurologic conditions, pharmacologic exposures, trauma and idiopathic presentations (Table 1). Hematologic disorders, such as SCD, glucose-6-phosphate deficiency, and hereditary spherocytosis, have been implicated in ischemic priapism.7,26,27 While SCD itself is a key risk factor, the presence of other SCD complications, including ischemic stroke, leg ulcers, and vaso-occlusive episodes, have been associated with priapism.28 To identify SCD patients at risk for priapism, hemolytic biomarkers were investigated and patients with a history of priapism have significantly lower hemoglobins and higher lactate dehydrogenase as compared


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to SCD patients without priapism.29,30 Moreover, polymorphisms in genes that regulate vascular tone, endothelial NO metabolism, coagulation, cell adhesion, and cell hydration have been linked to priapism in SCD.31,32 However, parameters are not readily available and further studies are needed to validate these findings.11

Recurrent Ischemic Priapism Recurrent ischemic priapism (RIP), also known as stuttering priapism, involves repeated episodes of ischemic priapism with intervening periods of detumescence.2 The natural history of RIP is heterogeneous; most episodes are transient and self-remitting, often occurring during sleep and lasting for 70% of SCD patients with a history of severe priapism have a history of RIP.6 Despite the relatively shorter duration, RIP is associated with a risk of cavernosal fibrotic injury and may lead to ED in 29-48% in patients.6,7,33

Non-Ischemic Priapism Non-ischemic (also known as high-flow or arterial) priapism is a non-emergent variant of persistent erections caused by unregulated cavernous arterial inflow and occurs in less than 5% of observed clinical presentations.2,20,34 This variant is typically consequent to disruptions of the cavernous arterial supply involving mechanisms of injury including arterial aneurysm, arterio-venous fistula, iatrogenic needle injury, or pelvic trauma resulting in arteriolar-sinusoidal fistula formation.11,20 Following trauma, fistula formation allows blood from the cavernous artery to enter the lacunar spaces rather than the helicine arteries, resulting in unregulated penile engorgement.35 Contrary to these “classic” mechanisms of non-ischemic priapism, several reports have identified this phenomenon in the absence of anatomical abnormalities and particularly in the presence of SCD.8,36 This may suggest a role of hematologic disorders in development of this characteristic hyperemic environment, although the


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underlying mechanism is unknown.37 In this variant, the corpora are usually tumescent, typically lacking rigidity and pain,2 and episodes may spontaneously resolve with little or no complications.11

Pathophysiology of RIP Until recently, the classic vaso-occlusive paradigms of erythrocyte sludging within vascular spaces associated with SCD fostered the belief that vascular stasis and increased viscosity in the penis were the primary causes of this disorder.38 Emerging evidence has uncovered a likely molecular basis underlying RIP in SCD involving decreased NO bioavailability. Studies with mouse models of SCD which exhibit priapism found aberrations in NO signaling as a primary mechanism underlying priapism.39 This and other mouse models of priapism exhibit decreased PDE5 production and basally lower cGMP levels.39 cGMP is reduced secondary to a chronic decrease in production of endothelium-derived NO, which results from vasculopathic damage in SCD.39-42 Hemolysis also serves as a basis for decreased NO because free hemoglobin avidly scavenges intravascular NO. Arginase is also released from hemolyzed red cells, which reduces L-arginine, a substrate for NO production. Furthermore, excessive reactive oxygen species (ROS) production, a chronic state in SCD, also impairs endothelium-derived NO formation and function.43-45 With neurologic erectogenic stimulation, which can occur with sexual activity or sleep, neuronally-derived NO production increases cGMP levels to promote cavernosal relaxation. However, down-regulation of basal PDE5 levels results in an inability to adequately terminate the resulting downstream vasodilatory effects of heightened cGMP release (Figure 1). Thus, the erectile response is uncontrolled, and the penis becomes priapic. Additional signaling pathways involving RhoA/ROCK, adenosine, and opiorphin pathways have been implicated in the molecular pathophysiology of priapism.13,46-48



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The goal of initial assessment lies in distinguishing between the ischemic and non-ischemic variants. An appropriate evaluation is essential because ischemic priapism is a urologic emergency. As such, history, physical examination, laboratory testing, and imaging are useful tools in determining both the etiology and subsequent treatment modality.

History and Physical Examination Prolonged pain is an important predictor of ischemic priapism. Clinical histories should also include duration, circumstances associated with onset, co-morbid conditions (SCD or coagulation disorders), history of previous episodes, pharmacotherapy (erectogenic, psychoactive or recreational drugs), alleviating maneuvers, prior treatments, and previous erectile function. Physical examination should include an evaluation of the phallus by inspection and palpation to determine the extent of tumescence, as well as overall for signs of trauma, hematological malignancy, or evidence of hemolytic disease. Unlike non-ischemic priapism, ischemic priapism is characterized by the presence of rigidity and tenderness of the cavernosal bodies with absence of glans/penis involvement.

Laboratory Testing Corporal aspiration and blood gas analysis from the priapic penis is crucial in diagnosing ischemic priapism.2 The presence of acidosis, hypoxia, and hypercapnia (pH72 hrs.

Surgical Management Surgical management of ischemic priapism is customarily considered if first-line therapies fail to resolve the priapism episode, or if the clinical history and review of prior therapies suggest that surgical management should be offered initially. The International Society of Sexual Medicine (ISSM) recommends that penile shunting procedures be considered for priapism episodes lasting >72 hrs, as “first-line” therapies are less likely to be effective. Prior to surgical intervention, it is paramount that a thorough, well-documented discussion occurs between the surgeon and patient, as this is a condition with a disproportionate level of medical-legal consequences. In addition to discussing the indications, risks, and benefits of the procedure, the patient should understand that the duration of priapism and resultant injury to corporal tissue, including necrosis and fibrosis, place him at high risk of permanent ED despite surgical intervention. The objective of shunting procedures is to establish a communication between the sinusoids of the corpora cavernosa and the glans, corpus spongiosum or vein for drainage to allow egress of blood. This involves making a window through the tunica albuginea. In general, the selection of shunting procedures is largely dependent upon the familiarity and comfort-level of the practitioner. The distal shunt, a corpora-glanular shunt, is generally preferred because it is easier to perform, and has lower complication rates when compared to proximal shunts. There are several variants from percutaneous to open approaches,90-96 which can be followed by penile prosthesis implantation. Proximal shunting has been reserved for priapism episodes refractory to distal shunting because it is a more complex procedure with higher complication rates. Proximal shunting involves creating a window between the corpus cavernosum and corpus spongiosum at the level of the crura typically through a perineal or transscrotal approach or utilization of venous anastomoses to shunt blood out of the corpora.97-99 Shunting procedures


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carry inherent risks of complications such as ED, infection, urethra-cavernous fistulas, cavernositis and urethral strictures.100 Complications that result from such shunting procedures should be distinguished from the risk of the disease, such as ED or changes in sensation. Complete detumescence may not be achieved due to turgor and edema. Penile color duplex ultrasonography can be used to confirm return of cavernosal blood flow. High flow priapism has been reported to occur following shunting with return of heightened blood flow in the cavernosal arteries as demonstrated by ultrasonography.101,102 Early penile prosthesis implantation is a third option, particularly in adult patients, that may be selected based on the likelihood of permanent ED. Priapism episodes lasting continuously for >36 hrs are almost invariably associated with permanent ED. This time frame may be altered as patients undergo treatments that achieve partial restoration of blood flow, but later fail. Thus, some urologists recommend 72 hrs from the initial event as a cutoff for strongly considering early penile prosthesis to reduce fibrosis and maintain penile length.23 Recommendations exist for penile prosthesis surgery in cases of refractory RIP as well. However, these uses are controversial. For major priapism, it may be difficult to obtain a well-deliberated consent from a distressed patient as well as timely approval for insurance costcoverage.103 Ultimately, the decision for penile prosthesis surgery must be reached jointly with the patient based on goals and risk/benefit determinations. The principles of priapism management are largely similar in both pediatric and adult populations, with technical exceptions relating to corporal aspiration volumes, sympathomimetic dosing, and anesthesia considerations.104

Future Perspectives Adequate prophylactic management strategies for RIP are lacking. Recent studies identifying multiple complementary signaling pathways underlying the pathophysiology of RIP offer new and exciting therapeutic approaches for RIP prevention and management. Recognition of the roles of NO,


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RhoA/ROCK, adenosine, and opiorphins may lead to the development of future agents potentially targeting these molecular effectors.39,46-48,105,106 Strategies involving the use of PDE5 inhibitors to correct the underlying aberrations in NO balance have met with some success, as well as challenges regarding cost and patient adherence.51-53,107 Preclinical investigations in animal models of SCD have uncovered alternative methods of restoring NO balance through the use of sustained NO-releasing compounds.108 The success of orinthine decarboxylase inhibitors and adenosine deaminase enzyme replacement in animal models as modulators of opiorphin and adenosine pathways, respectively, have also showed potential promise as plausible therapies in reducing the risk of priapism recurrence.47,109,110 The management of priapism should involve a multidisciplinary approach. Patient education and clinical cooperation are necessary in addressing the deficiencies created by our current health care policy. 111

The higher prevalence of priapism among patients with hematologic and coagulation disorders requires

comprehensive management strategies engaging hematologic and urologic care providers. Collaborative efforts within the medical community will be essential to advance treatment strategies.

Acknowledgments U.A.A. and B.V.L. performed literature searches and prepared the first draft of the manuscript; and L.M.S.R., and A.L.B. reviewed, edited, and approved the final manuscript. The authors declare that there are no conflicts of interest.


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Table 1 Causes of priapism Etiology


Sickle cell disease, thalassemia, glucose-6phosphate dehydrogenase

Hematologic disorders

Vasoactive erectile agents (papaverine, phentolamine, prostaglandin E1, combination therapy) Alpha-adrenergic receptor antagonists (prazosin, terazosin, tamulosin) anti-anxiety agents (hydroxyzine), anti-coagulants (heparin, warfarin), anti-depressants and antipsychotics (trazadone, bupropion, fluoxetine, sertraline, lithium, clozapine, risperidone, olanzapine, chlorpromazine, thioridazine, phenothiazines, anti-hypertensives (hydralazine, guanethidine, propranolol)


Alcohol, cocaine, marijuana

Recreational Drugs

Gonadotropin-releasing hormone, testosterone



Scorpion sting, spider bite, rabies, malaria


Amyloidosis, Fabry disease, gout Kidney, bladder, prostate, urethra, penis, testis, colorectal, lung

Neoplastic (regional infiltration or metastatic)

Syphilis, spinal cord injury, cauda equina syndrome, autonomic neuropathy, lumbar disc herniation, spinal stenosis, stroke, brain tumor, spinal anesthesia


General anxiety disorder, obsessivecompulsive disorder, post-traumatic stress disorder, panic disorder

Anxiety Disorders

General or regional


Straddle injury, coital injury, pelvic trauma, intracavernous injection needle injury

Trauma (Non-Ischemic)

Penile revascularization surgery, intracavernous needle injury, shunt surgery

Iatrogenic (Non-Ischemic)


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Prepublished online March 25, 2015; doi:10.1182/blood-2014-09-551887

How I treat priapism Uzoma A. Anele, Brian V. Le, Linda M.S. Resar and Arthur L. Burnett

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How I treat priapism.

Priapism is a disorder of persistent penile erection unrelated to sexual interest or desire. This pathologic condition, specifically the ischemic vari...
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