Treatment-resistant priapism associated with long-term low-molecular-weight heparin

Abstract

This case report summarises the case of a 56-year-old man with low-flow, ischaemic priapism requiring urgent insertion of a penile prosthesis following prophylactic anticoagulation with tinzaparin. Low-molecular-weight heparin (LMWH) has been proposed as a cause of ischaemic priapism, although reported cases of this are rare. This particular side effect of tinzaparin has been reported once in a case report in 2018, and there are scant other reports of LMWH-induced priapism. This case was refractory to the full treatment algorithm, including multiple aspirations, phenylephrine injection, cavernosal shunt and required transfer for implantation of a penile prosthesis. Only one other case of such a severe case of priapism has been documented, involving LMWH and warfarin. Documented evidence of possible causes of priapism are vital, given the rarity of this condition, the frequency of LMWH and the potentially devastating complications.

Introduction

Priapism is defined as a prolonged, persistent and usually painful penile erection not associated with sexual stimulation.^{1 2} Priapism is a medical emergency, posing a risk to potency as well as potentially leading to gangrene and necrosis. Low-flow or ischaemic priapism is considerably more dangerous than high-flow priapism, which can be treated electively. Kovac and colleagues³ discuss the pathophysiology of priapism with emphasis on dysregulated nitrous oxide release leading to exaggerated erectile response. Management follows a stepwise approach beginning with intracavernosal aspiration and irrigation, then injection of phenylephrine, or other vasopressor, then creation of a cavernosal spongiosal shunt. Cases progressing to penile gangrene require penectomy.

Causes of priapism are either primary/idiopathic, accounting for 35% of adult cases, or secondary. Secondary causes include haemoglobinopathies, haematological dyscrasias and neoplastic disease. Drug causes account for 25%–30% of cases. The most common causes of drug-induced priapism include antipsychotics, anti-impotence agents, with intracavernosal therapies being especially causative, vasoactive medications and illicit substances. Anticoagulants are among the extensive list of drug causes, including warfarin and heparin. There is certainly an association between heparin treatment and priapism, the pathophysiology of which is hypothesised to be due penile vascular stasis due to heparin-dependent antibody-induced platelet aggregation. This correlation is more frequently found in unfractionated heparin; low-molecular-weight heparin (LMWH) has much less evidence linking it to priapism. While the same pathophysiology could apply to LMWH, other sources emphasise alternate mechanisms for priapism in general, specifically reduced nitrous oxide availability.⁴ Given the near-ubiquitous short-term in-hospital use of LMWH and the low concurrent incidence of priapism, this would be an extremely rare complication.

This case report adds to the evidence that LMWH, tinzaparin specifically, is a potential cause of priapism. This would be the fourth reported case of LMWH causing priapism, including one attributed to tinzaparin,⁵ dalteparin⁶ and another which was not accessible.⁷ There is also a case of priapism preceded by LMWH (dalteparin) bridging for warfarin leading to priapism that progressed to penile gangrene.⁸ Another paper relevant to this case documented priapism in two patients who received prednisolone and intravenous heparin in combination.⁹ This paper is relevant as it includes a possible alternate pharmacological contributor to priapism, as is presented in this case report. The paucity of documented cases reflects the lack of clear causal link.

The severity of this case and the failure of response to the standard treatment algorithm are also of note. Previous case reports of priapism attributed to LMWH have documented aggressive treatment measures being required to achieve detumescence.

Case presentation

A 56-year-old man, with a background of valvular heart disease, contacted his cardiologist about a persistent, painful erection. He had previously undergone implantation of a bioprosthetic valve for bicuspid aortic valve and severe aortic regurgitation in 2008. He required aortic valve replacement with a metallic valve following paravalvular leak and thrombosis and thromboembolism to both legs and right kidney in the same year. Initially, he was started on warfarin which he tolerated for a number of years. This was discontinued while he was being investigated for a possible warfarin-induced vasculitic rash, and he was instead anticoagulated with 16 000 units of tinzaparin. This dose was calculated initially and then titrated upward to achieve adequate anticoagulation. The patient was self-administering LMWH. The rash in question had abated for several weeks after starting on a reducing course of prednisolone and promethazine but recurred 2 weeks following an influenza-like illness. The patient was restarted on the same treatment. At the time of presentation, he had been on tinzaparin for 6 weeks with good adherence to this regimen. His only other medications at the time were long-term omeprazole and atorvastatin.

Eight days after starting steroids and promethazine with his usual tinzaparin, he represented urgently with a persistent painful erection. He had 6–8 units of alcohol, took his usual tinzaparin and retired to bed as normal. However, without any intercourse, he developed an erection around 01:30, which persisted and became increasingly painful. He contacted his cardiologist that afternoon and was reviewed in the emergency department where he noted to have an extremely tense and solid erection and was in considerable pain.

Investigations and treatment

Recognising the emergency, the consultant urologist drained 100 mL of dark blood from the corpora cavernosa in the emergency department, with only mild detumescence. He was brought to theatre, and after multiple punctures, around 300–400 mL of dark, venous blood with oxygen saturation of 45% was removed with no response. A venous blood gas analysis of this showed a pH of 6.98, pCO₂ of 12.4 kPa and an O₂ of 3.99 kPa. Phenylephrine was injected at a dose of 200 µg every 3 min by six doses with no improvement. A 16-French biopsy gun was then passed through the corpus spongiosum and glans into the corpora cavernosa on both sides by three for a total of six passes of gun, creating a shunt (figures 1 and 2). This resulted in significant detumescence, which negated the need to progress to the next step in the treatment algorithm, such as a larger T-shunt or an open shunt. A sample of penile tissue was obtained to evaluate for evidence of fibrosis. Compression was applied to penis with extravasation of significant amount of blood. A sample of penile tissue was obtained to evaluate for evidence of fibrosis.

Figure 1.

Drainage of blood from corpora cavernosa, O₂ of 3.99 kPa, CO₂ of 12.4 kPa, pH of 6.98.

Figure 2.

Passing biopsy gun through glans to create a shunt between corpus spongiosum and both corpora cavernosa.

Unfortunately, after removal of the occlusive dressing the next morning, the priapism recurred, although not as significant as the previous day. This delayed recurrence necessitated escalation in management due to treatment resistance of an already rare condition. The patient was transferred to a specialist in the management of priapism in another hospital, which ultimately resulted in the decision to proceed to insertion of a penile prosthesis. This approach has been evaluated by Rees et al ¹⁰ with satisfactory outcomes, and avoids complications associated with delayed insertions.

Outcome and follow-up

Two weeks after this, he had been experiencing severe chronic pain associated with the prosthesis, preventing him from sitting down or lying on his side. The patient required extensive pain management, including opioids, anti-inflammatories, antidepressants, physiotherapy and psychosocial counselling. He declined involvement of psychosexual counselling.

Of note, the patient was restarted on warfarin and tolerated tinzaparin a year later for anticoagulant bridging of warfarin for a total hip replacement. He continued steroids for several months afterwards for persistent unexplained rash.

Differential diagnosis and discussion

As noted above, the causes of ischaemic priapism are many and varied. For this case, a detailed retrospective review of the patient’s history was conducted through his medical notes, documented medications, theatre notes and correspondence letters. There was no personal or family history of haematological disorders, no known or suspected substance abuse, and no notable psychological history. Investigation of previous Deep Vein Thromboses did not yield a specific diagnosis, the thromboembolism was attributed to his previous mechanical valve. The patient did not use herbal therapies or over-the-counter medications, beyond very occasional paracetamol. His blood work on admission was normal. While his medical history had been complicated, there was a clear sequence of events preceding the incident of priapism.

Given the rarity of priapism, and the absence of relevant risk factors, such as sickle cell disease, it was surmised that a drug cause was most likely. The patient had required ongoing management of several inter-related conditions which required alterations to drug regimens, with the rash being the most recent issue. His usual warfarin was discontinued and replaced with tinzaparin and he was started on prednisolone and promethazine. The remainder of his medications had been well-tolerated long term. The patient was adequately anticoagulated at the time of presentation. He had been started on his second course of steroids in combination with tinzaparin when the priapism occurred. Given the sequence of events, it seems that the combination of tinzaparin and steroids was the most likely causal factor in this case. There may have been a possible influence of alcohol; however, the patient had previously consumed alcohol on this treatment regimen with no complications. Also, the cause could be attributed to tinzaparin alone as there is some precedent for that. Due to the concurrent addition of prednisolone, however, it would be presumptuous to attribute this reaction to a single cause. Of course, the likelihood of coincidence is present but the correlation of medication change with onset of priapism would suggest a link, especially with pre-existing, although limited, evidence for such a side effect.

Contributory factors may be the combination of heparin and prednisolone, as documented elsewhere, although such an interaction has not been documented previously with LMWH. Another possible cause may be the treatment dose of tinzaparin, 16 000 units, which may have had an effect similar to unfractionated heparin. There is always the possibility that this was a coincidental event, and this was idiopathic priapism, unrelated to LMWH, although that seems less likely than a drug-related cause. Given the potential emergency that such a side effect could pose and severity of this particular case, awareness of the risks posed with LMWH and prednisolone must be documented appropriately.

Learning points.

• Priapism is a urological emergency, requiring emergency management, with potentially catastrophic consequences. It is best treated early in order to preserve potency and prevent gangrene and necrosis.

• Low-molecular-weight heparin is not free of adverse effects, some of which have not yet been documented.

• Valve replacement and many other cardiac conditions necessitate polypharmacy including anticoagulation and medications for secondary prevention. Intolerance of these and progression to second-line agents can increase the likelihood of unexpected interactions.

• Attributing causality to adverse events can be complicated and may rely on logical sequences of events.