Tranexamic acid-induced ureteric clot obstruction in a patient with urothelial cell carcinoma resulting in upper urinary tract perforation

Abstract

This is the first report of upper urinary tract (UUT) perforation secondary to tranexamic acid (TXA) induced ureteric clot obstruction. A 77-year-old woman was referred to the urology department with intermittent, painless visible haematuria from a lesion in the right upper calyx, suspicious of urothelial cell carcinoma. She did not have any flank pain or blood clots in her urine. Preoperatively, her haemoglobin level dropped from 113 g/L to 95 g/L and was prescribed oral TXA by her general practitioner, which led to extensive clot formation within the right kidney and ureter resulting in pain and ureteric obstruction. At ureteroscopy, a large ureteric blood clot was extracted and perforation close to the tumour with resultant urinary extravasation was noted. The patient subsequently underwent a successful nephroureterectomy, but risk of potential perforation-related complications such as tumour seeding, sepsis and urinoma formation could have been avoided. TXA in haematuria from the UUT should be strongly discouraged due to the risk of ureteric clot obstruction and UUT perforation.

Background

Tranexamic acid (TXA) is a synthetic inhibitor of plasminogen activation, which is commonly used in the management of menorrhagia, epistaxis, dental extractions, postpartum bleeding and trauma, where it has been shown to reduce the need for blood transfusions, bleeding-related morbidity and mortality without an increase in thromboembolic events.¹ However, the benefit of TXA in the management of upper urinary tract (UUT) bleeding has not yet been established. A few case reports have described the successful use of TXA in patients with visible haematuria (VH) due to autosomal dominant polycystic kidney disease (ADPCKD); however, there are no reports documenting the use of TXA, the treatment outcome and/or treatment-related adverse events in patients with symptomatic VH secondary to other upper tract pathology such as urothelial cell carcinoma (UCC).^2–4

Case presentation

A 77-year-old female patient was referred by her general practitioner (GP) with recurrent episodes of painless VH. The patient was an ex-smoker with a body mass index of 24 kg/m², a WHO performance status of 1 and a history of chronic kidney disease, hypertension and hypothyroidism.

On further questioning, she stated that she had noticed blood in her urine on three occasions in the last month. She described this as being frank blood with no clots and no associated flank pain. She denied any lower urinary tract symptoms such as dysuria, frequency, nocturia, hesitancy or poor flow. She did not have any change in her appetite, bowel habit or weight. Examination revealed a soft, non-tender abdomen with no palpable masses or organomegaly.

Investigations

Prior to being seen in our one-stop haematuria clinic, the patient had submitted three early morning urine cytology samples, neither of which revealed the presence of any malignant cells. An ultrasound scan of her renal tract was normal and a flexible cystoscopy did not reveal any abnormalities within the bladder or urethra. Dipstick urinalysis done prior to the cystoscopy did not show evidence of blood, leucocytes or nitrites in the patient’s urine.

Blood tests showed a haemoglobin (Hb) level of 113 g/L, a creatinine of 113 umol/L and an estimated glomerular filtration rate (eGFR) of 41 mL/min/1.73 m² (baseline: 55 mL/min/1.73 m²). A coagulation screen was normal: the international normalised ratio was 1.0, prothrombin time was 11.5 s and activated partial thromboplastin time was 23.8 s.

A CT scan with urographic phase revealed a 2.3×1.7×2.6 cm tumour in the right upper calyces and renal pelvis (figure 1), but no evidence of nodal or metastatic disease, hydronephrosis, clot formation or ureteric obstruction. The case was discussed at the departmental multidisciplinary team meeting and the patient was scheduled to undergo a right ureteroscopy and biopsy.

Figure 1.

Coronal (A) and transverse (B) section images from the preoperative CT with urographic phase showing tumour (arrowed) in the right upper pole calyces extending into the renal pelvis. The CT scan was obtained prior to the patient being commenced on TXA and showed no evidence of collecting system perforation, obstruction or retroperitoneal collection. TXA, tranexamic acid.

Seventeen days prior to the procedure, the patient presented to her GP with further episodes of VH and worsening anaemia (Hb: 95 g/L). Her GP prescribed oral TXA (1 g three times per day) for 5 days. The VH resolved but the patient developed new mild right-sided flank pain.

Blood tests performed on the day of surgery revealed that her Hb had increased to 107 g/L but the creatinine increased to 213 umol/L and eGFR had decreased to 19 mL/min/1.73 m². Cystoscopy revealed a normal bladder with clear urine. A rigid ureteroscope inserted into the right ureter revealed that this was filled with a large organised clot (figure 2A). A clot measuring 1×13 cm was extracted using a ureteroscopic biopsy forceps. Flexible ureteroscopy revealed residual clot filling the entire right renal pelvis (figure 2B) with multiple perforations secondary to obstruction by a large, organised clot (figure 2C, D). Biopsies were obtained from the upper calyces tumour (figure 2E).

Figure 2.

Semi-rigid (A) and flexible (B–E) ureteroscopic views during diagnostic ureteroscopy and photograph (F) of blood clot removed. The mid-ureter contained an old blood clot, measuring 1×13 cm (A and F), which was removed easily using semi-rigid ureteroscopic grasping forceps. On re-entering the ureter using a flexible ureteroscope, a larger clot was noted at the PUJ (B) with a large perforation of the PUJ and renal pelvis (C and D). The upper calyx contained papillary tumour (E) with an adherent clot. PUJ, pelvic–ureteric junction.

Treatment

A large clot was removed intraoperatively with the use of ureteroscopic forceps; however, a significant volume of blood clot remained within the renal pelvis. In such scenarios, a ureteric stent is usually inserted in an attempt to facilitate renal drainage and prevent further ureteric obstruction due to clot. However, in this case, it was deemed inappropriate to insert a ureteric stent due to the risk of the upper part of the stent slipping out through the perforated calyx, contributing to extravasation of urine into the retroperitoneal space and its associated morbidity.

Pathology results from the biopsies taking intraoperatively revealed high grade (2) UCC. The patient subsequently underwent a right laparoscopic nephroureterectomy with endoscopic lower end.

Outcome and follow-up

Histopathology from the nephroureterectomy specimen revealed high grade (2), pT1 UCC limited to the upper calyx. No lymphovascular invasion, carcinoma in situ or lymph nodes were identified. The perforations seen on ureteroscopy were commented on and located in the renal pelvis, which was also filled with organised obstructing clot extending into the proximal ureter.

The patient has recovered well from the surgery and will be followed-up with CT scans at regular intervals to assess for local or metastatic recurrence over the next 5-year period.

Discussion

The British National Formulary (BNF) does not list any urology-specific indications for the use of TXA, but haematuria is not on the list of contraindications to its use. It does advise caution in cases of ‘massive haematuria’, (avoid if risk of ureteric obstruction), but the BNF does not stipulate what classifies as ‘massive haematuria’ or define ‘risk of ureteric obstruction’.⁵ Similarly, the US Food and Drug Administration only lists heavy menstrual bleeding and short-term management of bleeding in patients with haemophilia as the indications for the use of TXA,^{6 7} although other non-urological off-label uses have been described in the international literature.⁸

An extensive review of the literature only revealed a small number of case reports that detail the use of TXA in upper tract bleeding. These case reports detail the use of TXA in a small number of patients with ADPCKD,^2–4 sickle cell disease⁹ and acute myeloid leukaemia.¹⁰ Two of these articles describe clot formation causing ureteric obstruction, which resulted in flank pain and renal failure,^{2 10} but there are no reports of UUT perforation due to clot formed following TXA administration in the literature. Hence, this case is the first report of UUT perforation secondary to ureteric obstruction by clot formed after the administration of TXA in a patient with symptomatic VH related to upper tract UCC (UTUCC).

UUT perforation due to clot formation is very rare.^{11 12} The most common cause of UUT perforation is urolithiasis (74%), especially small, distal ureteric stones.^{11 13} Other cause of UUT perforation include: malignant (8%) and benign (2%) extrinsic ureteric compression, iatrogenic injury (3.7%), pelvic–ureteric obstruction (2%), vesico–ureteric obstruction (1%) and bladder outflow obstruction (1%).¹¹ Perforation usually occurs at the renal fornix or calyx: severe cases which involved the renal pelvis are rare.¹²

The sequelae of UUT perforation may lead to increased morbidity due to urine extravasation leading to urinoma formation with associated local inflammatory response, lipolysis, risk of infection and abscess formation and risk of electrolyte imbalance due to resorption of urine.^{14 15} Flank pain, renal failure and retroperitoneal fibrosis can be seen in patients with UUT perforation, leading to increased need for medical treatment and hospitalisation.^{14 16}

The patient in this case report suffered from UTUCC. It is not clear what the impact of UUT perforation on this patient’s oncological prognosis might be, but the theoretical risk of tumour seeding following rupture of the renal collecting system or ureter in the presence of UCC is a feared complication by most urologists. UUT perforation following diagnostic ureteroscopy occurs in less than 10% of cases,¹¹ making it a rare phenomenon. Tumour seeding leading to locoregional metastasis from iatrogenic perforation of the urinary tract has been reported following percutaneous nephrostomy insertion¹⁷ and following perforation of the bladder during transurethral resection of bladder UCC.¹⁸ A striking example is a study of 34 patients who suffered from a bladder perforation after Transurethral resection of a bladder tumour (TURBT). Four patients required open operative management and were subsequently found to have tumour seeding resulting in peritoneal or metastatic disease. Three out of these four patients later died of metastatic disease, emphasising the risks associated with perforation of the urinary tract and seeding of TCC.¹⁸

It is likely that tumour seeding in the urine which has extravasated into the retroperitoneum has occurred in this case, due to the size and proximity of the perforation to the UTUCC. However, during radical laparoscopic nephroureterectomy, the area where extravasation occurred was routinely included in the resection margin, within Gerota’s fascia, and no gross evidence of metastasis was identified. Further follow-up CTs will monitor for the evolution of local and distant micrometastasis in this case.

Conclusion

This is the first case report of UUT perforation secondary to TXA-induced ureteric obstruction due to clot.

Extravasation of urine into the retroperitoneal space can lead to significant morbidity, including pain, sepsis, retroperitoneal fibrosis, tumour seeding and electrolyte disturbances. Hence, the use of TXA in the management of haematuria from the UUT should be discouraged until further clinical studies have been carried out along with evidence-based risk assessment. At present, such patients should be promptly referred for surgical or oncological intervention, which are proven and effective tools in dealing with these conditions.

Learning points.

• Based on the current evidence, tranexamic acid (TXA) should be avoided in the presence or as treatment of visible haematuria (VH) from the upper urinary tract due to the risk of ureteric obstruction and resultant perforation, even in cases of significant haematuria. Further studies are needed to assess the risks/benefits of TXA in such cases.

• Renal tract perforation carries high morbidity due to urine extravasation, which may lead to pain, urinoma formation, infection, sepsis, retroperitoneal fibrosis, electrolyte disturbances and prolonged hospital admission.

• Patients with VH from the upper tract should be promptly referred for urological interventions, which aim to diagnose and treat the cause of the haematuria.

Ethics statements

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