Successful Management of Urinary Bladder Clot with Intravesical Tissue Plasminogen Activator Infusion in a Cat

Introduction

Blood clot formation in the urinary bladder is a known sequela of hematuria. Etiologies of hematuria include trauma, coagulopathy, urolithiasis, urinary tract infection (UTI), neoplasia, trauma, or benign renal hematuria.¹ Urinary bladder clots causing secondary lower urinary tract obstruction is a well-described sequela to uro-logic diseases and procedures in humans and animals.^2–8 Along with management of the underlying disease causing hematuria, clot removal is an important aspect of therapy.

Various options are described in humans for bladder clot management, including cystoscopic breakdown, surgical removal via cystotomy,² and manual irrigation with saline or sterile water through a Foley catheter. Intravesical instillation of substances to promote thrombolysis has also been performed in humans, including hydrogen peroxide,³ streptokinase,⁴ chymotrypsin in sodium bicarbonate,⁵ N-acetylcysteine (N-AC),^9,10 and recombinant tissue plasminogen activator (tPA).¹¹ In veterinary medicine, similar methods of urinary clot removal have been described in dogs, including intravesical sterile saline flush¹² and instillation of intravesical tPA.^6,7 Surgical urinary blood clot removal in a cat has also been described.⁸ However, the use of intravesical tPA has not been reported in cats.

The purpose of this report is to describe the use of tPA for dissolution of a suspected traumatic urinary bladder blood clot in a cat.

Case Report

A 5 yr old, 4.3 kg, previously healthy male neutered domestic shorthair was presented to a veterinary referral center for minimal neurologic responsiveness and hemorrhage from the urogenital area. The indoor/outdoor cat was reported to be missing for 48 hr and after returning home seemingly normal was found several hours later lying in a sizable amount of blood with significant hind-end bleeding according to the client.

On initial presentation, the cat was laterally recumbent and obtunded. He was in shock with hypothermia at 36.2°C (37.7–39.1°C), bradycardia at 160 bpm (180–220 bpm), and tachypnea at 80 brpm (10–30 brpm). The blood pressure via Doppler was too low to be recorded, mucous membranes were pale pink, capillary refill time was greater than 2 s, and significant bruising in the pelvic and inguinal areas as well as torn toenails on the hind paws were noted. Based on the history and clinical presentation, trauma from a vehicle was highly suspected as the inciting etiology. The urinary bladder was large and firm and could only be partially expressed, and the penis was noted to be purple in color. The urine that was able to be expressed was markedly hematuric with a urine packed cell volume (PCV) of 18%.

Initial blood work revealed an anemia (PCV 20%; reference interval [RI] 35–55%) with low total solids (5.3 g/dL; RI 5.5–7.5 g/dL), azotemia (blood urea nitrogen [BUN] 74 mg/dL; RI 8–35 mg/dL, creatinine 2.0 mg/dL; RI 0.8–1.5 mg/dL), hyperglycemia (338 mg/dL; RI 81–125 mg/dL), and hypokalemia (3 mEq/L; RI 3.4–4.9 mEq/L). An abdominal-focused assessment with sonography for trauma (aFAST) scan did not show any evidence of peritoneal effusion. However, within the urinary bladder, a 5 cm freely movable hyperechoic nonshadowing structure, which was suspected to be a blood clot, was noted. Pulse oximetry and thoracic radiographs were normal.

After initial stabilization with three Normosol-R^a fluid boluses (11.6 mL/kg each), the cat received buprenorphine^b (0.01 mg/kg) and propofol^c IV to effect for urinary catheter placement. The perineal fur was clipped, and the skin was prepped with diluted chlorhexidine. A 3.5-French Slippery Sam Tomcat Catheter^d was aseptically placed with slight resistance and maintained in place with stay sutures. The urinary catheter was then attached to a closed collection system. The cat was subsequently maintained on Normosol-R^a (4 mL/kg/hr) with potassium chloride^e supplementation (16 mEq/L) and analgesic medication (buprenorphine^b 0.01 mg/kg IV q 8 hr). Blood type (type A) and crossmatch were performed, and a single compatible unit (7 mL/kg) of packed red blood cells was administered over 4 hr. Following the transfusion, the cat’s vital parameters normalized, and the peripheral PCV increased to 24%. Two hours after transfusion, repeat venous blood gas^f revealed resolved azotemia (BUN 16 mg/dL, creatinine 0.9 mg/dL), normoglycemia (glucose 111 mg/dL), and normokalemia (potassium 3.8 mEq/L).

The following morning (17 hr after admission), on repeat urinary bladder ultrasound, the intraluminal structure had reduced in size to 3 cm. A radiologist-performed abdominal ultrasound was recommended but declined by the owner. Intravesical sterile 0.9% saline^g flushes (20 mL q 6 hr) were added with monitoring of the size of the intraluminal structure via ultrasound. Because of the normal urine output and improvement in urine color, the urinary catheter was removed after a total of five saline flushes were performed over 32 hr, which was 49 hr after admission. The cat urinated normally twice after the urinary catheter was removed. The last measurement of the intraluminal structure before discharge was 2.5 × 3.5 cm. The cat was discharged on transmucosal buprenorphine^b (0.01 mg/kg q 8 hr) 12 hr after removal of the urinary catheter.

The cat was re-presented to the referral center 28 hr after discharge for evaluation of frequent trips to the litter box, dribbling urine, lethargy, and hyporexia. On physical examination, he was 5–6% dehydrated and had bruising as previously noted. His urinary bladder was large and firm but was easily expressed. A complete blood count^h and serum biochemical analysisⁱ were performed. Significant abnormalities included a normocytic, normochromic, regenerative anemia (hematocrit 19.2%; RI 29.5–47%, aggregate reticulocytes 143 × 10³ /μL; RI 4–66 × 10³/μL with 3 nucleated red blood cells /100 WBC), thrombocytosis (414 × 10³/μL; RI 110–413 × 10³/μL), elevated BUN (52 mg/dL; RI 12–39 mg/dL) with normal creatinine (1.4 mg/dL; RI 0.5–2.1 mg/dL), and hyperglycemia (253 mg/dL; RI 74–143 mg/dL. A coagulation panel^j showed hyperfibrinogenemia (quantitative fibrinogen assay 593 mg/dL; RI 77–206 mg/dL) with normal prothrombin time and activated partial thromboplastin time. Urinalysis via cystocentesis showed red/cloudy urine with a urine specific gravity of 1.019, 31 occult blood, pH 8.5, 41 protein, too numerous to count RBC/high-power field (hpf), 20–50 WBC/hpf, 0–2 nonsquamous epithelial cells/hpf, 0–5 struvite crystals/hpf, and many rods and cocci bacteria/hpf. A urinary culture was submitted. An aFAST scan showed a persistent intraluminal structure, which was believed to be the same as previously noted within the urinary bladder. Cytology was performed on a fine-needle aspirate of the intraluminal structure, which had a low density of erythrocytes without inflammatory cells but contained evidence of mixed extracellular bacteria (diplococci and rods).

The cat received a single dose of hydromorphone^k (0.05 mg/kg IV) and was re-hospitalized on Normosol-R^a (5 mL/kg/hr) and Ampicillin/Sulbactam^l (30 mg/kg IV q 8 hr) because of a concern for a UTI. He was started on famotidine^m (0.5 mg/kg IV q 24 hr) and feeding via a nasogastric tube (25% resting energy requirement) because of hyporexia. The following morning, he developed a urinary obstruction (UO) again and was sedated for placement of a urinary catheter, consistent with the earlier procedural description (20 hr after re-presentation). The urinary bladder clot was believed to be causing the intermittent UO and infection nidus; therefore, the novel therapy of intravesical instillation of mucolytics and thrombolytics were discussed with the owner, to which she consented. Because of the inability to obtain tPA (Alteplaseⁿ) until the following day, intravesical instillation of N-acetylcysteine^o (10 mL of 50% N-AC [1.1 g/kg] + 10 mL of saline per treatment q 8 hr) was started (23 hr after re-presentation). N-acetylcysteine/saline solution was infused and retained for 1 hr by clamping the urinary catheter line. Before each instillation, the size of the intraluminal clot was measured with ultra-sound, and 20 mL of saline was used to flush the bladder after ensuring the bladder was as empty as possible. Instillation of N-AC didnot change theclot sizeafter threetreatments(48 hr after re-presentation), at which point the tPA was available and the N-AC was discontinued.

Intravesical tPA therapy was performed by diluting 0.5 mg (0.11 mg/kg) of tPA in 10 mL of sterile saline q 8hr(50hrafterre-presentation). The full 10 mL of diluted tPA was instilled into the urinary bladder and retained for 2 hr. Following therapy, the urinary bladder was flushed with 30 mL of saline. Before each infusion, the intraluminal clot was measured with ultrasound (Table 1). After the first infusion, there was significantly more debris noted in the urinary collection system, such that saline flushes (5–10 mL each) were added in between each tPA infusion to help ensure the urinary catheter remained patent. The initial clot size and echogenicity (Figure 1) decreased throughout the four tPA infusions and was unable to be identified 8 hr after the last infusion. The urinary catheter remained in place, and the saline flushes were continued until no debris was noted within the urinary bladder.

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TABLE 1 Ultrasound Measurements and Subjective Observations of Changes in a Suspected Urinary Bladder Clot Before and After a Series of Intravesical Infusions of tPA in a 5-Year-Old Male Neutered Domestic Shorthair

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Theday after the completion of thetPA infusions, theurine culture results were available, which showed growth of Escherichia coli that was resistant to penicillin but susceptible to fluoroquinolones; therefore, Ampicillin/Sulbactam^l was discontinued and marbofloxacin^p (5.8 mg/kg per os q 24 hr) was started (90 hr after re-presentation). Seventy-two hours after the urinary catheter was replaced, it was removed. There was no evidence of spontaneous hemorrhage around the IV catheter site, prepuce, and the feeding tube site. A repeat urine culture was then performed via cystocentesis, which was later reported as negative. The cat was discharged on buprenorphine^b and marbofloxacin^p. The cat had a recheck examination through his primary veterinarian 3 wk after discharge. He was normal at home with a PCV of 37%. Urine culture was declined by the owner because of a lack of urinary signs. At 11 mo after discharge, he had no recurrent urinary symptoms as reported by the owner.

Discussion

The cat in this report likely had a urinary bladder clot secondary to suspected trauma, which was causing his recurrent UO. Intravesical clot formation has been reported to occur secondary to hematuria in a male cat, dogs, and people.^2–8,11 Trauma as an underlying cause of this cat’s hematuria was supported by the history and physical examination findings consistent with trauma. Lack of evidence of hemostatic disorders on blood work at the time of re-presentation to the hospital makes a coagulopathy less likely; however, hemostatic testing was not performed at the original presentation. Although the urinary bladder clot was still noted on the aFAST scan before the initial discharge, the cat urinated twice following removal of the urinary catheter and the clot was not thought to be causing an active obstruction. The cat was discharged with the expectation that the clot could break down over time. However, the cat continued to have lower urinary tract signs and a recurrent obstruction developed within 2 days of his initial discharge. The clot was a similar size at re-presentation as it was at the time of the last measurement before discharge. The urinary bladder clot was considered the primary cause of recurrent UO; however, other possible reasons, such as urethral blood clots and/or mucoid plugs, urethral spasm, and UTI, for continued lower urinary tract obstruction signs could not be excluded.

Clot removal via surgical cystotomy in a male cat has been reported⁸ and would be considered as an option for resolution. A less invasive option might include cystoscopic breakdown, although feline urethral size would be the limiting factor. Medical breakdown via N-AC for urinary tract mucolysis is reported in humans^9,10 because it reduces the disulfide bonds inside multimeric proteins.¹³ Even though the efficacy to reduce urinary bladder mucus production is controversial in humans,^9,10 N-AC was elected for the management of intravesical bladder clot in this cat because of hospital availability and low perceived risk while thrombolytics were obtained.

In humans, thrombolytics have been described to treat urinary bladder clots.^4,11 tPA is the thrombolytic of choice because, unlike streptokinase, it only binds to clot-bound plasminogen and is less likely to induce a systemic fibrinolytic state.¹⁴ A previous study showed that tPA successfully re-established the patency of occluded dialysis catheters in dogs and cats¹⁵ and successfully dissolved canine urinary bladder clots.^6,7 In humans, the relatively large molecular size of tPA precludes its absorption through intact bladder mucosa.¹⁶ In this cat, no systemic complications were observed, and the thrombolytic effect appeared to remain localized to the bladder.

tPA has a reported short IV half-life of 3–9 min in humans¹¹ and 2–3 min in dogs.¹⁷ The half-life in cats has not been reported. Varying doses of tPA have been used to treat feline acute arterial thromboembolism from 1 mg/kg over 1 hr to 5 mg per cat over 4hr.^18,19 For treatment of intravesical urinary bladder clots in dogs, both 1 hr and 4 hr dwell protocols were successful.^6,7 The dosing of tPA in this cat was extrapolated from the canine reports and was significantly lower than the intravascular infusion dose. The dwell time of 2 hr was chosen arbitrarily because both the 1 and 4 hr protocols have been successful in dogs. This protocol appeared to be successful for clot dissolution in this cat.

One major limitation is that the intraluminal structure could not be conclusively proved to be a blood clot. In order to confirm the composition of the structure, histopathology is required. Other limitations include that clot dissolution may not have been solely due to tPA, because earlier intravesical saline and N-AC infusion and/or antibiotic treatment may have contributed to the breakdown of the clot. The clot size was assessed by ultrasound in two planes. For a true volume calculation, three-dimensional ultrasound, computed tomography, or MRI would have been required. Additionally, neither the traditional coagulation nor viscoelastic testing was performed during or after treatment for monitoring systemic anticoagulation. However, no systemic hemorrhage was reported in the cat.

Conclusion

This is the first case report to use tPA for dissolution of a urinary bladder clot in a cat. In this case report, the use of tPA appeared to be safe and successful and may be considered as a minimally invasive technique for intravesical thrombolysis in cats with lower urinary tract obstruction secondary to urinary bladder clots. The optimal dose, frequency, and dwell time are unknown and will need to be prospectively investigated.