The incidence of prostate diseases increases progressively with age, and among them, benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptoms (LUTS) in men [1,2]. As the prostate enlarges, it can lead to various LUTS such as urinary frequency and urgency [3]. In cases of BPH, surgical treatment is considered in various situations, including when medical treatment is ineffective, recurrent urinary tract infections (UTIs) occur, or urinary obstruction is present. The most effective surgical treatment for BPH is trans-urethral resection of the prostate (TURP), which has been widely regarded as the gold standard [4].

Holmium laser enucleation of the prostate (HoLEP) is indeed a safe and effective surgical procedure for BPH patients with LUTS. Compared to TURP, HoLEP offers several advantages, including reduced in blood loss, shorter hospital stays, and a lower risk of complications. Due to these benefits, HoLEP is preferred by many urologists as an alternative to TURP [5,6]. Trans-urethral enucleation with bipolar (TUEB) using the the trans-urethral resection in saline (TURis) bipolar system (Olympus, Tokyo, Japan) is also a procedure that has been developed as an alternative to HoLEP for the surgical treatment of BPH. TUEB aims to achieve similar outcomes in terms of efficacy and stability for patients. Several studies have investigated TUEB using the TURis bipolar system and reported positive results, suggesting that it can be an effective option for BPH treatment comparable to HoLEP [7-9].

Various complications can arise during trans-urethral prostate surgery, including the risk of surgical site bleeding. Significant bleeding may necessitate interventions such as continuous bladder irrigation (CBI), blood transfusion, or clot evacuation. Excessive bleeding can have serious consequences, including cardiopulmonary events, acute myocardial infarction, and even hypo-volemic shock in severe cases [10-14]. It is important for surgeons and medical teams to be vigilant in managing and preventing complications related to bleeding during and after the procedure. Indeed, there are several proposed techniques to reduce bleeding at the surgical site following prostate surgery. These include the administration of oral tranexamic acid or the injection of substances such as thrombin, phenol, and epinephrine into the prostatic fossa. These techniques aim to promote hemostasis and reduce postoperative bleeding. However, further research is necessary to evaluate their effectiveness, safety, and optimal application in clinical practice [14-17].

In this study, the authors implemented thrombin agent instillation in the prostatic fossa, the surgical site following trans-urethral prostate surgery. We evaluated various hematologic changes as well as post-operative parameters.

The goal was to compare and analyze the efficacy of blood loss after surgery. Additionally, the study aimed to investigate the impact on voiding function safety by employing uroflowmetry (UFM) before and after the surgical procedure. By assessing these factors, we sought to evaluate the effectiveness and potential benefits of thrombin agent instillation in reducing post-operative bleeding and preserving voiding function.

1. Materials

The data were collected from January 2019 to March 2023 from the outpatient population of the Department of Urology at this hospital, comprising individuals who presented with LUTS. We diagnosed BPH based on the patient’s medical history, urinalysis (UA), serum prostate-specific antigen (PSA) level, International Prostate Symptom Score (IPSS), trans-rectal ultrasonography (TRUS), digital rectal examination (DRE), peak flow rate (Qmax), voided volume, and post-void residual (PVR).

The study included a total of 122 patients (Figure 1). As a control group, we selected a total of 109 patients who were diagnosed with BPH and underwent trans-urethral prostate surgery, but did not receive peri-urethral thrombin instillation after the surgery from January 2019 to December 2021. Among them, 89 patients were finally selected as the control group, excluding 15 patients diagnosed with prostate cancer in biopsy, 3 patients discharged with Foley catheter insertion state and 2 patients who did not undergo CBI after the surgery.

Figure 1. Flow chart of patient’s selection process. 5-ARI: 5-alpha reductase inhibitor.

As a test group, we selected 39 patients who were diagnosed with BPH and underwent trans-urethral prostate surgery, followed by peri-urethral thrombin instillation from January 2022 to March 2023. Among them, 33 patients were ultimately selected as the test group, excluding 2 patients diagnosed with prostate cancer in biopsy, 4 patients discharged with Foley catheter insertion state after the surgery.

In all patients of both group, we checked the past medical history, including the use of anti-coagulant medications and 5-alpha reductase inhibitor (5-ARI) prior to the surgery. The pre-operative factors included in this study were prostate size through TRUS, PSA level, IPSS score, hemoglobin (Hgb) level, Prothrombin Time/International Normalized Ratio (PT/INR), platelet count, and UFM results. As post-operative factors, the following parameters were compared with their pre-operative values: operation procedure, resected prostate weight (in grams), Hgb level, PT/INR, platelet count, and UFM results. Additionally, we compared the duration of CBI, Foley catheter indwelling period, and inpatient period after the surgery. We also evaluated the occurrence of post-operative blood trans-fusion and monitored for potential complications such as urinary retention, UTIs, hematuria, urinary incontinence, and the need for re-operation. The surgical procedures were carried out by three experienced surgeons, each with their own expertise. It is important to note that this study was conducted retrospectively using computerized medical records.

2. Methods

All patients underwent surgery in the lithotomy position under either spinal or general anesthesia. Following the trans-urethral prostate surgery, a 22 Fr-3way Foley catheter was inserted, and saline ballooning of 30 cc was performed. Foley catheter traction was applied for 3 hours for hemostasis. After 6 hours, the balloon size was reduced from 30 cc to 20 cc to alleviate bladder irritation.

In the test group, a 5 Fr feeding tube was inserted into the prostatic fossa through the urethra adjacent to the Foley catheter. The feeding tube, which was 20 to 23 cm long, was positioned below the balloon hanging on the bladder neck. Meanwhile, we prepared the thrombin agent by dissolving Reyon Thrombin Lyophilized Powder 5,000 IU (a domestic product) with 5 cc of normal saline. The solution was then transferred to a new 5 cc syringe. After inserting the feeding tube into the prostatic fossa, the thrombin agent was instillated into the surgical site (prostatic fossa) through the feeding tube.

After positioning the tip of the feeding tube to the distal part of the balloon, ballooning was performed by inserting both the Foley catheter and feeding tube together, as shown in Figure 2. By positioning the balloon at the bladder neck, we anticipated that it would act as a barrier, preventing the thrombin agent from entering the bladder when the surgeon instillates the agent through the feeding tube. After the instillation of the thrombin agent, the feeding tube was removed. However, bladder manual irrigation was not performed to prevent the agent from being washed out from the surgical site. Blood transfusion was considered if the Hgb level was less than 10 mg/dL. After surgery, CBI was initiated at a full dose. If gross hematuria symptoms were resolved and corresponded to Hematuria Grade (HG) III, the CBI rate was gradually reduced to approximately one drop per second. Subsequently, if gross hematuria symptoms improved and corresponded to HG I or II, the CBI was discontinued. After holding the CBI, if HG I or II hematuria was maintained, the CBI was stopped, and the Foley catheter was removed [18].

Figure 2. Positioning the tip of feeding tube to the distal part of the balloon.

3. Statistical analysis

To test the differences in numerical values before and after surgery between the two groups, parametric variables were analyzed using independent t-tests, and non-parametric variables were analyzed using the Mann-Whitney U test. The analysis of continuous variables was conducted using independent t-tests. All statistical analyses were performed using IBM SPSS Statistics version 25.0 (IBM Corp., Armonk, NY, USA), and a significance level of P<0.05 was considered statistically significant.

In Table 1, the clinical characteristics of the two groups participating in the study are presented. The average prostate size and mean PSA level were 54.05±24.73 g, 5.47±5.78 ng/mL in the test group and 64.52±28.43 g, 6.41±11.44 ng/mL in the control group. The resected prostate weight after the surgery in the test group was 24.97±15.77 g and 27.58±17.00 g in the control group.

Table 1 . Clinical characteristics of the patients.

Group	Age (year)	TRUS (g)	TRUS_TZ (g)	PSA (ng/mL)	IPSS	Resection weight (g)
Test group (n=33)	71.52±7.15	54.05±24.73	32.94±21.61	5.47±5.78	18.91±12.31	24.97±15.77
Control group (n=89)	71.38±8.22	64.52±28.43	37.73±21.44	6.41±11.44	11.58±13.56	27.58±17.00
P-value	0.935	0.065	0.278	0.654	0.008	0.443

Group	Procedure (%)			Past history (%)
	TURP	TUEB	HoLEP	HTN	DM	Brain	Heart	Lung	Liver	Cancer	5-ARI	Anti-coagulant
Test group (n=33)	48.48	39.39	12.12	75.76	30.30	12.12	15.15	21.21	12.12	0.00	72.73	39.39
Control group (n=89)	24.72	34.83	40.45	52.81	26.97	7.87	14.61	10.11	3.37	5.62	66.29	25.84
P-value	0.330	0.007	<0.001	0.022	0.718	0.470	0.941	0.108	0.066	0.167	0.502	0.147

TRUS, trans-rectal ultra-sonography; TZ, transitional zone; PSA, prostate-specific antigen; IPSS, International Prostate Symptom Score; TURP, trans-urethral resection of prostate; TUEB, trans-urethral enucleation of bipolar; HoLEP, holmium laser enucleation of the prostate; HTN, hypertension; DM, diabetes mellitus; 5-ARI, 5-alpha reductase inhibitor..

In the test group, TURP was performed in 16 patients (48.48%), TUEB in 13 patients (39.39%), and HoLEP in 4 patients (12.12%). In the control group, TURP was performed in 22 patients (24.72%), TUEB in 31 patients (34.83%), and HoLEP in 36 patients (40.45%). In the test group, 13 patients (39.39%) were taking anticoagulant medications, while in the control group, 23 patients (25.84%) were taking anticoagulant medications. However, all patients discontinued anticoagulant medications at least one week before the surgery (Table 1).

The comparison of hematologic data before and after prostate resection between the two groups is shown in Table 2. In the control group, the changes in Hgb and platelet levels were −1.07±0.97 and −27.93±40.49, respectively. In the test group, the changes in Hgb and platelet levels were −1.05±0.81 and −42.79±35.59, respectively. The difference in Hgb change before and after surgery between the two groups was not statistically significant (P=0.857). However, there was a statistically significant difference of platelet reduction in the test group than the control group (P=0.033).

Table 2 . Comparison of the outcome between test group and control group - hematologic data (pre vs. post).

Group	Hgb (g/dL)		Platelet (×103/mL)		PT/INR		Hgb difference (g/dL)	Platelet difference (×103/mL)	PT/INR difference
	Pre	Post	Pre	Post	Pre	Post
Test group (n=33)	13.57±1.44	12.52±1.22	230.94±46.31	188.15±38.75	1.00±0.07	1.06±0.07	−1.05±0.81	−42.79±35.59	0.06±0.07
Control group (n=89)	13.70±1.44	12.62±1.59	238.48±65.12	210.55±58.83	1.01±0.16	1.07±0.08	−1.08±0.97	−27.93±40.49	0.05±0.14
P-value	0.650	0.745	0.543	0.045	0.512	0.685	0.857	0.033	0.624

Hgb, hemoglobin; PT/INR, Prothrombin Time/International Normalized Ratio; Pre, pre-operative value; Post, post-operative value..

The comparison of voiding parameters before and after trans-urethral prostate surgery between the two groups is shown in Table 3. When comparing the voiding patterns using UFM before and after surgery, there was no statistically significant difference in the change of UFM between the two groups. This suggests that peri-urethral thrombin instillation does not have a significant impact on post-operative voiding dysfunction in the patients.

Table 3 . Comparison of the outcome between test group and control group - voiding parameter (pre vs. post).

Group	Q max (mL/s)		Voided volume (cc)		PVR (cc)		Q max difference (mL/s)	Voided volume difference (cc)	PVR difference (cc)
	Pre	Post	Pre	Post	Pre	Post
Test group (n=33)	10.50±5.61	13.58±8.50	161.50±102.45	188.01±105.14	125.00±112.04	58.07±47.78	−3.38±7.84	−25.16±97.94	64.93±103.25
Control group (n=89)	9.46±7.17	14.92±8.41	125.97±81.87	189.19±113.66	85.44±110.00	64.20±61.66	−5.62±8.90	−68.31±113.74	33.18±110.86
P-value	0.490	0.458	0.077	0.960	0.112	0.622	0.254	0.086	0.202

Q max, peak flow rate; PVR, post-void residual; Pre, pre-operative value; Post, post-operative value..

Table 4 compares the CBI application time, Foley catheter indwelling time, and inpatient period between the two groups after surgery. In the control group, the mean CBI application time, Foley catheter indwelling time, and inpatient period were 34.42±22.68 hours, 70.33±33.95 hours, and 6.03±2.74 days, respectively. In the test group, these values were 21.31±12.15 hours, 50.97±14.63 hours, and 4.94±2.05 days, respectively. When comparing the CBI application time (P<0.001), Foley catheter indwelling time (P<0.001), and inpatient period (P=0.0205) between the two groups, statistically significant differences were observed. These indicate that the degree of hematuria improved more rapidly in the test group after surgery compared to the control group, allowing for a faster return to daily activities.

Table 4 . Comparison of the outcome between test group and control group - post operative relating period.

Group	CBI application time (hour)	Foley catheter indwelling time (hour)	Inpatient period (day)
Test group (n=33)	21.31±12.15	50.97±14.63	4.94±2.05
Control group (n=89)	34.42±22.68	70.33±33.95	6.03±2.74
P-value	<0.001	<0.001	0.0205

CBI, continuous bladder irrigation..

When we look at the complications that occurred in both groups after surgery, there were no blood transfusion in the test group, while 3 blood transfusions were done in the control group due to a decrease in Hgb levels. Also there were no re-operation in the test group on the other hand there was one patient in the control group who underwent trans-urethral coagulation due to persistent hematuria. Complications after trans-urethral prostate surgery in the control group such as urinary retention, UTIs, hematuria, and urinary incontinence were observed in 7, 12, 16, and 5 patients, respectively. In the test group, the respective numbers were 6, 1, 3, and there were no patients complaining of urinary incontinence (Table 5).

Table 5 . Comparison of the outcome between test group and control group - post operative relating period.

Group	Transfusion (n)	Re-operation (n)	Complication(n)
			Urinary retention	UTI	Hematuria	Urinary incontinence
Test group (n=33)	-	-	6	1	3	-
Control group (n=89)	3	1	7	12	16	5

UTI, urinary tract infection..

Therefore, in this study, we could observe that performing peri-urethral thrombin instillation resulted in fewer complications compared to the control group. This could be seen more clearly when it comes to hematuria. However, the number of samples in the test group was smaller than the control group, so further studies are expected in the future with a larger sample size.

Prostate diseases, including BPH, are highly prevalent worldwide among adult males. The prevalence of these conditions is estimated to be between 15% and 60% among 40s and can reach up to 80% among 80s. Moreover, the prevalence tends to steadily increase with age [1,2]. Currently, TURP, TUEB, and HoLEP are widely regarded as the gold standard surgical treatments for BPH. While these procedures may have slight variations in technique, they share the common goal of improving voiding function by removing or resecting the enlarged prostate [4,5,7-9].

When it comes to complication, hematuria is frequently reported after trans-urethral prostate surgery. In severe cases, it can lead to hemodynamic instabilities, including low Hgb levels, which may necessitate blood transfusion. Failure to address excessive bleeding can result hypovolemic shock, myocardial infarction, renal failure, brain ischemia, and septic shock due to post-operative infection. These outcomes can have a substantial impact on economic costs as well as increase surgical morbidity and mortality rates [10-14]. The etiology of bleeding before and after trans-urethral prostate surgery is multifactorial and involves the activation of the surgical trauma and fibrinolytic system of the prostatic dorsal venous plexus. In a systematic review conducted by Longo et al. [14], six studies reported blood loss values during surgery, and the use of tranexamic acid was found to reduce bleeding (standardized mean difference [SMD] −1.93, 95% confidence interval [CI] −2.81 to −1.05).

Thrombin agents, when applied to the wound surface, serve as hemostatic agents and promote tissue adhesion, aiding in the cessation of bleeding. In the context of this study, the application of thrombin agents in a liquid state demonstrated the ability to stop bleeding without adversely affecting voiding function, as confirmed through postoperative UFM. Additionally, the use of thrombin agents was observed to prevent hemodynamic instabilities. It is also worth considering the potential effects of post-operative thrombin agent instillation on thrombus formation or thromboembolic events in other organs such as the brain and heart. Previous reports have indicated that approximately 1-5% of patients undergoing urological surgery experience venous thrombo-embolism [19]. However, in this study, no patients experienced such complications. Based on these findings, it can be assumed that there are no significant safety concerns associated with the application of thrombin agents in this context.

In this study, the test group showed a significantly greater decrease in platelet level compared to the control group before and after the surgery. Although thrombin instillation itself does not directly cause platelet reduction, it was suggested that it may induce platelet activation and aggregation by affecting glycoproteins within the platelet, leading to their consumption and resulting in a temporary decrease in platelet level [20]. Furthermore, studies by George et al. [21] have shown that von Willebrand factor (vWF) binds to glycoproteins on platelet receptors, facilitating platelet aggregation. However, the instillation of thrombin disrupts vWF binding, hindering its role as a hemostasis mediator. Considering this, it can be hypothesized that the thrombin agent used in this study temporarily decreased platelet level.

The results of this study showed that after trans-urethral prostate surgery, the test group had shorter CBI application time, Foley catheter indwelling time, and inpatient period compared to the control group. Also, none of the patients in the test group required post-operative blood transfusion or re-operation due to surgical site bleeding. However, it should be noted that the study did not classify patients based on prostate size. Therefore, further research with a larger sample size is needed to determine the effectiveness of post-operative thrombin instillation specifically in patients with a large prostate size.

Several studies have demonstrated the potential benefits of liquid fibrin glue and thrombin agents in reducing post-operative blood loss and the need for blood transfusion in trans-urethral prostate surgery. Some studies have focused on the use of fibrin glue during and after trans-urethral prostate surgery, showing a reduction in blood loss in most cases, although the effect on the patient’s LUTS score was not clearly demonstrated [16,17]. In the study conducted by Luke et al. [17], it demonstrated a significant reduction in post-operative blood loss in 15 patients who underwent fibrin glue instillation at the prostatic fossa after TURP (P<0.01). According to Mebust, the two most common complications after trans- urethral prostate surgery, including TURP, are bleeding requiring blood transfusion (3.9%) and clot retention (3.3%) in the bladder. Additionally, other considerations after surgery may include temporary urinary retention and UTIs [22]. In the test group of this study, compared to the control group, thrombin agent instillation was found to have no significant impact on voiding function and a notably lower frequency of complications such as urinary retention, UTIs, hematuria, and urinary incontinence. This suggests that thrombin agents do not have a significant effect on voiding function and are not associated with an increased risk of UTIs caused by external substances.

However, this study has several limitations that should be considered.

The trans-urethral prostate surgical techniques were not standardized and were not performed by a single surgeon. This lack of standardization may have introduced variability in surgical outcomes, as each surgeon may have had different propensities and approaches. And, the patient group included in the study was relatively small. A larger sample size would provide more statistical power and enhance the generalizability of the findings.

The study was conducted retrospectively, and the follow-up period after surgery was relatively short. A longer follow-up duration would allow for a more comprehensive evaluation of the outcomes and potential complications. Additionally, this study primarily focused on assessing improvements in voiding function through UFM results and relied on patients’ self-reported postoperative complications when they visited the hospital. Further evaluation using additional objective measures and longer-term follow-up would provide a more comprehensive understanding of the outcomes. Therefore, it is important to acknowledge these limitations and further research is needed to address these gaps and provide more robust evidence.

In conclusion, we have confirmed that thrombin instillation at prostatic fossa after trans-urethral prostate surgery could contribute to shortening CBI application periods as well as Foley catheter indwelling periods to improve significant complication, hematuria. This intervention could also lead to a faster recovery and a quicker return to daily activities for patients following surgery.

No potential conflict of interest relevant to this article was reported.