Advancement of haemostatic self-assembling peptides in the treatment of gastrointestinal bleeding: What role for PuraStat®?

Abstract

PuraStat^® is a novel self-assembling peptide (SAP) used as a haemostatic agent in endoscopy, with widespread application in surgical settings. While the current evidence, though deserving further expansion, demonstrates a good haemostatic performance profile for this substance, there remains significant heterogeneity among studies, and an analysis of this SAP as monotherapy is not always available. The recent study by Bellester et al in the World Journal of Gastrointestinal Endoscopy provided an optimal effectiveness profile of this SAP in 45 patients treated for gastrointestinal (GI) bleeding, particularly highlighting data on its use as monotherapy in upper GI bleeding. This invited article outlines the current evidence on PuraStat^® and offers a commentary on the recently published study.

Key Words: PuraStat^®; Haemostasis; Digestive endoscopy; Gastrointestinal bleeding; Self-assembling peptides; Haemostatic therapy; Peptic ulcers

Core Tip: PuraStat^® is a novel self-assembling peptide haemostatic agent used in digestive endoscopy. This commentary summarises the efficacy and safety profile of PuraStat^® as discernible from the current literature, focusing on the study published in the World Journal of Gastrointestinal Endoscopy, highlighting its potential role and the need for further investigation.

TO THE EDITOR

We have read with interest the original work recently published in the World Journal of Gastroenterology by Ballester et al[1], entitled “Efficacy and applications for PuraStat^® use in the management of unselected gastrointestinal bleeding: A retrospective observational study”, in which the authors assessed the performance of PuraStat^® in achieving initial endoscopic haemostasias in a gastrointestinal (GI) bleeding setting. New haemostatic mechanisms are growing, including novel haemostatic gels, new haemostatic powders, and over-the-scope methods such as calcium electroporation[2-5]. The examination of new haemostatic techniques is therefore necessary in endoscopy. Thus, we aim to provide further discussion points in this invited commentary.

Hemostasis in gastrointestinal endoscopy: What is the current status of nonvenous bleeding? Standards of care

Currently, in upper GI nonvariceal haemorrhage, endoscopic treatment is tailored to the aetiology of the bleeding event. In the case of peptic ulcer, a prevalent cause, active bleeding (Forrest Ia, and Ib) is preferably managed with combination therapy involving epinephrine injection along with a second haemostatic technique (typically contact thermal or mechanical methods)[6]. A cap-mounted over-the-scope clip is particularly indicated for complex ulcers, such as huge ones (i.e., > 2 cm) or those with a large bleeding vessel[6]. For non-actively bleeding ulcers (i.e., Forrest IIa), various options are recommended, including thermal therapy, mechanical therapy, or sclerosant injection therapy, either as monotherapies or in combination with epinephrine injection (the latter never being used as monotherapy)[6]. In cases of persistent bleeding, rescue therapy generally involves the application of a topical haemostatic spray or an over-the-scope clip[6]. In the case of lower GI bleeding, mechanical haemostasias is generally recommended, using through-the-scope or over-the-scope clips or endoscopic band ligation for diverticular haemorrhage[7]. Argon plasma coagulation is the preferred approach for bleeding of angiodysplasia origin[7]. Lastly, for post-polypectomy bleeding, both the aforementioned treatments and a topical haemostatic agent as a rescue therapy are advised[7].

PuraStat^®: Mechanism of action and available evidence

PuraStat^® (3-D Matrix Europe SAS, France) is a synthetic transparent peptide solution that, upon contact with blood, forms a three-dimensional matrix induced by a pH shift driven by blood ions[8]. It is supplied in pre-filled 3 mL syringes and is administered via a dedicated through-the-scope catheter (PuraStat^® Nozzle System Type-E, 2.8 mm, TOP Corporation, Tokyo, Japan)[8]. Due to these characteristics, PuraStat^® belongs to the category of self-assembling peptides (SAP).

Dhindsa et al[8] conducted a meta-analysis on SAP as a novel method of endoscopic haemostasis, identifying seven studies involving 427 patients, of which five were prospective and only three were of high quality. The pooled haemostatic success rate was 93.1% (95%CI: 84.7-95.2), with study heterogeneity exceeding 70%. The pooled rebleeding rate was 8.9% (95%CI: 5.3-14.4), with heterogeneity of 55.8% among the included studies. Notably, no adverse events were reported in the studies involving SAP. An interesting finding was that combination haemostatic therapy increased the pooled haemostasias rate by 3% compared to SAP monotherapy (96% vs 93.1%). It is worth noting that most treated lesions resulted from endoscopic mucosal resection or endoscopic submucosal dissection, while only a minority were due to peptic ulcers or bleeding tumours.

Additional studies not included in the aforementioned meta-analysis are listed in Table 1[9-20]. The table shows that this SAP is gradually emerging in the endoscopic field for various indications. However, the number and design of studies remain insufficient to generate high-quality, robust evidence for a strong recommendation as a frontline agent in the various described settings.

Table 1 Recent studies on the use of PuraStat^® in digestive endoscopy as a haemostatic agent for gastrointestinal bleeding.

Ref.	Study design	n	Treated lesion(s)	Efficacy
Oza et al[9], 2024	Case series	10	Anastomotic ulcers	90%1
Higashino et al[10], 2024	Case report	1	Mallory-Weiss syndrome	100%2
Yamaguchi et al[11], 2024	Retrospective	25	Colonic diverticular bleeding	100%3
Maselli et al[12], 2024	Retrospective	91	Various (active bleeding)	98.9%
Yoshida et al[13], 2024	Retrospective	122	Perioperative colorectal cold snare polypectomy under anticoagulant	92.6%
Gomi et al[14], 2024	Retrospective	101	Post-endoscopic submucosal dissection ulcer prevention	94.1%4
Murakami et al[15], 2023	Case series	25	Various (active bleeding)	92%5
Okumura et al[16], 2023	Case report	1	Endoscopic submucosal dissection bleeding	100%
Nakahara et al[17], 2023	Case report	1	Fistula bleeding (endoscopic ultrasound-guided hepaticogastrostomy)	100%
Kubo et al[18], 2023	Case series	6	Various (active bleeding)	100%
Ishida et al[19], 2022	Case series	6	Sphincterotomy-related hemorrhage	100%
Gagliardi et al[20], 2021	Case report	1	Solitary rectal ulcer syndrome	100%6

¹In this series, only 4 out of 10 patients had active gastrointestinal bleeding at the level of the anastomotic ulcer. Therefore, the primary focus was on assessing the potential of PuraStat^® to promote ulcer healing and improve the patients' clinical condition. Over a three-month follow-up period, ulcer healing was observed, with clinical improvement in 9 out of 10 patients.

²The case was initially treated with mechanical haemostasias (clipping) without success.

³Two patients were treated with monotherapy, while the majority (23 patients) received combination therapy—13 out of 23 with endoscopic band ligation and 10 out of 23 with mechanical haemostasias using clipping.

⁴The efficacy rate was calculated considering that 6 out of 101 patients (5.9%) developed post-endoscopic submucosal dissection bleeding among those who had been preventively treated with PuraStat^® after gastric endoscopic submucosal dissection.

⁵PuraStat^® was used as monotherapy in 6 out of 25 cases.

⁶Although the patient had anaemia, there was no overt bleeding as the primary clinical manifestation.

A subsequent meta-analysis of 17 studies was published by Voiosu et al[21] in 2024, one year after the previously described meta-analysis, including 925 patients. This analysis demonstrated a pooled haemostasis rate of 87.7% (95%CI: 38%-100%) and a pooled rebleeding rate of 4.7% (95%CI: 0%-16.2%). Safety outcomes were favourable, with less than 1% of adverse events. Among the SAP-related adverse events, one case of mild elevation of uric acid and liver transaminases and one case of hyperamylasaemia following endoscopic sphincterotomy were reported.

One of the challenges associated with using gels or, more generally, non-mechanical/thermal haemostatic methods is the potential migration of the applied substance, which poses a particular risk of rebleeding and the transient nature of the treatment. Despite this, various techniques have been proposed for PuraStat^® to address these issues. Sugawara et al[22] introduced the "dumpling method" in a case report of endoscopic submucosal resection for early gastric cancer complicated by post-procedure bleeding on day five, which had already failed treatment with radiofrequency coagulation. The authors created a pocket using an indwelling snare and clip to retain PuraStat^®, enhancing its stability at the bleeding site. Additionally, Ogura et al[23] have suggested that haemostasis achieved with this SAP can be assessed using red dichromatic imaging.

What data does this new study provide? Considerations about data and study limitations

This new study by Ballester et al[1] conducted a single-center retrospective analysis over two years (2020-2022), including cases of GI bleeding treated with PuraStat^®. The outcomes assessed were initial haemostasis (cessation of bleeding after SAP application), persistent bleeding (continuation of bleeding despite SAP application), rebleeding, and survival rates at 30 days following endoscopic haemostasis with this SAP. The study included 45 patients, generally of advanced age, with a mean age of 65.8 years and a Charlson score > 2 in over half of the cases (60%). The most common causes of bleeding treated were primarily peptic ulcers (accounting for 77.7% of procedures, which were gastroscopies) and post-endoscopic mucosal resection bleeding. SAP monotherapy was performed in 36% of cases, with no significant differences observed compared to combination therapy. The initial haemostasis rate was 100%, with a 30-day rebleeding rate of 11.1% and a 30-day survival rate of 82.2%.

This study confirms the good performance of this new SAP in the endoscopic treatment of GI haemorrhagic lesions. As an add-on, it also examined the endoscopist's experience using the haemostatic gel, reporting ease of use in 88.9% of cases without any folding or other alterations of the through-the-scope catheter during the procedures. However, there are some additional elements for discussion. In addition to what has already been reported by the authors, the sample size is minimal for a haemostatic device that has been on the market for several years and within a dataset where this SAP was used as monotherapy in only a small minority of cases—an additional limitation that restricts the weight of its standalone efficacy. Furthermore, we do not entirely agree with the authors on some definitions of outcomes. The study refers to efficacy; however, the study design, neither randomised nor controlled, prevents using this term. Instead, this study primarily addresses the effectiveness of this haemostatic device. It is well known that these two definitions are distinct, with efficacy characteristic of trials and not observational studies, particularly retrospective ones[24].

Moreover, this SAP as monotherapy was used in 87.5% of cases of upper GI bleeding, preventing firm conclusions from being drawn for lower GI bleeding.

An additional statistical limitation is the lack of indication from the authors regarding the normality of the distribution of variables, despite using a Student’s t-test, even though the sample size is extremely small[25]. This raises concerns about the appropriateness of a parametric test in this scenario. However, this issue pertains to sub-analyses that would, in any case, be considered exploratory. Thus, the most relevant data in this study remain the crude rates of haemostatic effectiveness, which are not influenced by these statistical tests.

Despite these limitations, this study presents data that, although highly heterogeneous and challenging to interpret regarding bleeding aetiologies, remain necessary given the ongoing need to gather further evidence on this SAP. This is particularly relevant considering the marked inter-study heterogeneity that meta-analyses have highlighted.

CONCLUSION

In conclusion, this new retrospective study adds data on the use of the SAP PuraStat^® in treating GI bleeding endoscopically, whereas much of the existing literature, as is well known, has been derived from surgical practice. More extensive studies are imperative to provide further insights, particularly regarding using this agent as a first-line haemostatic therapy and comparing it with other haemostatic agents and techniques.