Hemostasis: Role of PuraStat® in the prevention and management of gastrointestinal bleeding

Abstract

The management of gastrointestinal (GI) bleeding patients during endoscopy remains a challenge. Hemorrhage is still one of the significant causes of morbidity and even death. Several therapeutic options have been used over the years depending on the extent, site and cause of bleeding. These include thermal therapy, injection therapy, and mechanical methods of hemostasis (e.g., endoscopic clips and ligation bands). Patients with refractory bleeding, high-risk ulcer lesions, malignant disease, antiplatelet medications, and chronic kidney disease are at increased risk of upper and lower GI bleeding (LGIB). In this editorial, I commented on the paper by Ballester et al. Their work aimed at evaluating PuraStat^® (TDM-621), a novel hemostatic agent, particularly its efficacy, applications, feasibility, and safety in treating GI bleeding lesions. The authors concluded that PuraStat^® is an effective therapy for GI bleeding and is usually easy to use. Although the authors recommended its consideration as a frontline therapy in the future, they did not explore the clinical and GI uses of PuraStat^®. This editorial focuses on the pharmacology of PuraStat^® and how it differs from Hemospray^® (TC-325) (hemostatic powder). It also explores the current experience of using PuraStat^® in upper and LGIB, its uses and safety, and the need for further research to fully understand its potential.

Key Words: PuraStat^®; Hemostatic; Prevention; Management; Endoscopy; High-risk bleeding; Procedure; Safety; Efficacy; Gastrointestinal bleeding

Core Tip: Patients experiencing upper or lower gastrointestinal (GI) bleeding, whether due to a medical condition or an endoscopic procedure, should be managed immediately using a simple, effective and safe agent or technique. PuraStat^® (TDM-621) is a novel transparent, self-assembled hydro-peptide gel with a hemostatic effect that has been used in endoscopic and surgical procedures, particularly for preventing and managing GI bleeding. It is unique in its ability to adhere to the bleeding site, forming a protective barrier and promoting rapid hemostasis. It has been proven effective and safe compared to currently used agents.

INTRODUCTION

The management of gastrointestinal (GI) bleeding during endoscopy remains challenging. GI bleeding, both upper and lower, continues to contribute significantly to morbidity and mortality[1,2]. In the United States, approximately 350000 hospital admissions occur annually for upper GI bleeding (UGIB)[3], commonly due to peptic ulcer disease, esophagogastric varices, and erosive esophagitis. Incidence increases with age and is more prevalent in men. Clinical presentation includes melena, hematemesis, and hematochezia in severe hemodynamic compromise[4,5].

Lower GI bleeding (LGIB) encompasses a wide range of causes[6,7]. In the United Kingdom, diverticular bleeding accounts for 26.4% of LGIB cases[8]. A Japanese multicenter study of 10342 patients with acute hematochezia utilized computed tomography (69%) and colonoscopy (88%), achieving a diagnostic yield of 94.9%, with diverticular bleeding most common[9]. Other frequent causes include ischemic colitis, hemorrhoids, angioectasias, colorectal neoplasia, post-polypectomy bleeding, and inflammatory, infectious, or radiation-induced colitis[10,11]. Diagnosis is typically guided by clinical presentation, examination, and confirmed via endoscopy. Initial management prioritizes resuscitation, followed by endoscopic diagnosis and therapeutic intervention to control and prevent rebleeding.

This editorial emphasizes endoscopic therapies for UGIB and LGIB, focusing on hemostatic options used over time based on severity, site, recurrence, and etiology. Modalities include: (1) Injection therapy (e.g., epinephrine, sclerosant); (2) Ablation therapy [e.g., thermotherapy, electrotherapy, argon plasma coagulation (APC), laser phototherapy]; (3) Mechanical therapy (e.g., endoscopic clipping, band ligation); and (4) Combination therapy (e.g., injection plus ablation or mechanical methods).

Patients with refractory bleeding, high-risk ulcers, malignancy, antiplatelet therapy, or chronic kidney disease have elevated risk. Hemostatic agents are mostly made of animal-derived collagen or human blood products such as thrombin and fibrin-coated collagen fleece[12], known for biocompatibility but associated with risks of viral transmission and allergic or anaphylactic reactions due to animal components[13].

PuraStat^® (TDM-621), a novel transparent, self-assembling hydrogel peptide, has emerged as a hemostatic agent in endoscopic and surgical contexts[14]. It is now used for bleeding from small GI vessels. Its efficacy and lack of the risks linked to traditional agents enhance its clinical appeal[15]. This editorial will explore the pharmacologic and physiologic mechanisms of PuraStat^®, contrast it with Hemospray^® (TC-325), a hemostatic powder, and evaluate its uses, efficacy, and safety in diverse GI bleeding scenarios.

PHYSIOLOGY OF HEMOSTASIS AND ENDOSCOPIC THERAPY

Historically, surgical bleeding was controlled with heated cautery (thermotherapy). In the 1500s, Ambroise Paré introduced ligation of major vessels and limb amputation for hemorrhage control[16,17]. The advent of electric cautery advanced intraoperative hemostasis (electrotherapy). Despite transfusion use during major blood loss, transfused red cells can elicit systemic inflammation and nonspecific immunosuppression, thus reinforcing the importance of meticulous surgical technique to minimize hemorrhage and coagulopathy[18].

Hemostasis is the physiological process that halts bleeding[19]. It depends on a balance between procoagulant and anticoagulant factors and proceeds in four phases: (1) Primary; (2) Secondary; (3) Tertiary; and (4) Quaternary.

Primary phase involves vasoconstriction at injury sites via vasoactive substances (e.g., thromboxane A2, serotonin) and platelet aggregation to form a platelet plug[15]. This principle is applied in endoscopic therapies such as injections of epinephrine, normal saline, sclerosants, thrombin, or fibrin glue. Diluted epinephrine (1:10000) is widely used in acutely bleeding peptic ulcers due to vasospasm, tamponade, and prothrombotic effects. It is easy to administer, has immediate effects, and is relatively safe in patients without coronary artery disease, although rebleeding may occur due to transient effect and absence of durable clot formation. Multiple studies have evaluated dosing strategies and compared epinephrine to saline and sclerosants[20-22].

Normal saline, while safer for patients with cardiac comorbidities, lacks vasoconstrictive effects and primarily exerts tamponade[23]. Sclerosants (e.g., polidocanol, ethanolamine) act through chemical irritation, causing local inflammation, oedema, and thrombogenesis, but are less effective than epinephrine and rarely used. Sequential epinephrine-sclerosant injection is more efficacious in active bleeding[22,24]. Thrombin injection has not demonstrated superiority over sclerosants like polidocanol[22,25,26]. Fibrin sealants, promoting clot formation via local thrombin and fibrin mixing, have limited clinical success and are associated with rebleeding[27].

Secondary phase activates the coagulation cascade through tissue factor and factor VIIa, culminating in thrombin formation, fibrin conversion, and stable thrombus formation. This mechanism underlies thermal endoscopic therapies, including thermotherapy, electrotherapy, APC, and laser phototherapy. These approaches promote coagulation via: (1) Thermal denaturation and clotting; (2) Cascade activation leading to platelet aggregation and fibrin formation; and (3) Vasoconstriction and vascular hemostasis[28]. Thermotherapy and electrotherapy involve contact, while argon plasma and laser techniques do not. Argon plasma achieves coagulation through ionized gas, is cost-effective, and safer than laser therapy, which is largely obsolete due to a higher perforation risk (3%), cost, and reduced efficacy[29].

The tertiary phase involves endogenous anticoagulants that modulate coagulation, while the quaternary phase activates fibrinolysis to limit thrombus propagation[19]. Though these phases are not directly targeted in endoscopic interventions, mechanical therapies such as endoscopic clipping and band ligation emulate surgical ligation by providing immediate mechanical vessel occlusion. Clipping (e.g., homoclip) is highly effective for primary hemostasis, and band ligation remains the mainstay for esophageal variceal bleeding[30].

LIMITATIONS OF CURRENTLY USED INJECTION AGENTS, ABLATION THERAPY AND MECHANICAL THERAPY

Optimal endoscopic therapy should be straightforward, safe, promptly effective, minimize rebleeding risk, and remain efficacious across diverse comorbidities. However, as previously discussed, conventional modalities are not without limitations and may result in complications (Table 1)[23,29-39].

Table 1 Limitations and disadvantages of methods used in endoscoping therapy of gastrointestinal bleeding.

Endoscopic therapy method		Limitations/disadvantages	Ref.
Injection therapy	Epinephrine	May cause systematic effects on the cardiovascular system including hemodynamic changes. Comparing injecting actively bleeding ulcers at endoscopy with epinephrine alone or in combination with absolute alcohol shows initial hemostasis in 97.5% with epinephrine and 94.9% in the combination group. No significant differences between the groups in rebleeding (9 vs 6), emergency surgery (12 vs 9), transfusion needs, hospital stay (5 days vs 4 days), mortality (94 vs 7), or ulcer healing at 4 weeks (50 days vs 46 days). Systematic changes including severe hypertension, and ventricular tachycardia, following epinephrine injection. Endoscopic injection of a small volume (3-11 mL) of diluted epinephrine caused a rise in the plasma epinephrine concentration by 4-5 times above the basal level. Hypertensive emergency and ventricular tachycardia were reported. Rebleeding has been reported (10%-20%)	Schlag et al[31], Chung et al[32], von Delius et al[33], Sung et al[34], Stevens et al[35]
	Normal saline	Less effective compared to injecting epinephrine. It is usually used in patients with coronary artery disease. It may act by producing primary tamponade. It has no vasospasm effect. Rebleeding usually occurs if used alone	Pinkas et al[23]
	Sclerosant (e.g., polidocanol, ethanolamine, ethanol)	Polidocanol is not commonly used. It has no benefits over epinephrine. The incidence of complications from sclerotherapy vs banding in patients with esophageal varices were: Esophageal stricture formation 25.6% vs 1.9%, ulcer bleed 25.4% vs 5.7%, esophageal perforation 2.2% vs 0%, and massive esophageal hematoma 16% vs 0%	Bataller et al[36], Schmitz et al[37]
Ablation therapy	Thermotherapy and electrotherapy	Higher rebleeding rates after the use of contact thermal therapy for gastrointestinal-related tumor bleeding, despite initial successful hemostasis	Ofosu et al[38]
	APC	Endoscopic APC for treating hemorrhagic radiation proctitis was successful (79%), patients had self-limiting early complications (18.7%), late complications of rectal stenosis (3.3%). Depth of injection is unpredictable and may fail to stop bleeding	Siow et al[39]
	Laser phototherapy	Is becoming obsolete. A higher risk of gastrointestinal perforation. Less effective in stopping bleeding compared to other methods	Kay et al[29]
Mechanical therapy	Endoscopic clipping band ligation	Requires highly skilled endoscopist. Applications of the clips can be difficult with massive bleeding. Sometimes clips dislodge prematurely causing recurrent bleeding	Ji et al[30]

APC: Argon plasma coagulation.

PuraStat^® (TDM-621)

PuraStat^® (also known as PuraBond^® or 3-D Matrix-621) is a synthetic, transparent, self-assembling hydrogel peptideproven effective in hemostasis for GI bleeding[40]. It consists of a 2.5% RADA16 formulation, a class II medical device for human hemostatic use. RADA16 is a linear oligopeptide with a repeating 4-amino acid sequence composed of arginine (R), alanine (A), and aspartic acid (D) residues[41]. In this editorial I am using PuraStat^® all through the manuscript. PuraStat^® forms an extracellular scaffold upon exposure to blood, creating a mechanical barrier that aids intrinsic hemostasis. The peptide solution solidifies into a hydrogel when contacted with blood and tissue potential of hydrogen (pH)[42].

What do we mean by self-assembling

Self-assembly refers to the spontaneous molecular organization into structured arrangements, a process occurring naturally across scales, from cells to large organisms. This phenomenon is thermodynamically driven, with kinetics influencing structural and functional integration[43,44].

What is the role of extracellular matrix in underlying hemostasis mechanism

The extracellular matrix (ECM) is composed of collagen nanofibers that provide structural support and guide cell function during tissue remodeling. Collagen offers tensile strength, while elastin provides flexibility, essential for tissue repair[45]. Hydrogel peptides, like PuraStat^®, mimic the ECM by forming nanofiber networks, enabling biodegradability and non-toxicity, making them ideal for hemostatic use[46]. Originally studied in vascular surgery, PuraStat^® has been applied in vascular anastomoses[47], nasal endoscopic surgery[48], prevention of nasopharyngeal adhesions[48,49], endocrine procedures (e.g., thyroidectomy)[50], and GI bleeding[51].

Hemostatic powder

Hemospray^® (TC-325) is a hemostatic mineral-based powder that achieves hemostasis via a multimodal mechanism. It contains no human, animal, or botanical components and has no known allergens. Upon contact with blood or tissue fluids, its granules absorb water, swell, and adhere to bleeding sites, forming a mechanical barrier that seals bleeding within seconds[52]. Hemospray^® (TC-325) is biocompatible and non-toxic, as shown in an animal study by Giday et al[53], where all treated animals achieved hemostasis within one hour and showed no rebleeding or adverse histological outcomes.

Administered via endoscopic spray, Hemospray^® (TC-325) is activated only at bleeding sites and is eliminated within 12–24 hours. Despite its ease of use and safety profile, limitations include: (1) The necessity of direct application; (2) Risk of catheter blockage from ambient moisture; (3) Ineffectiveness in variceal bleeding; and (4) Potential for only temporary control, necessitating adjunctive therapy[54]. Hemospray^® (TC-325) has been used effectively in upper GI bleeding[55], as monotherapy for acute GI bleeding (AGIB)[56], in tumor-related bleeding[57], and in both upper and lower GI bleeds[58].

COMPARING PURASTAT^® (TDM-621) AND HEMOSPRAY^® (TC-325)

Table 2 compares the pharmacological and clinical uses of PuraStat^® and the standard hemostatic powder [Hemospray^® (TC-325)] to highlight their differences][41,42,47-50,52,59].

Table 2 summarises the pharmacological and clinical aspects of PuraStat^® and hemostatic powder [Hemospray^® (TC-325)].

Item	PuraStat® (3-D Matrix-621)	Hemostatic powder spray [Hemospray® (TC-325)]	Ref.
Structure and active component	A synthetic hydrogel peptide. It is a 25% RADA16, a linear oligopeptide containing 16 amino acids as repeated 4-amino acids sequence containing R (positively charged arginine), A (hydrophobic alanine), and D (negatively charged aspartic acid) residues	A mineral-based hemostatic powder. It is calcium-based or silicate minerals	Sankar et al[41]
Human and animal proteins	N/A	N/A
Mechanisms of action	It forms an extracellular scaffold matrix when activated by the change in potential of hydrogen that occurs upon contact with blood	The granules once exposed to blood or tissue fluids; absorbs all the water causing its swelling and adherence to the bleeding sites	Uraoka et al[42], Sung et al[52]
Clinical uses	Used for upper and lower GI bleeding. Also, bleeding after EMR or esophageal and colonic submucosal dissection, and other surgical procedures	Primarily used for non-variceal GI bleeding	Stenson et al[47], Friedland et al[48], Wong et al[49], Gangner et al[50]
Application in endoscopic procedures	Applied via a catheter through an endoscope	The powder is delivered via a spray mechanism using inert gas e.g., nitrogen
Biocompatibility	Nontoxic	Biocompatible and nontoxic
Degradation	Is absorbable. It does not require removal after application	Is absorbable. It does not require removal after application
Immunogenicity	Nonimmunogenic	Nonimmunogenic
Clinical safety	Quite safe	Quite safe, and it washes out at 12 hours to 24 hours
Limitations and adverse effects	Less effective in massive and large bleeding areas. In a multicenter prophylactic randomised controlled trial testing its hemostatic prophylactic effect after EMR (large lesions in the duodenum and colorectum, no reduction in the rate of delayed bleeding observed)	Any type of moisture in the area will result in amalgamation of the powder which may block the delivery catheter. Not suitable for variceal bleeding	Drews et al[59]

EMR: Endoscopic mucosal resection; GI: Gastrointestinal; N/A: Not applicable.

USE OF PURASTAT^® IN GASTROINSTINAL BLEEDING

Critical assessment of studies on PuraStat^® in treating patients with upper, lower or other GI bleeding and current evidence on its efficacy, safety, and associated side-effects is crucial.

UGIB

In a single center randomized controlled trial, Subramaniam et al[40] studied 101 patients undergoing endoscopic esophageal and colonic submucosal dissection (ESD). Participants were randomized into a control group (bleeding was controlled using diathermy), and an intervention group (bleeding was controlled using PuraStat^®). At 4 weeks both groups underwent fellow up endoscopy. The authors found that in the interventional group there were significant reduction in the use of heat therapy compared with the control group (49.3% vs 99.6%, P < 0.001). However, there were no differences between the two groups in the duration of the procedure or time for hemostasis or delayed bleeding. At follow up endoscopy, 4 weeks later, there were complete wound healing in 48.8% of patients in the intervention group compared with 25.0% in the control group (P = 0.02). Another study on the use of PuraStat^® to prevent bleeding after ESD of a gastric tumor was reported recently by Gomi et al[60]. The authors recruited 101 patients (intervention group) who underwent ESD for gastric diseases and received PuraStat^® for post-ESD ulcers. They explored retrospectively another group of 297 patients who underwent ESD for gastric diseases at the same hospital but not managed using PuraStat^® (control group). They reported post-ESD bleeding in 5.9% and 6.7% in the intervention and control group, respectively. The difference was not significant. The stomach lesser curvature or anterior wall was the bleeding site in all 6 patients who experienced postoperative bleeding in the PuraStat^® group. Further analysis using multivariate analysis, the odd ratios for resection diameter, and oral anticoagulant use were 6.63 and 4.04, respectively. The adjusted odds ratio of post-ESD bleeding and PuraStat^® was 1.28. The authors concluded that the use of PuraStat^® is not associated with post-ESD bleeding. However, gravitational forces may affect the effectiveness of applied PuraStat^®[60].

Branchi et al[14] in a prospective, multicentre pilot study evaluated the feasibility, safety, efficacy and indications of PuraStat^® in 111 patients with acute non-variceal GI bleeding. Primary and secondary applications of PuraStat^® were examined. The efficacy of using PuraStat^® was evaluated during the procedure and at the third and seven and 30 days after the procedure. Seventy percent of patients had UGIB, and 30% had LGIB. Primary application of PuraStat^®, resulted in initial hemostatic success in 94% of patients, and in 75% of patients when PuraStat^® was used as a secondary hemostatic agent (standard techniques failed to cause hemostasis in these patients). The follow up at 3 days and 7 days post-procedure showed success rates in 91% and 87% after primary use, and 87% and 81% in both groups. Overall, rebleeding rate at 30-day follow up was 16%. Five patients finally required surgery. The authors concluded that PuraStat^® is effective as temporary agent in hemostasias and stabilisation[14].

de Nucci et al[15] aimed to assess the ease of use, safety and efficacy of PuraStat^® in controlling AGIB. Their study included 77 patients who were treated for acute upper and lower AGIB. In half of the patients, bleeding occurred as a complication of a previous endoscopic procedure, mainly endoscopic mucosal resection (EMR) and endoscopic retrograde cholangiopancreatography (ERCP). Other patients in the study had bleeding peptic ulcers, angiodysplasia, cancers, and surgical anastomoses. PuraStat^® was used after the failure of at least two conventional hemostatic methods. PuraStat^® achieved successful hemostasis in over 90% of patients. In 41 patients, once hemostasis was obtained with PuraStat^®, endoscopists further stabilized hemostasis by using at least one additional method. Recurrence of bleeding was observed in 8 patients (10.4%). In 16 patients with intraprocedural bleeding, it was possible to complete the procedures (14 EMR, 2 ERCP) using PuraStat^® hemostasis. No adverse events related to PuraStat^® were recorded. Misumi et al[61] reported a case study of a 55-year-old patient with gastric antral vascular ectasia (GAVE) who had undergone Fontan surgery for tricuspid regurgitation more than 20 years prior. He developed hepatic cirrhosis as a complication following Fontan surgery. GAVE is a gastric hemorrhagic disease associated with chronic liver disease. The patient presented with progressive anemia and black stool (melena). During upper GI endoscopy, bleeding from GAVE was detected. The standard treatment to control gastric hemorrhage in patients with GAVE is APC. APC is relatively safe in endoscopic procedure. However, it is not suitable in some cases, such as in patients with pacemakers. The authors reported the use of PuraStat^® to control gastric bleeding instead of using APC. Thirteen days post-surgery, the patient underwent upper GI endoscopy, and the authors observed that the density of the capillaries in the antrum was significantly decreased, with a trend toward disappearance was observed.

Case reports by Kubo et al[62] reported the use of PuraStat^® in 6 cases of AGIB (5 cases of ulcer bleeding, and one case ruptured gastric varices). Two of them were on antithrombotic drugs and one on nonsteroidal anti-inflammatory drugs. The bleeding treated were oozing bleeding from visible vessels (n = 3) and spurting bleeding from visible vessels (n = 2) and grom gastric varices (n = 1). In all patients, complete hemostasis was achieved with no rebleeding. Another case by Higashino et al[63] reported the use of PuraStat^® as secondary therapy for hemostasis in patients with Mallory-Weiss syndrome and were on oral antithrombotic medications, and difficult-to-achieve hemostasis. The patient is 67-year-old and had undergone coronary artery bypass grafting one month earlier and was taking an antithrombotic medication. The patient was treated with clipping. However, the oozing did not stop because of the large oesophageal laceration. The patient was treated by applying PuraStat^®. A follow up endoscopy the next day confirmed hemostasis. The authors concluded that PuraStat^® can achieve complete hemostasis when other methods such as clips and endoscopic band ligation fail to seal bleeding. A third case reported the success of PuraStat^® in achieving hemostasis in patients undergoing endoscopic gastrostomy even when they were taking antithrombotic therapy[63].

LGIB

Yamaguchi et al[64] in a multicenter pilot study evaluated the efficacy and safety of endoscopic hemostasis of using PuraStat^® in patients with colonic diverticular bleeding (CDB). The study included 25 patients with CDB (intervention group) (2 treated with PuraStat^® monotherapy and 13 with combination therapy PuraStat^® + endoscopic band ligation, and 10 with PuraStat^® + clipping). The treatment outcomes and adverse events were assessed and compared with a previous cohort of patients who underwent endoscopic hemostasis without PuraStat^® for CDB (control group). The success rates were comparable between the intervention group and the control group (P = 1.000). The rate of recurrent bleeding within 30 days was significantly lower in the intervention group compared with the control group (4.0% vs 20.9%, P = 0.047). Multivariate analyses revealed that the addition of PuraStat^® was associated with a reduction of risk of recurrent bleeding (P = 0.045). Another study by White and Henson[65] conducted a comprehensive examination of the efficacy of PuraStat^®-delivered endoscopy for treating patients with severe refractory hemorrhagic radiation proctopathy (RP). The study involved twenty-one patients with RP (experiencing pain and/or anemia and showing no response to rectal sucrafate) who were treated with PuraStat^® (applied endoscopically at four weekly intervals three times). The study meticulously recorded the severity of bleeding, endoscopic grade, and hemoglobin levels. Despite ten patients being on antithrombotic medication, one having thrombocytopenia, and thirteen having anemia at baseline, the results were promising. The median bleeding episodes were reduced from 4.5 (0-27) to 2 (0-16) in 7 days, and endoscopic grades showed improvement. The mean hemoglobin levels increased from 116.0 to 122.7 with no reported complications[65].

A third interesting study by Ortenzi and Haji[66] investigated the safety and feasibility of PuraStat^® in laparoscopic colorectal surgery. In a non-randomized, prospective observational study, 20 patients undergoing laparoscopic colorectal surgery were recruited. Patients were included if the bleeding needed a secondary hemostatic method (e.g., traditional methods to control bleeding were insufficient or not recommended). The mean time to apply PuraStat^® was 40 seconds, whereas the mean time to achieve hemostasis was 17.5 seconds. There were no post-operative complications. The mean operative time overall was 185 minutes. None of the patients experienced post-operative rebleeding and the mean hospital stay was 5 days.

In a retrospective trial, Pioche et al[67] assessed the safety and efficacy of PuraStat^® in preventing delayed bleeding after endoscopic resections. Consecutive patients (n = 56) with endoscopic resections were enrolled. These patients had 65 Lesions [oesophagus (n = 8), stomach (n = 22), duodenum (n = 10), ampullary (n = 3), colon (n = 7), and rectum (n = 15)]. Among these lesions, 29 were resected in high-risk situations (9 uninterrupted aspirin therapy, 6 heparin bridge therapies, 5 cirrhosis and portal hypertension, 1 both cirrhosis and heparin bridge, 3 both cirrhosis and uninterrupted aspirin, 3 large duodenal lesions > 2 cm, and 2 on clopidogrel. PuraStat^® was applied immediately after resection to cover the whole ulcer bed. The resection technique was endoscopic submucosal dissection (ESD) in 40 cases, en-bloc EMR in 16, piecemeal EMR in 6, and pulpectomy in 3. The mean lesion size was 37.9 mm with a mean area of 6.3 cm. No difficulty was observed during the application. Four delayed overt bleedings occurred (3 hematochezia, 1 hematemesis) requiring endoscopic hemostasis. No adverse events reported. The authors concluded that the use of this novel ECM scaffold may help to reduce post-endoscopic resection bleeding, including in patients at high risk of bleeding[67].

Murakami et al[68] reported in a retrospective study examined the efficacy of PuraStat^® in twenty-five patients with GI bleeding who underwent emergency endoscopy. Six patients were receiving antithrombotic agents, and 10 patients with refractory GI bleeding had undergone at least one endoscopic hemostatic procedure. The breakdown of bleeding was gastroduodenal ulcer/erosion in 12 cases, bleeding after gastroduodenal or colorectal endoscopic resection in 4 cases, rectal ulcer in 2 cases, postoperative anastomotic ulcer in 2 cases, and gastric cancer, diffuse antral vascular ectasia, small intestinal ulcer, CDB, and radiation proctitis one in each case. The method of hemostasis was only by applying PuraStat^®(n = 6), and hemostasis in combination with high-frequency hemostatic forceps, hemostatic clip, APC, and hemostatic agents (i.e., thrombin) in the remaining cases (n = 19). Rebleeding was observed in three cases. Hemostatic efficiency was observed in 23 cases. The authors concluded that PuraStat^® has the expected hemostatic effect on GI bleeding during emergency endoscopy. Another study by Subramaniam et al[69], comprising 100 patients undergoing endoscopic resection was aimed to assess the efficacy and safety of PuraStat^® when used to control intraprocedural bleeding or to prevent delayed bleeding in endoscopic resection. The study included 31 colorectal, 48 oesophageal, 11 gastric and 10 duodenal procedures. The mean lesion size was 3.7 cm and 30% of the patients were on antithrombotic therapy. Intraprocedural bleeding occurred in 64%. PuraStat^® was an effective hemostat in 75% of these cases. The delayed bleeding rate was 3%. The authors concluded that PuraStat^® is an effective hemostat for controlling GI bleeding during endoscopic resection. It is safe, easy to use, and does not interfere with endoscopic procedures.

Other GI bleeding

Nahm et al[70] in a prospective cohort study (n = 80) examined the efficacy and safety of PuraStat^® in liver resections performed for metastatic tumors. The primary endpoint was time to hemostasis and the secondary endpoints were blood loss, total postoperative drainage volume, transfusion of blood products, and ease of use of PuraStat^® (described as excellent or good or poor). A total of 190 bleeding sites out of a total of 207 that were treated with PuraStat^® reached hemostasis (91.7%). The mean time to hemostasis was 1:1 (mm: ss). Ease of use of PuraStat^® (excellent or good) was in 98.8% of patients. No serious adverse effects were observed. Binda et al[71] in a multicenter retrospective pilot case series study (n = 10) from Italy evaluated the safety and efficacy of PuraStat^® in preventing and controlling bleeding of walled-off pancreatic necrosis (WOPN) drainage using lumen-apposing metal stents (LAMS) and direct endoscopic necrosectomy (DEN). The patients were treated with PuraStat^® after LAMS placement for the drainage of symptomatic WOPN. All patients underwent at least one session of DEN. Technical success of PuraStat^® was achieved in all patients. In seven patients, PuraStat^® was applied for post-DEN bleeding prevention, one patient of them experienced bleeding after DEN. In 3 cases, PuraStat^® was applied to manage active bleeding. No rebleeding was observed and no adverse effects related to PuraStat^® were reported.

Ogura et al[72] aimed to prospectively evaluate the safety and efficacy of PuraStat^® for persistent endoscopic sphincterotomy (EST) bleeding as a first-line hemostatic technique. Using a single-arm prospective study, the authors included 1080 ERCP procedures in the study. They defined clinical success as the absence of oozing for 180 seconds after PuraStat^® application. Adverse events associated with procedures and secondary bleeding were secondary outcomes. PuraStat^® application was performed using the embankment method. A total of 108 patients experienced complications with EST bleeding. Among these, endoscopic hemostasis was required in 51 patients. These patients enrolled in this prospective study. All patients successfully underwent PuraStat^® application. The technical success rate was 98% (50/51). Severe adverse events associated with the procedures were not observed, although mild acute pancreatitis was observed in 2 patients. The authors concluded that PuraStat^® application may be safe for oozing after EST without increasing the frequency of acute pancreatitis. In a case report, Ishida et al[73] reported 6 cases of EST related hemorrhage with initial hemostasis achieved using PuraStat^®. Bleeding occurred during the same session as EST in 5 of 6 cases, with the remaining case showing bleeding 4 days after EST. The authors selected PuraStat^® as first-line hemostasis in all cases. Hemostasis was confirmed without additional procedures in all cases, and they observed no adverse events after the procedures.

DISCUSSION AND CLINICAL IMPLICATIONS

Firstly, PuraStat^®, a self-assembling peptide hemostatic agent, has demonstrated efficacy, safety, and easy application through endoscopy procedures in controlling emergency GI bleeding including non-variceal upper and LGIB[14,15]. This is particularly significant when standard methods used in hemostasis failed to control bleeding and PuraStat^® demonstrated effectiveness[14], safety, no adverse effects[69,71,72] and no re-bleeding post-procedure in 81%-97% of cases[14]. PuraStat^® has also demonstrated effectiveness in controlling bleeding in patients with EMR, ESD, EST bleeding, bleeding gastroesophageal varices, resection of liver metastasis, bleeding from Mallory-Weiss tear, and CDB.

Secondly, PuraStat^® has demonstrated hemostasis in patients with GI bleeding while they were on antithrombotic and non-steroidal anti-inflammatory medications[62,63,65,68,69]. This is particularly significant in managing patients with emergency GI bleeding and are treated with any of these medications. This is because the pathophysiological mechanism underlying PuraStat^® hemostasis do not involve coagulation factors. PuraStat^® forms an extracellular scaffold matrix when activated by the change in pH that occurs upon contact with blood. It creates a stable mechanical barrier at the bleeding site, aiding intrinsic in vivo hemostasis. The peptide solution is provided as a liquid but solidifies into a hydrogel that seals the bleeding point when exposed to blood and tissue pH[43].

Thirdly, despite all these promising outcomes of using PuraStat^® in achieving hemostasis in GI bleeding there are deficiencies in current research: (1) Most studies are observational, small-scale, non-randomised, limited to one center or case studies covering a few patients. To assess different aspects related to PuraStat^® there is a need for large-scale, multi-center, randomised controlled clinical trials. Recently, a multicenter prospective randomised controlled trial testing the hemostatic prophylactic effect of PuraStat^® after EMR (large lesions in the deudenum and colorectum) reported no reduction in the rate of delayed bleeding[59]; (2) Studies are lacking long-term data and more evidence about hemostatic effectiveness particularly rebleeding in 6-12 months post-procedural applications; (3) There are deficiencies in studies comparing the outcomes of PuraStat^® with Hemostatic powder spray [Hemospray^® (TC-325)] in GI hemostasis; (4) Studies are lacking assessment of PuraStat^® in patients with severe upper and LGIB including patients with cirrhosis and bleeding gastroesophageal varices[67], resection of liver metastasis[70], bleeding from Mallory-Weiss tear[63], CDB[64], EMR, ESD, EST bleeding; (5) Most of current studies have patient selection bias or are case studies. There is a need for clinical trials that are randomised and controlled and compare the use of PuraStat^® alone with the use of PuraStat^® plus clipping or band ligation; and (6) There is a lack of regulatory and guides of using PuraStat^® in GI bleeding with consideration for indications, and the cost-effectiveness of PuraStat^® compared with other hemostatic agents.

CONCLUSION

PuraStat^® (PuraBond^®, 3-D Matrix-621) is a synthetic self-assembling hydrogel peptide that facilitates hemostasis in GI bleeding by forming a pH-responsive gel barrier upon contact with blood. Current evidence suggests its potential utility across a spectrum of GI bleeding scenarios. While several studies have reported promising results in both upper and LGIB, the data remain heterogeneous, with variability in effectiveness across clinical contexts. Notably, a recent multicenter, prospective randomized controlled trial evaluating the prophylactic application of PuraStat^® following EMR of large duodenal and colorectal lesions found no significant reduction in delayed bleeding rates[59]. Most available studies are limited by small sample sizes, observational or retrospective designs, single-center settings, and lack of control groups. Recently, Ballester et al[74] present an observational, retrospective, single-center study assessing PuraStat^® in 45 patients with GI bleeding, administered as monotherapy (n = 16) or in combination with other hemostatic techniques (n = 29). The study found no statistically significant differences in rebleeding (P = 0.64) or 30-day mortality (P = 0.69) between the groups. However, the interpretation of these findings is limited by several methodological shortcomings. The combination group utilized seven different hemostatic modalities, introducing heterogeneity that undermines statistical power and precludes meaningful comparison. Additional confounding factors include lack of clarity regarding allocation of blood transfusions, the diverse aetiologies and severities of GI bleeding (e.g., peptic esophagitis, duodenal ulcers, neoplasia, post-ERCP bleeding, EMR-related hemorrhage), and the absence of subgroup-specific mortality data. Despite these limitations, Ballester et al[74] contribute valuable preliminary insights into the real-world application of PuraStat^®, particularly in complex bleeding contexts involving diverse pathologies and therapeutic strategies. However, the current evidence's fragmented and uncontrolled nature underscores the urgent need for rigorously designed, multicenter, randomized controlled trials. Future studies must focus on long-term clinical outcomes, rebleeding rates, and direct comparisons of PuraStat^® monotherapy with its combination use alongside conventional hemostatic interventions such as clipping or band ligation. Furthermore, systematic evaluation of patient- or lesion-specific factors associated with treatment failure or recurrence is critical to delineating the optimal role of PuraStat^® in contemporary endoscopic hemostasis.