Background

Gastrointestinal bleeding (GIB) is associated with significant morbidity and mortality. Despite improved endoscopic practices for GIB, approximately 8-15% of patients fail primary endoscopic therapy, which includes injection, thermal, and mechanical therapy. These techniques require precise localization of the bleeding source and may not be as effective in patients with lesions that are difficult to access, have tumor-associated bleeding, or broad based bleeding sources. Additionally, a high level of endoscopic expertise is required for these modalities which may not be available at smaller hospitals. 

Recently, topical endoscopic hemostatic agents were introduced to treat GIB. These agents have had promising results as salvage therapy or even as primary therapy without requiring precise localization or extensive technical expertise.^3, There are five approved agents (Table 1): hemostatic agent TC-325 (Hemospray^TM, Cook Medical Inc, Winston-Salem, North Carolina, US), synthetic self-assembling peptide agent (PuraStat^TM, 3D-Matrix, Europe Ltd., France), Endoclot^TM (Endoclot Plus Inc., Santa Clara, California, US) polysaccharide hemostatic system (PHS), biocompatible natural polymer UI-EWD (Nexpowder^TM, NextBiomedical Co., Incheon, South Korea) and erythrocyte protein network (Ankaferd Blood Stopper^TM, ABS, Ankaferd Health Products Ltd., Turkey).

Table 1. Summary of Topical Endoscopic Hemostatic Agents 

Agent/Trade Name	Composition	Mechanism of Action	Approved Application
TC-325 (HemosprayTM)	Granular mineral-based	Absorbs water and activates the clotting cascade to form a mechanical tamponade	Peptic ulcer disease, variceal GIB, lower GIB, tumor bleeding
PuraStatTM	Synthetic self-assembling peptide agent	Peptide solution forms a 3-dimensional nano-fiber hydrogel scaffold of beta-sheets	Bleeding secondary to therapeutic endoscopic procedures
EndoclotTM	Absorbable starch-based modified polysaccharide	Absorbs water and concentrates platelets and clotting factors to create a mechanical tamponade	Peptic ulcer disease, malignant tumors, esophageal ulcers, esophagitis, post-interventional bleeding
UI-EWD (NexpowderTM)	Biocompatible natural polymer	Forms adhesive hydrogel in presence of water	Prophylaxis post-intervention, Peptic ulcer disease, malignant tumors, and post-interventional bleeding
Ankaferd Blood StopperTM	Erythrocyte protein network	Encapsulated protein network provides focal points for erythrocyte aggregation	Only approved in Turkey:  non-variceal upper GIB (Case reports: peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding)

Topical endoscopic hemostatic agents are intended to control active non-variceal GIB (NVGIB) by delivering a substance over the bleeding site through a catheter via the endoscope working channel. The main advantage of topical agents is that less precision is required when applying the agent to the bleeding site. This allows for treatment of lesions that may be difficult to access or refractory to standard therapy. Although recent studies have shown that hemostatic agents were effective in NVGIB, there had been reports of high re-bleeding rates.⁵ Topical agents can also be used prophylactically to reduce the risk of bleeding following polypectomy, endoscopic mucosal resection (EMR), or endoscopic submucosal dissection (ESD). These agents can also be used to treat or reduce the risk of sphincterotomy bleeding during endoscopic retrograde cholangiopancreatography (ERCP). 

This manuscript aims to discuss the efficacy, safety, advantages, and disadvantages of the FDA-approved topical endoscopic hemostatic agents.

Hemostatic agent TC-325/Hemospray

Hemostatic agent TC-325 is a metabolically inert, nontoxic, granular mineral-based inorganic powder that when in contact with blood will induce hemostasis by absorbing water and activating the clotting cascade. As a result, a mechanical tamponade and adhesive barrier form over the bleeding site. Hemospray is deployed through the endoscope-integrated catheter in short bursts when a compressed carbon dioxide propellant is activated by the device’s trigger.

Hemospray has been shown to be successful in controlling bleeding from peptic ulcer disease, variceal GIB, and lower GIB as both monotherapy and as an adjunctive therapy to conventional therapy.^8,9,10,11 (Figures 1 and 2) Sung et al. and Kwek et al. reported hemostasis in 90% of patients with monotherapy and 100% of patients as an adjunctive therapy.^, In another study, Ibrahim et al. reported 100% hemostasis in nine patients treated with monotherapy. In regards to lower GIB, Hemospray was effective in achieving hemostasis for spurting post-polypectomy bleeding that did not respond to clipping. Additionally, in a systematic review and meta-analysis by Facciorusso et al., the immediate hemostasis rate for Hemospray monotherapy in 8 studies with 175 patients was 96.2% (95% CI 93.5-99.7%). Bleeding from gastrointestinal tumor may sometimes be diffuse and lack a specific target suitable for endoscopic hemostasis. In these cases, Hemospray is a good option to provide short-term hemostasis. In a large multicenter study conducted by Pittayanon et al., they found that hemostasis was achieved with Hemospray in 98% of cases. 

However, the downside of Hemospray monotherapy is that studies show high rebleeding rates at 7 days typically ranging between 15-49%.^12,,, Facciorusso et al. found that there was a 9.8% (95% CI 3.8-15.8%) pooled 7-day rebleeding rate and a 12.3% (95% CI 6.0-18.7%) pooled 30-day rebleeding rate. A study by Cahyadi et al. found even higher rebleeding rates at 3 days (43.1%) and at 7 days (49.0%). This is likely due to the fact that while Hemospray induces coagulation, it generally does not treat the underlying cause of a bleed. Recent guidelines published in the Annals of Internal Medicine recommend that Hemospray be used only as a temporizing measure when primary endoscopy therapy fails and should not be used as a monotherapy due to the high re-bleeding rates. 

Hemospray can often limit endoscopic visualization after deployment, and when it is used before other hemostatic agents, there may be a risk of obscuring the boundaries of a lesion (making it more difficult to implement other hemostatic options if they are needed). As Hemospray is sprayed, the cloud of powder can temporarily fill the endoscopic field of view and if the endoscope’s tip is too close to the site of application, the powder can adhere directly to the lens. To avoid this, we recommend releasing the powder in short 1- to 2- second bursts and maintaining the endoscope’s tip at least 1-2 cm away from the lesion.

PuraStat

PuraStat is a biocompatible synthetic peptide gel consisting of a repeating sequence of the amino acids Arginine, Alanine, and Aspartic Acid. Once Purastat gel comes in contact with blood, the peptide solution is neutralized to form a 3-dimensional nano-fiber hydrogel scaffold of beta-sheets. This structure, similar to the extracellular matrix, forms a physical barrier over the bleeding vessel or bleeding site to achieve hemostasis.

PuraStat is currently intended for prophylaxis of bleeding secondary to therapeutic endoscopic procedures such as endoscopic submucosal dissection (ESD) or endoscopic mucosal resection (EMR), although it has been used in a wide variety of contexts. (Figures 3 and 4) Prior studies have shown that post-ESD, there was a smaller mean number of any secondary temporizing measures required when PuraStat was used initially compared to the control group without PuraStat (1.0±1.4 vs 4.9±5.2, p<0.001), demonstrating the efficacy of PuraStat in managing intraoperative bleeding. ^, In a study by Uraoka et al., only 1 out of 51 included patients had post-ESD bleeding after being treated with PuraStat. However, Gomi et al. 2024, in a more recent and larger study of 101 patients, did not find that PuraStat was associated with improved rates of post-ESD bleeding, highlighting the need for further research in this area. 

The efficacy of PuraStat in managing post-sphincterotomy bleeds has also been studied. Ogura et al. found that 98% of patients achieved complete cessation of bleeding with PuraStat monotherapy. Kishore et al. found that 96.5% (95% CI: 92.3-100) of patients achieved complete cessation of bleeding with PuraStat monotherapy, with a rebleeding rate of 3.10% (95% CI: 0.50-5.60). 

Furthermore, in a recent meta-analysis, three studies showed PuraStat to be effective in both primary and rescue hemostasis for bleeds caused by peptic ulcer disease, large polyps, tumors, and capillary lesions. ^20,,, For primary hemostasis, the pooled immediate hemostasis rate was 87% (95% CI 75%-94%) and the pooled rebleeding rate within 30 days was 10% (95% CI: 6%-16%).^20,26,27,28  In Bianchi et al.’s study, 111 patients were included with an initial hemostatic success rate of 94% (95% CI 88-99%). When used as a secondary hemostatic product, PuraStat had a hemostatic success rate of 75% (95% CI 59-91%). The rebleeding rates at 3 and 7 days were 9% and 15% after primary use and 13% and 19% after secondary use, respectively. The overall rebleeding rate at 30 days was 16%.²⁰ 

In comparison with Hemospray, PuraStat is a transparent hemostatic agent that does not compromise endoscopic visualization after deployment. This makes it possible to check post-therapy bleeding status and continue further interventions, if needed. It is already prepared for the endoscopist in a single prefilled, ready-to-use syringe and deployed through the endoscopic catheter. Given that PuraStat is a gel, it is also highly versatile and can be used in narrow spaces where the bleeding site is difficult to reach with a hemoclip or a thermal probe.  

However, similar to Hemospray, the downside of PuraStat is it has a high rebleeding rate of 10%-15% at 7 days if used as monotherapy.^{20, 26} This is a drawback of hemostatic agents in general given they can only bind to sites with active bleeding for 12-24 hours. However, one recent retrospective study showed there was no statistical significant differences in rebleeding (p=0.64) or mortality (p=0.69) when comparing initial PuraStat use and the standard care (i.e. injection, hemoclips, etc.). 

Endoclot

Endoclot is a starch-derived compound consisting of biocompatible absorbable hemostatic polysaccharide that when in contact with blood, will rapidly absorb water. This causes a high concentration of clotting factors, red blood cells, and platelets to accumulate at the bleeding site accelerating the hemostasis process.³ Afterwards, the polysaccharide will form a gelled, adhesive matrix providing a mechanical barrier to seal and potentially protect the wound site from further bleeding.

Endoclot is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, esophageal ulcers and esophagitis, as well as post-interventional bleeding. ^,,,, In a recent meta-analysis of 5 studies and 398 patients, the immediate hemostasis rate for any GIB after Endoclot monotherapy was 86% (95% CI: 80%-90%), with a rebleeding risk within 30 days of 10% (95% CI 6%-16%).²⁶ In a recent multicenter analysis of 43 patients by Hagel et al., the immediate hemostasis rate was 81.8% when Endoclot was used as a salvage therapy. In one study, among patients with tumor bleeding, there was a 0% rebleeding rate after treatment with Endoclot as monotherapy.³⁵ 

Furthermore, Endoclot is delivered differently compared to other hemostatic agents. Hemospray is delivered at high pressure with a carbon dioxide cartridge which can be advantageous in situations with high pressure bleeding. However, the high-pressure application from the carbon dioxide can potentially cause tissue injury as well. Two studies have shown perforation in their patient cohort after Hemospray application due to high-pressure carbon dioxide application.^35, In contrast, the pressure at which Endoclot is sprayed is much lower making it more suitable for localized bleeding lesions and has lower risks of causing tissue injury.

The main disadvantage of Endoclot, similarly to other hemostatic agents, is the risk of rebleeding due to low binding times of the adhesive matrix to the bleeding site. Limited studies report the advantages and disadvantages of Endoclot compared to other forms of hemostatic agents. Beg et al. reported on the use of Endoclot by novice operators. In their study, assisting nurses who had no specific training using Endoclot had success and ease of use when it was applied.³² 

Nexpowder

Nexpowder is a biocompatible natural polymer composed of oxidized dextran and succinic anhydride that gets converted to adhesive hydrogel when in contact with water. It then forms a mechanical barrier at bleeding site(s) to promote hemostasis.³⁹ It is deployed by insoluble air propellant and uses a pre-installed battery as its power source, allowing air pressure generated from the air pump in the delivery system’s spray body to provide a force to move the powder into the delivery catheter.³⁹ The advantage of Nexpowder is that it does not require active bleeding to work which allows it to have a potential role in prophylaxis post-procedural. However, most studies show promising results for Nexpowder as a role in primary hemostasis or prophylaxis post-intervention as well.^,,

Nexpowder is indicated as either monotherapy or rescue therapy for both upper and lower GIB, with studies showing efficacy in hemostasis for peptic ulcer disease, malignant tumors, and post-interventional bleeding.^40,41,42 It can also be used as prophylaxis post-intervention.^40,42 In a recent meta-analysis of 3 studies and 114 patients, the immediate hemostasis rate for any GIB after Nexpowder monotherapy was 96% (95% CI: 91%-99%), with a rebleeding risk within 30 days of 8% (95% CI 3%-20%).²⁶ Shin et al. found that there was immediate hemostasis in 100% (n=23) of their patient cohort when using Nexpowder monotherapy for active bleeds secondary to luminal malignant tumors. However, there was a high rate of rebleeding within 1 month in 26.1% and 22.5% of their patients when using Nexpowder as monotherapy and salvage therapy, respectively.⁴² All three studies used Nexpowder post-intervention as a prophylaxis for acute bleeding.^40,41,42 

One advantage of Nexpowder is it has a lower rebleeding rate within 30 days (8%) compared to other hemostatic agents (subgroup differences: p < 0.01).²⁶ In a study conducted by Park et al., they found that only 2 out of 54 patients (3.7%) had rebleeding within 30 days after using Nexpowder as a monotherapy.⁴¹ In another study, Park et al. used a second-look endoscopy after 24 hours of applying the Nexpowder as a monotherapy and saw that the hydrogel from Nexpowder was still attached to the bleeding site in 69% of their patients 24 hours later.⁴⁰ Shin et al. found that the when using Nexpowder as a monotherapy, the hydrogel was reported to be present at 70.2% of sprayed bleeding sites using second-look endoscopy at 24 hours. 

Ankaferd Bloodstopper

Ankaferd Bloodstopper (ABS) is a hemostatic agent only approved in Turkey and Bosnia-Herzegovina and composed of a mixture of plants, including Thymus vulgaris, Glycrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. The mechanism of action of ABS is it rapidly forms an encapsulated protein network that provides multiple focal points for erythrocyte and leukocyte aggregation, including fibrinogen, which, in turn, induces protein aggregation.^, ABS is a topical powder application that is sprayed via a catheter through the working channel of the endoscope. ABS is currently approved in Turkey and Bosnia-Herzegovina for upper and lower GIB that is only refractory to conventional hemostatic measures.³

There has been a relative paucity of studies analyzing the effectiveness and safety of ABS monotherapy and salvage therapy. No safety concerns have been reported to date. A case series of 27 patients with active, non-variceal GIB showed an immediate hemostasis rate of 73% when ABS was used as a monotherapy and 100% when used in combination with standard therapy.⁴⁶ Rebleeding within 48 hours was seen in 15.8% of patients with ABS monotherapy and 33.3% with ABS salvage therapy. There are multiple case reports of the success of immediate hemostasis using ABS monotherapy in patients with peptic ulcer disease, malignant GIB, esophageal variceal bleeding and post-polypectomy bleeding.^,,,,,,, 

Conclusion

Topical hemostatic agents have been shown to be effective in hemostasis for gastrointestinal bleeding, especially when used in combination with conventional methods or as salvage therapy. Limited studies have demonstrated high primary hemostasis rates in both upper and lower GIB when used as monotherapy but with some risk of rebleeding. Topical hemostatic agents are simple to use and do not require a high level of endoscopic expertise to employ.   

References

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