Topical hemostatic agents and powders are an emerging modality in the endoscopic management of upper and lower gastrointestinal bleeding. This systematic review demonstrates the effectiveness and safety of these agents with special emphasis on TC-325 and Ankaferd Blood Stopper. The unique noncontact/nontraumatic application, ability to cover large areas of bleed, and ease of use make these hemostatic agents an attractive option in certain clinical situations, such as massive bleeding with poor visualization, salvage therapy, and diffuse bleeding from luminal malignancies.
Key points
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Topical hemostatic agents and powders are an emerging modality in the endoscopic management of upper and lower gastrointestinal bleeding.
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This systematic review demonstrates the effectiveness and safety of these agents with special emphasis on TC-325 and Ankaferd Blood Stopper.
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The unique noncontact/nontraumatic application, ability to cover large areas of bleed, and ease of use make these hemostatic agents an attractive option in certain clinical situations, such as massive bleeding with poor visualization, salvage therapy, and diffuse bleeding from luminal malignancies.
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Because of their temporary and short luminal residency time, the effectiveness of these topical agents may not be optimal as monotherapy in lesions at high risk of rebleeding beyond a 24-hour period, such as peptic ulcer hemorrhage.
Introduction
Gastrointestinal (GI) bleeding from both the upper and the lower GI tract is a common cause for hospitalization, resulting in significant mortality, morbidity, and resource utilization. In the United States, nonvariceal upper GI bleeding (NVUGIB) is associated with a hospitalization rate of 60.6 to 78.4 per 100,000 adults and a mortality of 2.1% to 2.45%. Lower GI bleeding (LGIB), on the other hand, is accompanied by a hospitalization and mortality rate of 21 per 100,000 adults and 2% to 4%, respectively. The advent of endoscopic hemostatic therapies, such as clips, injection therapy, thermocoagulation, and argon plasma coagulation, have changed the management of GI bleeding and, in the case of NVUGIB, a potential benefit in mortality, need for surgery, and transfusion requirement. However, these devices have their limitations, such as the risk for perforation, worsening of bleeding, and possible difficulty in using with large, friable bleeding surfaces, such as hemorrhage arising from GI tumors.
Over the past few years, innovative topical hemostatic modalities have been developed for endoscopic use. Although these agents are new in digestive endoscopy, topical hemostatic agents have existed over the past 50 years with widespread medical applications. They were first introduced in 1909, with the use of topical fibrin for surgical hemostasis. Indeed, fibrin sealants marked the beginning of a wide spectrum of topical hemostatic agents to be used in surgery. More recently, novel hemostatic products, such as the Ankaferd Blood Stopper (ABS; Ankaferd Health Products Ltd, Istanbul, Turkey), TC-325 (Hemospray; Cook Medical, Winston-Salem, NC, USA), and EndoClot (AMP; EndoClot Plus Inc, Santa Clara, CA, USA), have been adapted to digestive endoscopy and the management of GI bleed. Uncontrolled data from both TC-325 and ABS have shown promising results in a variety of bleeding pathologic abnormalities from both the upper and the lower GI tract. In the following, the use of endoscopic topical hemostatic agents is discussed, focusing on ABS and TC-325 in terms of their composition, mechanism of action, clinical data and application, and related complications.
Introduction
Gastrointestinal (GI) bleeding from both the upper and the lower GI tract is a common cause for hospitalization, resulting in significant mortality, morbidity, and resource utilization. In the United States, nonvariceal upper GI bleeding (NVUGIB) is associated with a hospitalization rate of 60.6 to 78.4 per 100,000 adults and a mortality of 2.1% to 2.45%. Lower GI bleeding (LGIB), on the other hand, is accompanied by a hospitalization and mortality rate of 21 per 100,000 adults and 2% to 4%, respectively. The advent of endoscopic hemostatic therapies, such as clips, injection therapy, thermocoagulation, and argon plasma coagulation, have changed the management of GI bleeding and, in the case of NVUGIB, a potential benefit in mortality, need for surgery, and transfusion requirement. However, these devices have their limitations, such as the risk for perforation, worsening of bleeding, and possible difficulty in using with large, friable bleeding surfaces, such as hemorrhage arising from GI tumors.
Over the past few years, innovative topical hemostatic modalities have been developed for endoscopic use. Although these agents are new in digestive endoscopy, topical hemostatic agents have existed over the past 50 years with widespread medical applications. They were first introduced in 1909, with the use of topical fibrin for surgical hemostasis. Indeed, fibrin sealants marked the beginning of a wide spectrum of topical hemostatic agents to be used in surgery. More recently, novel hemostatic products, such as the Ankaferd Blood Stopper (ABS; Ankaferd Health Products Ltd, Istanbul, Turkey), TC-325 (Hemospray; Cook Medical, Winston-Salem, NC, USA), and EndoClot (AMP; EndoClot Plus Inc, Santa Clara, CA, USA), have been adapted to digestive endoscopy and the management of GI bleed. Uncontrolled data from both TC-325 and ABS have shown promising results in a variety of bleeding pathologic abnormalities from both the upper and the lower GI tract. In the following, the use of endoscopic topical hemostatic agents is discussed, focusing on ABS and TC-325 in terms of their composition, mechanism of action, clinical data and application, and related complications.
Methods
A computerized systematic literature review from January 1950 through August 2014, by using OVID MEDLINE, EMBASE, CENTRAL, and ISI Web of Knowledge 5.6, was initiated. Articles were selected by using a combination of MeSH headings and text words related to TC-325, nanopowder, hemostatic or haemostatic agent, granule or powder, TC-325, Ankaferd Blood Stopper, and microporous polysaccharides. Recursive searches and cross-referencing were also carried out by using a similar articles function; hand searches of articles were identified after an initial search. Included were all adult human studies in French or English.
Study selection
Of an initial 3799 articles, 105 articles were identified that were related to ABS as a topical hemostatic agent; however, after excluding nonendoscopic data, review articles, in vitro studies, and animal models, 17 articles were left on the endoscopic use of ABS in GI bleeding. Also identified were 23 original articles related to TC-325 use in GI bleeding and 21 articles after the exclusion of animal studies. There is only one published article on the use of AMP; therefore, most of this brief review on AMP is based on the information provided by the manufacturer’s Web site.
Composition of hemostatic powders and technical application
Ankaferd Blood Stopper
The ABS is an herbal extract derived from 5 different plants approved in Turkey for topical application. Each 100 mL of ABS is composed of 5 mg Thymus vulgaris , 9 mg Glycyrrhiza glabra , 8 mg Vitis vinifera , 7 mg Alpinia officinarum , 6 mg Urtica dioica . Although the exact mechanism for hemostasis remains unclear, it likely achieves bleeding control by promoting the formation of a protein network behaving as an anchor for erythrocyte aggregation that then integrates the classic coagulation cascade without directly acting on coagulation factors and platelets. Interestingly, ABS may have other therapeutic effects beyond hemostasis, such as its influence on angiogenesis, cellular proliferation, and vascular dynamic, which has led to investigations into its possible anti-infective, antineoplastic, and wound-healing potentials. Currently, ABS experience is limited mostly to Turkey and has not been approved by the Food and Drug Agency (FDA) in the United States.
Hemospray
TC-325 is composed of a proprietary inorganic biologically inert powder that, when put in contact with moisture in the GI tract, becomes coherent, thus serving as a mechanical barrier for hemostasis. In addition, it may provide a scaffold, enhancing platelet aggregation and possibly activating clotting factors. Data from an in vitro model by Holster and colleagues showed decreasing clotting time with the application of TC-325 in a dose-dependent fashion. Following hemostasis, the powder sloughs off the intestinal mucosa and is completely eliminated from the GI tract, likely within 24 hours of application. It is important to note that the powder only adheres to actively bleeding lesions; therefore, its use in high-risk lesions without active spurting or oozing, such as in nonbleeding visible vessels, is likely ineffective in providing appropriate hemostasis. The endoscopic use of TC-325 is currently approved in Canada, Mexico, and several countries in the Caribbean, South America, Europe, and Asia; however, it is not FDA approved.
EndoClot
AMP is composed of proprietary hemostatic polysaccharides that are derived from plant starch. It is adhesive, ultra hydrophilic, and fast degrading and induces hemostasis by rapidly absorbing water from blood and thereby concentrating red cells, platelets, and coagulation factors at the bleeding site. Similarly to TC-325, AMP is delivered through a catheter inserted into the operating channel of the endoscope and propelled by an air compressor onto the bleeding lesion. AMP is currently approved in Turkey, Europe, Malaysia, and Australia according to the company’s Web site. At the time of this review, only one peer-reviewed publication on the use of AMP was found in the literature. It described the application of AMP in LGIB after endoscopic mucosal resection (EMR) showing excellent hemostasis of 90% (18/20), time to hemostasis of 1.7 min, 3 documented cases of rebleeding, and no procedural related complications.
Method of Delivery
At the time of this review, there were no published articles focused on the technical application of ABS. In addition, given that ABS is only available in Turkey, the authors have no technical experience and cannot provide an expert opinion as to how the hemostatic agent should be optimally delivered. They do know that ABS comes in 3 forms: ampoules, tampons, and sprays. Sprays can then be applied through a disposable catheter in the operating channel of an endoscope in 50-mL vials.
TC-325, on the other hand, is propelled from a canister under CO 2 pressure and delivered through a catheter unto the bleeding lesion. The catheter should be maintained 1 to 2 cm from the high-risk lesion and application should be noncontact. As mentioned, the endoscopic powder will aggregate immediately when it comes into contact with moisture; therefore, efforts should be made to keep the tip of the catheter dry and to avoid suctioning while it is in use or while the powder is settling. Flushing the accessory channel with a 60-mL syringe of air before TC-325 application is also recommended to ensure that the tip of the catheter does not come into contact with moisture during insertion.
Clinical data on the use of Ankaferd blood stopper in gastrointestinal bleeding
ABS has been extensively studied and deemed systemically safe in animal models and human data in a variety of nonendoscopic settings, such as dental, ocular, orthopedic, urologic, liver injury, epistaxis, plastic surgery, head and neck, and cardiothoracic surgery. Intravascular application of ABS is considered a contraindication due to the potential for vascular embolization, as demonstrated by animal data. In terms of ABS use in the digestive tract, high-dose oral administration of the hemostatic agent in 8 rats and 12 rabbits proved to be safe without significant deleterious effects. In addition, oral administration of ABS in rats with caustic esophageal injury was shown to be associated with improved mucosal healing.
Kurt and colleagues reported one of the first cases of endoscopically applied ABS in the human digestive tract; more specifically, it was used in a case of gastrojejunostomy anastomic bleed refractory to conventional therapy. Several other case reports and series then followed describing the successful use of ABS in NVUGIB due to peptic ulcer (PUD), anastomotic ulcer, tumor, Dieulafoy lesion, gastric antral vascular ectasia (GAVE), arteriovenous malformation (AVM), Mallory-Weiss syndrome, postprocedural bleeding, esophagitis, and diffuse bleeding due to severe coagulopathy. Karaman and colleagues described the first large retrospective series of variceal and NVUGIB treated with ABS with an immediate hemostasis of 86.7% (26/30) and no documented rebleeding. Gungor and colleagues then demonstrated a more modest immediate hemostasis rate of 73% (19/26) in NVUGIB with PUD as the major cause.
Ankaferd Blood Stopper in the Management of Nonvariceal Upper Gastrointestinal Bleeding
Overall, there are a total of 83 cases of ABS-treated NVUGIB of various causes in the literature with an immediate hemostasis of 88.0% (73/83). Table 1 displays the immediate hemostasis rates of NVUGIB treated with ABS stratified according to cause and risk of rebleeding. In terms of PUD bleeding, there are a total of 34 cases treated with ABS reported in the literature with an immediate hemostasis rate of 73.4% (25/34). Gungor and colleagues showed a rebleeding rate of 15.8% in PUD treated with ABS monotherapy. These modest results suggest that the protein network and erythrocyte aggregation provided by ABS application may not be enough to attain optimal tamponade and successful hemostasis in PUD bleeding and that a second modality such as thermal or mechanical clip is needed to obliterate the bleeding vessel. There are also 10 cases of upper GI bleeding due to a luminal malignancy treated with ABS with excellent immediate hemostasis of 100% and no documented rebleeding. As with TC-325, ABS may be ideal for malignant bleeding given its noncontact and nontraumatic delivery and ability to cover large areas of bleed. In addition, in vitro and animal data suggest that ABS may have some healing properties and antineoplastic activity, while Turhan and colleagues reported decreased tumor vascularization post-ABS application in 2 patients with luminal cancer; however, these findings need to be confirmed and reproduced in larger trials.
| High-Risk Rebleed | N | Immediate Hemostasis | Low-Risk Rebleed | N | Immediate Hemostasis |
|---|---|---|---|---|---|
| PUD total | 34 | 76.5% (26/34) | Mallory-Weiss syndrome | 4 | 100% (4/4) |
| Anastomotic ulcer | 3 | 100% (3/3) | Gastroduodenal erosion | 1 | 100% (1/1) |
| Tumor bleeding | 10 | 100% (10/10) | Postbiopsy | 5 | 100% (5/5) |
| AVM | 1 | 100% (1/1) | Postpolypectomy | 12 | 100% (12/12) |
| Dieulafoy | 5 | 100% (5/5) | Postsphincterotomy | 2 | 100% (2/2) |
| Amyloidosis ulcer | 1 | 100% (1/1) | Diffuse UGIB due to coagulopathy | 1 | 100% (1/1) |
| GAVE | 3 | 100% (3/3) | Esophagitis | 1 | 100% (1/1) |
| Total | 57 | 86.0% (49/57) | Total | 26 | 100% (26/26) |
Ankaferd Blood Stopper in the Management of Variceal Bleeding
Although direct intravascular application of ABS has been shown to lead to systemic embolization in animal models, the use of this novel hemostatic powder has been described in 12 cases of variceal bleed (7 gastric, 4 esophageal, 1 duodenal) without evidence of systemic embolization. Immediate hemostasis was excellent at 91.7% (11/12) with only 1 documented case of rebleeding. Although use of ABS seems to be safe in this setting, this topical agent is unlikely to become a definite therapy in variceal bleeding given its inability to eradicate vascular structures and may play a more important role in terms of rescue or bridging therapy. In addition, the pooled sample size is quite small and more data will be needed to confirm its safety in variceal hemorrhage.
Ankaferd Blood Stopper in the Management of Lower Gastrointestinal Bleeding
The use of ABS in LGIB has been reported in 19 cases with an excellent immediate hemostasis of 100% and no documented rebleeding. Causes of hemorrhage include luminal malignancy, postpolypectomy, radiation colitis, diverticular bleeding, and solitary rectal ulcer. Interestingly, Ozaslan and colleagues reported a case of severe radiation colitis treated with 4 sessions of ABS on a weekly basis and demonstrated healing of the ulcerated and mildly necrotic mucosa. This finding again may highlight the potential healing characteristics of ABS; however, as aforementioned, larger, controlled data are needed to confirm this property.
Complications Related to Ankaferd Blood Stopper Use
The safety of ABS has been demonstrated in a wide variety of medical indications in animal, in vitro, and human studies. In terms of endoscopic application, there are a total of 115 cases described in the literature. Beyazit and colleagues reported the only complication found at the time of this review by describing a case of duodenal perforation post-ABS application in a patient with amyloidosis involving the GI tract. However, it is unclear whether the perforation was related to the endoscope, the use of ABS, or to the amyloid deposits. Although systemic embolization has been reported with direct ABS use in intravascular structures in animals, this has not been found in human subjects even when ABS was applied in variceal bleeding. Finally, congruent with animal studies, no intestinal toxicity or intestinal obstruction has been described with the endoscopic use of ABS. Overall, the use of ABS in the GI tract appears to be safe; however, as with all novel medical devices, larger trials and continuous monitoring are needed to confirm its safety.
Clinical data on the use of TC-325 in gastrointestinal bleeding
Giday and colleagues were the first to demonstrate the effectiveness and safety of TC-325 in a porcine model. Ten animals with Forrest Ia bleeding, artificially induced in the stomach by dissecting the gastroepiploic vessel, were randomized to TC-325 treatment or sham. Immediate hemostasis in the treatment arm was achieved in 100% of the animals with only 1 case of rebleeding at 24 hours. Necropsy at 1 week revealed healed bleeding sites without evidence of systemic embolization. A subsequent study focused on local and systemic effect of TC-325 therapy in 6 animals with artificially induced Forrest Ia bleeding showed no macroscopic or microscopic evidence of residual powder, no resultant gross or histologic evidence of embolization or bowel obstruction, and no systemic coagulopathic effect on necropsy.
Sung and colleagues were the first to describe the use of TC-325 in human subjects. This initial prospective, pilot study included 20 patients with NVUGIB stemming from gastroduodenal ulcers with high-risk stigmata (mostly Forrest Ib). Immediate hemostasis was excellent at 95% with TC-325 monotherapy and a rebleeding rate of 10.5% (2/19). Second-look endoscopy at 72 hours, performed in all subjects, showed healing of the ulcers without any remnants of the hemostatic powder. Following this pilot study, several case reports and small case series demonstrated the successful use of TC-325 in a variety of bleeding pathologic abnormalities, including PUD, anastomotic ulcer, luminal malignancies, AVM, Dieulafoy, Mallory-Weiss tears, esophagitis, and postprocedural bleeding (therapeutic and diagnostic). Smith and colleagues were the first to perform a large retrospective study on the use of TC-325. This study included 63 patients with TC-325-treated NVUGIB composed of 30 subjects with PUD and 33 patients with a variety of non-PUD-related NVUGIB. The compiled initial hemostasis rate was 87.3% (55/63) with a 7-day rebleed rate of 16.4% (9/55). More recently, the authors’ group performed a retrospective study involving 67 cases of TC-325 application in a variety of nonportal hypertensive bleeding pathologic abnormalities, including 21 nonmalignant NVUGIB, 19 malignant upper GI bleeding (UGIB), 11 LGIB, and 16 instances of intraprocedural bleeding ( Fig. 1 ). The initial hemostasis was 98.5% (66/67) with a 3-day rebleeding rate of 9.5% (6/63). Interestingly, the second-look endoscopy data showed no remnants of hemostatic powder even in patients who had a repeat endoscopy as early as 24 hours (3 patients), suggesting that TC-325 is eliminated by the GI tract within 1 day of application.
Overall, there are a total of 195 cases of NVUGIB treated with TC-325 published in the literature at the time of this review. Combining the above prospective series, retrospective studies, and case reports yielded an immediate hemostasis of 92.3% (180/195) and 7-day rebleed of 20.6% ( Table 2 ). Table 3 displays the combined immediate hemostasis, early rebleeding (≤72 hours), delayed rebleeding (>72 hours), and 7-day rebleeding rates stratified according to the specific bleeding cause and risk of rebleeding in time. In lesions that are considered high risk for rebleeding, such as Forrest Ia and Ib ulcers and tumor bleeding, the combined immediate hemostasis was 91.6% (120/131) with a 7-day rebleeding rate of 25.8% (31/120). Lesions at low risk of rebleeding were associated with an immediate hemostasis rate of 93.5% (29/31) and a 7-day rebleeding rate of 0% (0/29). It is important to note that many of the studies did not include data on cause-specific rates of immediate hemostasis and timing of rebleeding, therefore explaining the variable denominators and numerators shown in Table 3 .
| NVUGIB | Portal-Hypertensive and Variceal GIB | LGIB | |
|---|---|---|---|
| N | 195 | 20 | 28 |
| Immediate hemostasis | 92.3% (180/195) | 100% (20/20) | 100% (28/28) |
| Rebleed ≤72 h | 20.2% (18/89) a | 0% (0/9) | 7.4% (2/27) |
| Rebleed >72 h | 12.4% (11/89) a | 0% (0/9) | 0% (0/27) |
| 7-d Rebleed | 20.6% (37/180) a | 0% (0/8) | 7.7% (2/26) |
| Complications |
| Perforated viscus (unclear if due to TC-325) | None |
a Many of the reviewed literature did not differentiate between rebleed 72 h or less and rebleed greater than 72 h and only provided data on 7-day rebleed, therefore, explaining the variable denominators.
Related posts:
Advances and Improvements in the Management of Upper Gastrointestinal Bleeding
Epidemiology and Risk Factors for Upper Gastrointestinal Bleeding
Role of Medical Therapy for Nonvariceal Upper Gastrointestinal Bleeding
Endoscopic Diagnosis and Therapy in Gastroesophageal Variceal Bleeding
Unusual Causes of Upper Gastrointestinal Bleeding
Tips and Tricks on How to Optimally Manage Patients with Upper Gastrointestinal Bleeding
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