Peptic ulcer is the most common cause of acute hemorrhage in the upper gastrointestinal tract, accounting for 28%-59% of all episodes of upper GI bleeding[28,29]. Endoscopy with hemostatic therapy has clearly been shown to aid in proper diagnosis, prognosticate requirement for blood transfusions and, in the majority of instances, obviates the need for surgical intervention[30,31]. Despite the improvements in achieving hemostasis, recurrent bleeding still occurs in about 15% to 20% of GI bleeding cases. Moreover, the reported mortality for patients with a bleeding peptic ulcer still amounts to 15%[32]. Early effective hemostatic intervention is of great importance in the treatment of bleeding peptic ulcer disease, due to the high risk of morbidity and mortality. However, additional development is eagerly awaited for the therapeutic armamentarium of GI bleeding, which is safe, effective and easy applicable in difficult or intolerant patients[33,34]. In this setting, ABS could be the candidate hemostatic agent in the controlling of peptic ulcer bleeding, based on the previous successful anecdotal reports in GI bleeding with various clinical outcomes[13-22].

There is growing evidence in favor for the use of ABS in distinct states of GI bleeding, particularly in patients with bleeding due to peptic ulcer disease. In an observational study of “intention-to-treat” analysis by Ozaslan et al[35], five adult patients with bleeding peptic ulcer disease, in which ABS was used as a primary hemostatic agent due to difficulties or inappropriateness of the conventional measures, were reported to attained success in controlling of the bleeding within minutes. Similarly, Purnak et al[36] reported a successful hemostasis control in a patient with a bleeding peptic ulcer complicated with defective hemostasis. In this reported case, at the time of bleeding, the patient was under-treated with a cytotoxic chemotherapeutic agent leading to thrombocytopenia. Furthermore, platelet dysfunction and prolonged PT due to neutropenic sepsis had further complicated the hemostatic status. This “difficult-to-manage” situation was effectively controlled with topical ABS application and provided a critical time gain to the clinician until hemostasis could be returned to the normal level. Since ABS performs cellular hemostasis mainly through erythrocytes, it is reasonable to suggest that bleeding due to defective hemostasis (such as from a low platelet count, due to a warfarin overdose or because of chronic nonsteroidal anti-inflammatory drug use) could be controlled more efficiently with ABS as in this reported case[36]. Likewise, the in vivo hemostatic effect of ABS with defective hemostasis, due to aspirin and low-molecular weight heparin administration, has been investigated in experimental models and ABS was found to be effective in shortening the bleeding duration and decreasing the amount of bleeding[37]. Furthermore, the first pediatric experience with ABS in an infant with bleeding peptic ulcer was recently demonstrated by Yarali et al[38]. Both of these reports seem to be encouraging for the justification of the use of ABS in peptic ulcer bleeding based on future controlled clinical trials.

GI bleedings due to tumoral lesions (primary gastrointestinal tumors, direct local invasion by other malignancies, or metastatic disease to the gastrointestinal tract) are among the frequently encountered causes of GI bleeding, accounting for nearly 5% of severe upper GI bleeding cases[39]. Severe bleeding is a bad prognostic sign for upper GI tumors, and endoscopic hemostasis in this setting is often a temporary measure prior to staging and surgical resection. Several methods have been used to control bleeding from gastroduodenal malignant lesions, including thermal contact probes (tumor probe, bipolar probes, or heater probe), epinephrine injection, laser coagulation and injection of sodium tetradecyl sulphate with a success rate of 66%-100%[39-41]. Unfortunately, these intervention modalities were associated with high re-bleeding rates; up to 80% in a 1 mo period[39,40].

In the setting of malignant GI bleeding, ABS was effectively used previously in several reports. Application of ABS successfully controlled GI bleeding within seconds in a patient with major GI bleeding from a recurrent lesion at the hepaticojejunostomy anastomosis following surgery for distal cholangiocellular carcinoma[42]. In a case series by Kurt et al[43], topical application of ABS in seven patients with neoplastic upper GI hemorrhages, with appropriate bleeding control and post-procedural complications, were documented. In their summary, complete hemostasis was achieved in all of those patients within seconds of the endoscopic topical application of ABS, with no immediate complications. A recent report by Ozaslan et al[44] also supported the effectiveness of ABS in tumoral GI bleedings as a primary hemostatic agent. In their observational study, six patients suffering from malignant GI bleeding were reported to achieve hemostasis with topically applied ABS during endoscopy by a sclerotherapy needle or a heater probe catheter. The control of bleeding was obtained with ABS in five cases during the first endoscopic session, while the remaining one required a second application.

Apart from the mechanical hemostasis achieved by ABS, Turhan et al[45] disclosed that ABS decreases tumor vascularization in bleeding gastrointestinal carcinomas. In this report, topical ABS was applied in two patients with distinct tumoral GI bleedings due to gastric and rectal cancer. Tumor neo-vascularization/angiogenesis before and after the application of ABS were measured as tumor microvessel density (MVD). Topical ABS administration to the tumoral lesion resulted in complete control of the bleeding. Furthermore, ABS significantly decreased MVD measurements in both of the GI neoplastic tissues in comparison to the MVDs from the biopsy specimens before the ABS administration and the unexposed native neoplastic tissues of the stomach and rectum[45]. Based on these preliminary findings, the authors suggested the presence of a secondary, more sustained, mechanism of hemostasis induced by ABS beyond the initial protein network.

Although the management of tumoral GI bleeding in a pediatric population is a difficult to manage situation, ABS was also shown to be effective in a 10-year-old boy with esophageal tumor bleeding related to disseminated intravascular coagulation (DIC) during the post-chemotherapy period[46]. Since the endoscopic procedure was contraindicated due to DIC and associated co-morbidities in this patient, nasogastric tubes were used for the topical application of ABS. The bleeding was stopped within a very short period of time following the 6 milliliters of topical ABS application, with no observation of re-bleeding or side effects.

Endoscopic sphincterotomy (EST), which has became an essential procedure in therapeutic endoscopy for the management of pancreatic and biliary problems, raises concerns about procedure-related complications, such as hemorrhages, pancreatitis, cholangitis and perforation[47]. Hemorrhage is one of the most frequently encountered, and sometimes fatal, complications of EST and the incidence is reported as 1%-10%[47]. Though delayed hemorrhage may develop several days after EST, most of the bleedings occur just after EST. For this reason, effective control of intra-procedural hemorrhage is of great importance for the prevention of late post-EST bleedings. Several methods were suggested to control EST-related bleedings, with various grades of success[48]. The classical therapeutic methods for the EST-induced hemorrhages are endoscopic, surgical and radiological interventions. The reported means of endoscopic management consist of: argon plasma coagulation, electrocoagulation, injection therapy with various agents, and hemoclipping[49,50]. Since complete control of hemorrhages are not always possible via using those methods, novel hemostatic agents like ABS offer promising results in controlling post-sphincterotomy bleedings. We have recently reported the successful application of ABS in a 43-year-old woman that has underwent ERCP for cholangitis due to multiple bile duct stones[13]. After mild sphincterotomy, early bleeding from the sphincterotomy site was observed. Despite management with electrocoagulation and injection therapy with epinephrine, the bleeding remained uncontrolled. Subsequently, we injected 3 mL of ABS via the working channel of the duodenoscope to the bleeding areas. After a rapid and effective hemostatic response was successfully achieved, the procedure was terminated. Figure 3 shows an early bleeding during the endoscopic sphincterotomy, which has been controlled via the topical application of ABS.

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Figure 3 Ancaferd application during endoscopic sphincterotomy. A: Early bleeding during the endoscopic sphincterotomy; B: Ankaferd blood stopper (ABS) topically applied to the bleeding area; C: Hemorrhage was immediately controlled just after topical ABS administration; D: The bleeding site was covered by the hemostatic network related with the ABS application and hemorrhage was stopped.

Mallory-Weiss syndrome (MWS) was determined to be the cause of upper GI bleeding in 3%-10% of cases[51]. Bleeding in MWS usually stops spontaneously and patients can benefit from conservative medical treatment. Unfortunately, patients, especially those with stigmata of active bleeding and unstable vital signs at admission and/or associated co-morbid diseases, may require hemostatic intervention like hemoclip application, adrenaline injection and band ligation[52-54]. In a report by Ozaslan et al[35], a 62-year-old man with bleeding MWS was successfully treated with 13 mL of ABS. In another report, topical administration of ABS after unsuccessful combined endoscopic treatment in a warfarin-treated patient with bleeding MWS resulted in successful control after 7 mL of ABS application[22]. This case demonstrates the effectiveness of ABS even in patients receiving anticoagulant therapy, which could possibly broaden the use of ABS in distinct states of gastrointestinal bleeding with hemorrhagic diathesis.

Dieulafoy’s lesion (DL) is an uncommon, but important, cause of upper gastrointestinal bleeding consisting of a submucosal ectatic artery in the gastrointestinal tract and has a high mortality rate when diagnosis and treatment are delayed. It accounts for 0.3%-6.7% of all causes of upper GI bleeding[55-57]. Endoscopic therapy is the current “standard-of-care” for patients with DL, because the lesions are commonly in an accessible localization with upper GI endoscopy[56]. Unfortunately, endoscopic therapy sometimes fails to control active bleeding, resulting in hemorrhagic shock, circulatory collapse associated with increased morbidity, and even mortality. The first experience with ABS in a 63-year-old patient with DL was reported by Kurt et al[21]. In a recent paper, ABS was also shown to be effective in bleeding DL as an adjuvant modality in two patients[22].

Variceal bleeding is one of the most serious and life-threatening complications of cirrhosis and portal hypertension, with mortality exceeding 50% in severe or advanced liver disease in acute variceal hemorrhage[42]. Gastroesophageal varices are present in approximately 50%-60% of patients with cirrhosis. The prevalence of variceal hemorrhage is approximately 5%-15% yearly, and early variceal rebleeding has a rate of occurrence of 30%-40% within the first 6 wk[29]. Despite urgent endoscopic and/or pharmacological therapy, variceal bleeding cannot be controlled, or recurs early, in about 10%-20% of patients with considerable morbidity and mortality rates[58]. Although, endoscopic band ligation (EBL) and sclerotherapy are the choice of endoscopic treatment modalities for both active variceal bleeding and for secondary prophylaxis, application difficulties during active bleeding necessitated a search for new techniques and agents that are effective and safe. Furthermore, ease of administration, not requiring much experience and non-toxicity (even if the endoscopist could not locate the exact bleeding site), and injecting ABS to the close proximity to the suspected bleeding area may stop the variceal bleeding immediately. For that reason, ABS seems to offer a practical alternative in the setting of gastroesophageal variceal bleeding. Recently Tuncer et al[14] reported a patient with a fundal variceal hemorrhage that was effectively treated with 6 mL of ABS. Immediate hemostasis was achieved in 18 s without any further treatment. Control endoscopy was performed on day 5 that revealed clean surface fundal varices and a successful variceal obscuration by cyanoacrylate injection that was performed subsequently. Similarly, in a case report by Ozaslan et al[15], a patient with alcoholic cirrhosis who developed severe bleeding during an elective EBL session due to immediate band slippage underwent endoscopic topical application of ABS, which was then associated with the cessation of the hemorrhage. Although both of these reports seem to be encouraging, further controlled randomized studies are required to validate the effectiveness of ABS in the therapy of gastroesophageal varices. Current data regarding the use of ABS in GI bleedings is summarized in Table 1.

Bleeding following endoscopic polypectomy is the most common complication of colonic polypectomy[59], occurring in 0.3%-6.1% of polypectomies in various reports[60-62]. Bleeding can occur immediately following polypectomy or be delayed for hours or even up to 29 d[63]. Acute bleeding is due to the involvement of an underlying artery or inadequate coagulation of the polyp stalk and is usually self limiting, although active arterial bleeding can occur acutely.

The effectiveness of ABS for post-polypectomy bleeding was shown by Karaman et al[16] in 7 patients with post-polypectomy bleeding (5 cases of colonic, 2 cases of gastric polypectomy). ABS application was reported to be performed as a first choice in 5 cases, and after failed attempts with endoscopic interventions in 2 patients. Bleeding following polypectomy was stopped with ABS application in all of the cases without any other complication or re-bleeding. In a recent case series by Kurt et al[22], ABS application in a total of 11 patients (8 gastroduodenal, 3 colonic) with post-polypectomy bleeding resulted in the successful control of active bleeding.

Radiation proctitis (RP) is a relatively common late complication of pelvic radiation, commonly given for prostate, rectal, and gynecologic malignancies. The main symptoms of chronic RP are hematochezia (sometimes quite severe), urgency, constipation, tenesmus, diarrhea, and rectal pain. While mild cases may settle spontaneously over some months, severe hemorrhagic RP may required repeated blood transfusions and is difficult to treat with medical therapy such as sulfasalazine, corticosteroid enemas, and sucralfate (given orally or as an enema)[64,65]. Currently, argon plasma coagulation (APC) and local application of formalin are being used as main successful measures for therapy of RP, while APC treatment offers a safe non-contact method of delivering hemostasis compared to formalin[64-66]. Although complete healing of RP is not expected, even with APC or formalin, the measurement of efficacy with current treatments have been reported as decreased rectal bleeding, reduced transfusion requirement, improvements in endoscopic appearance and quality of life for the patients. In this setting, ABS may offer an exciting alternative in the treatment of RP, due to its ease of application, non-toxicity, and speed of action. It has a short procedure time and very simple technique (only spraying targeted or even just close to the bleeding area), and does not require expensive equipment like APC. Moreover, it offers two unique advantages to other modalities that are used in APC therapy; it doesn’t requires precise localization of the site of bleeding when applied, and simple topical application over the whole lesion could suffice for the entire coating of the affected mucosa (Figure 4).

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Figure 4 Endocopic images of the distal rectum in a patient with radiation proctitis. A: Before Ankaferd blood stopper (ABS) application with fresh bleeding; B: After ABS application with grayish-yellow coagulum formation covering the diseased area.

The first case of successful ABS application in radiation colitis was reported by Ozaslan et al[17] in a 71-year-old woman who had undergone pelvic radiotherapy due to cancer of the cervix. A total of 20 mL ABS was used with a sclerotherapy needle on the lesion and resulted in a greyish-yellow discoloration of the affected mucosa with cessation of bleeding. Three further sessions were carried out on a weekly basis to complete the healing with no signs of re-bleeding in the following days. At follow-up, the giant ulcerated lesion was reported to have almost disappeared, with only mild residual erosions and friability remaining. A difficult case of radiation proctitis that was managed by ABS was also reported by Shorbagi et al[18] in a 70-year-old patient with failed management of both medical and endoscopic interventions with APC. In this report, approximately 20 mL of ABS solution was applied to the affected areas by using a disposable washing pipe, which resulted in the immediate control of bleeding. The authors concluded that ABS would be a useful adjuvant to APC since, by controlling the active bleed, it may help to better localize and target telangiectasias. Kurt et al[22] reported 3 patients with radiation colitis which was primarily managed with APC. Adjuvant application of ABS in these patients resulted in a more sustained control of bleeding. Aside from this reports, an observational study was also conducted in 8 patients with bleeding due to chronic RP in which ABS was applied as a primary therapy[19]. In this study, ABS was instilled onto the bleeding areas by sclerotherapy needle or heater probe catheter, once a week, at a dose of 20-30 mL per session. ABS-induced hemostasis lasted for 1-8 d per session, and was achieved in seven of eight cases. In the eighth case, bleeding was only lessened. However, recurrence of bleeding was seen in all patients and ABS was found to be ineffective on telangiectasia at the last follow-up. As a result, ABS was only found to be effective in healing radiation-induced ulcers with no prolonged effect on bleeding telangiectasias due to RP.

Based on current observations, ABS may lead to the apparent healing of ulcers, but it might not be useful for the healing of telangiectasia or as a definitive therapy for bleeding in patients with chronic RP.

Solitary rectal ulcer (SRU) is a rare rectal disorder that can be present with bleeding, passage of mucus, straining during defecation, and a sense of incomplete evacuation[67]. Although bleeding due to a rectal ulcer commonly stops spontaneously, re-bleeding is a major matter of concern, despite effective endoscopic interventions. Recently in a paper by Ibis et al[20], topical application of 10 mL of ABS onto the ulcer through a disposable washing pipe resulted in successful control of the bleeding. Furthermore, complete healing of a bleeding SRU located adjacent to the anal canal prevented a potential risk for infection with fecal passage.

Colon cancer is the predominant cause of neoplastic bleeding. It accounts for up to 2%-9% of cases of hematochezia and is, by far, the most frequent cause of iron-deficiency anemia and the source of chronic lower GI bleeding[68]. The bleeding is usually low-grade and recurrent, occurring as a result of erosions and ulceration on the surface of the tumor and often exacerbated by the use of NSAIDs. Although several endoscopic treatment modalities can be used to achieve hemostasis, when the bleeding tumoral lesion is identified in a colonoscopic examination, the majority of patients require surgical management due to increased re-bleeding rates, which can be as high as 80% up to 1 mo after the procedure. For that reason, alternative approaches are required, especially in inoperable cases or as a bridge to elective surgery. In this setting, ABS as a novel hemostatic agent could have a potential benefit in controlling bleeding from GI tumors. In a retrospective analysis, the effectiveness of ABS in lower GI bleeding due to rectal carcinoma was shown in three patients[43]. Hemostasis was achieved in all three patients within seconds following ABS application, with no adverse events.