In most patients a definitive bleeding site, defined as a lesion that is either actively bleeding or possesses an adherent clot, is not identified and the bleeding source is attributed to diffuse areas of active inflammation[4]. When found, the source of bleeding is more commonly described as a deep ulcer eroding into a blood vessel[9]. On rare occasions, a large pseudopolyp in the ileum or colon has been identified as the source of bleeding[2,10]. The majority of bleeds originate from the ileum and colon as visualized on pathology after surgery, endoscopy or imaging studies. Only a small number of episodes have been attributed to a jejunal or upper GI source. Isolated colonic bleeding accounts for 3%-50% of hemorrhagic CD, diffuse ileo-colonic lesions for 22.7%-68.5%, and 19%-66% originate from the small bowel[2-5,7]. Although it may seem logical to assume that the presence of significant disease activity and symptomatic CD would result in a higher incidence of acute lower GI bleeding, two series have shown 65%-78% of patients had quiescent CD at the time of bleeding[2,3].

The incidence of severe lower GI bleeding in CD has ranged from 0.6%-4%. Cirocco et al[7] reported an incidence of 0.6% in their 631 patients diagnosed with CD while Kim et al[3] reported an incidence of 4% in their study of 1731 patients. Other large series reported incidences from 1.3%-1.6%[4,5]. Some studies describe a similar incidence in males and females[2,5] whereas others have found a higher incidence in males[3,4,7]. The average age of presentation has been around 30 years ranging from 27-45 years[2-5,7]. Since the peak age for the diagnosis of CD is in the 20’s, it is possible that patients present with severe bleeding after having the disease for some years.

A study to evaluate risk factors for acute hemorrhage in CD showed that patients on corticosteroids had a higher rate of bleeding when compared to a control group of CD patients with no bleeding but this was not confirmed on multivariate analysis[3]. The same study showed that Azathioprine/6-Mercaptopurine (6-MP) could actually have a role in preventing severe hemorrhage in CD OR = 0.53 (95%CI: 0.30-0.91).

Only 2 case series studies have utilized upper endoscopy (EGD) for diagnosis[3,4]. Kim et al[3] analyzed 30 patients who underwent an EGD with no diagnostic yield. In the second study, EGD was performed in patients with suspected upper GI bleed or with a negative colonoscopy, and the source of bleeding was identified in 2 patients but there was no mention of the total number of patients undergoing EGD.

There are 3 large case series that have utilized colonoscopy for diagnosis producing variable results as demonstrated in Table 1. Pardi was the first to evaluate the role of colonoscopy in the diagnosis and treatment of hemorrhagic CD. Patients included in this study underwent colonoscopy within 24 h of presentation and the source of bleeding was identified in 78%. Only 3 patients were treated endoscopically with no subsequent recurrence of bleeding[4]. Belaiche et al[2] found the yield of colonoscopy in identifying the bleeding site at 60% (18/30). Ulcers located in left and sigmoid colon were recognized as the cause of bleeding in 95% cases while one patient bled from a pseudopolyp. In contrast to the previous two studies, the diagnostic yield for colonoscopy was only 10.6% in a Korean case series. Some of the factors that may have led to a lower yield of colonoscopy in this study include a delay in colonoscopy examination, as its timing was not specified[3], and location of the bleeding site as in most cases in this study the bleeding site originated from the small bowel. As demonstrated in these case series, colonoscopy was not only useful in determining the site of bleeding but also could be used therapeutically.

There is very limited literature demonstrating the utility of angiography and radionuclide scan with variable results, success ranging from 26% to 75% for angiography and 0% to 75%[2-4] for radionuclide bleeding scan (Table 1). These modalities do not ascertain if the site of bleeding is resulting from CD but in some instances a presumptive diagnosis can be established based on angiographic signs that have been associated with CD. These signs include the presence of mesenteric neovascularity, an increased contrast staining of bowel loops, early and prominent venous return, skip lesions, and the “zoning” sign[11-13]. The zoning sign refers to a double-layer appearance of the bowel wall with a densely staining inner wall representing a hypervascular submucosa and mucosa and a thick but relatively avascular outer muscle layer.

CT enterography of the small bowel was introduced in 1997 and was found helpful in assessing the extent and severity of CD[14]. The underlying principle was the combination of neutral (low-density) oral contrast with ‘‘enteric phase’’ CT to enhance contrast resolution between mucosa and lumen to better characterize small bowel abnormalities. CT enterography has been utilized in detecting obscure GI bleed[14]. Its utility to detect hemorrhage in patients with CD was demonstrated only in one series where CT enterography diagnosed the site of bleeding in 9/46 (19.6%)[3].

The role of capsule endoscopy has not been studied in patients with hemorrhagic CD likely due to concern of capsule retention secondary to strictures or previous surgeries[15]. The role of capsule endoscopy has been limited to diagnosing obscure GI bleeds in patients with CD. In these cases capsule endoscopy has been found to be superior to push enteroscopy and small bowel radiography[16].

Treatment of CD has evolved over the years. In the early 1990’s the most common strategy for the management of CD with hemorrhage was surgery. However beginning in the late 1990’s there has been a paradigm shift in the management with a tendency to avoid surgery and instead utilize medical management[2,4]. Besides blood transfusions, medical management consists of medications used to treat CD including corticosteroids, mesalamine, antibiotics and continuation of 6-MP[2,4,17]. Belaiche et al[18] successfully achieved hemostasis with the use of infliximab in non-surgical candidates presenting with GI hemorrhage and attributed this success to the high rates of mucosal healing with this medication. Since then, additional case reports and case series have reported the effectiveness of infliximab in cessation of GI hemorrhage[19,20]. Aniwan et al[21] recently published a case series in which bleeding was controlled within 24 h in 6/7 patients who received infliximab. No rebleeding episodes were reported after 30 d of follow up and surgery was avoided in all patients. The potential advantage of infliximab in the treatment of patients with unclear site of bleeding was described. There are at least 11 additional reports of patients presenting with CD related GIB treated with infliximab with successful control of bleeding in all the cases[18,21-25]. Patients selected for treatment with infliximab in these case reports included poor surgical candidates and those who developed recurrent bleeding after undergoing surgery.

There is only one comparative study evaluating medical therapy for CD presenting with severe bleeding in the era of biologics consisting of 70 cases[3]. All patients were initially managed with 5-ASA, azathioprine/ 6-MP or corticosteroids. Eleven patients required additional intervention including embolization, endoscopic management, surgery or infliximab (5 patients) to treat the index bleeding. A total of eleven patients underwent treatment with infliximab (5 first bleeding and 6 rebleeding) and only 1 patient had further bleeding episodes requiring surgery. The benefits of infliximab therapy did not reach statistical significance when compared to patients undergoing other treatments because of the small sample size. The study suggests that medical treatment can have better outcomes than what has been previously reported and surgery could be reserved for patients who fail initial medical treatment or exhibit recurrent bleeding.

There was one case report utilizing recombinant factor VIIa in the management of GI hemorrhage secondary to CD. Recombinant factor VIIa improves hemostasis and has been shown to be effective in treating hemorrhage in patients with hemophilia A or B. The standard dose for these conditions is 90 to 110 μg/kg every 2 to 3 h for two to three doses[26]. In this case report they used 2 doses of 120 μg/kg three hours apart with cessation of bleeding over the next 12 h.