Angiodysplasia

Article Author:
Maryam Aghighi
Article Author (Archived):
Mehran Taherian
Article Editor:
Ashish Sharma
Updated:
11/27/2019 8:53:43 PM
PubMed Link:
Angiodysplasia

Introduction

The gastrointestinal (GI) tract is the most frequent site in the body for several types of abnormal blood vessels, which represent irregularities in the normal form of the affected arteries, veins, or capillaries. Vascular abnormalities can be benign or malignant such as hemangiomas or angiosarcomas, respectively. Also, they can be congenital, such as hereditary hemorrhagic telangiectasia or mostly acquired, such as angiodysplasia.[1] Angiodysplasia is an abnormal, tortuous, dilated small blood vessel in the mucosal and submucosal layers of the GI tract. The abnormal vessels consist of endothelium with scant or no smooth muscle.[2] Angiodysplasia is the most frequent etiology of small bowel bleeding or formerly called obscure gastrointestinal bleeding (OGIB) in patients more than 60 years of age.[3] Angiodysplasia is not related to any hereditary, skin, or systemic disease and can affect any part of the GI tract.[4]

Etiology

Although the exact etiology of angiodysplasia is unclear, many ideas appear in the literature, including age-related degeneration of small blood vessels and also cardiovascular and pulmonary disease, which may cause hypoperfusion of microvessels leading to ischemic necrosis of abnormal vascular lesions.[4] Angiodysplasia can be related to aortic stenosis.[5] Another reported the cause of angiodysplasia was the mucosal hypoperfusion associated with cardiac disease.[6] In von Willebrand disease (VWD), there has been bleeding reported from upper and lower GI angiodysplasia lesions.[7]

Epidemiology

In the general population, the most common vascular abnormality in the GI tract is angiodysplasia, which mainly occurs in patients over 60 years of age.[8][9] The prevalence of angiodysplasia increases with age. It may have no symptoms or present with GI bleeding.[10] There are reports of non-variceal upper GI bleeding caused by angiodysplasia in approximately 5% to 10% of patients.[11] Small bowel angiodysplasia is the most common cause of obscure GI bleeding (OGIB) in patients older than 50 years old. In contrast, small bowel tumors are the common cause in patients under 50 years old with OGIB[3][12]. The most common site of angiodysplasia in the GI tract is the colon.[13] Angiodysplasia has been reported to be associated more with some conditions in literature such as end-stage renal disease (ESRD), Von Willebrand disease, left ventricular assist device (LVAD), and aortic stenosis (Heyde syndrome).

End-stage renal disease - Peptic ulcer disease remains the most common cause of GI bleeding in end-stage renal disease patients. Still, angiodysplasia is another sizeable cause of both upper and lower GI bleeding in these patients and accounts for almost 20% to 30%, respectively. According to one report, one-half of patients with recurrent bleeding in chronic renal failure were because of angiodysplasia.[14][15]

Aortic stenosis (Heyde syndrome) - Heyde in 1958 first suggested association of unknown cause of GI bleeding, which was later attributed to angiodysplasia and aortic stenosis. The association is still subject to debate, and there are mixed small case-control and retrospective studies both in favor and against the association. There have also been reports of cessation of recurrent GI bleed on long term follow up after aortic valve replacement.[16][17][18]

Systemic sclerosis (SSc) - Gastric antral vascular ectasia (GAVE or watermelon stomach) is vascular malformation of gastric antral mucosa sometimes is considered a variant of angiodysplasia under the broad spectrum of vascular anomalies however many authors consider it as a systemic disease such as systemic sclerosis-related vascular ectasia. The prevalence of GAVE has been estimated at 5.7% in patients with SSc based on one large retrospective disease[19].

There is no causal association found yet and the association between these diseases, and angiodysplasia could be secondary to more endoscopic investigation related bias because patients with these conditions are more prone to have gastrointestinal bleeding secondary to underlying coagulopathy such as uremic platelet dysfunction in ESRD and acquired Von Willebrand factor deficiency in aortic valve stenosis and left ventricular assist device (LVAD).[20][20][21][22][23]

Pathophysiology

Although the mechanism of angiodysplasia is not clear, the hypothesis is that as a result of increased contractility at the level of muscular propria, submucosal veins may become obstructed. Chronic obstruction of these vessels may result in age-related angiodysplasia lesions. Congestion of the capillaries and precapillary sphincter failure, lead to the formation of arteriovenous collaterals.[24]

Angiogenesis is an important mechanism of the development of new vessels, which increases vascularity in the case of hypoxia or ischemia. In hypoxia, the expression of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor increase in angiodysplasia. These factors are significant in the development of angiodysplasia and changing the risk of bleeding.[25][26]

In endothelial cells, inhibition of von Willebrand factor (VWF) expression is shown to increase proliferation by VEGF and angiogenesis showing a correlation between hemostasis and angiogenesis, which is useful in the treatment of patients with angiodysplasia and VWD.[27]

Histopathology

Although usually readily apparent on colonoscopy and angiography, angiodysplasia is often extremely difficult to detect on the gross examination of a resected specimen without the use of specific injection techniques. As a result of vascular injection studies of resected colons, the determination was that angiodysplasia develops as a result of intermittent partial obstruction of small veins that drain the colonic mucosa and submucosa as they course through the muscularis propria. Over time, obstruction of the penetrating veins of the muscularis propria leads to dilation and tortuosity of the submucosal veins and, consequently, the venules and capillaries that drain them.

Angiodysplasias are often challenging to diagnose in pathologic specimens. In resected specimens examined while fresh, one may visualize only a small focus of enhanced vascular markings and erythema, and even these subtle signs may be absent. In specimens examined after formalin fixation, the lesions are usually not visible on the mucosal surface. If a vascular lesion is detected, the histologic examination typically reveals a discrete cluster of dilated, tortuous veins and venules within the submucosa, some associated with dilated capillaries in the overlying mucosa as well.[28]

History and Physical

Patients with angiodysplasia may be asymptomatic or present with mild to moderate occult lower GI bleeding without abdominal pain. History should include all the same elements as it would in the evaluation of upper and lower GI bleeding. Patients may present with occult blood in stool and iron deficiency anemia. Physical examination in a hemodynamic patient may show symptoms and signs of anemia. A systolic ejection murmur during the cardiac examination may raise suspicion for underlying aortic stenosis. Angiodysplasia lesions may be found incidentally in endoscopy for other reasons. Orthostasis or hypotension may rarely occur in acute and heavy bleeding. Although bleeding stops spontaneously in most patients, it may recur. Angiodysplasia-related GI bleeding can happen anywhere in the GI tract but more frequently seen in the cecum, rectosigmoid area, the rest of the colon, small intestine, and stomach in descending order.[29]

Evaluation

Angiodysplasia is usually diagnosed as an incidental finding during colonoscopy for colorectal cancer screening exams or when evaluating the patient for acute or chronic blood loss related anemia. The initial diagnostic modality depends on the characteristics of bleeding and suspicion for the location of the source. Slow bleeding from the stomach or small bowel may present as melena, while a colonic origin may present as fresh red blood per rectum. The clinician should be mindful that sometimes heavy bleeding from the upper GI tract may also show fresh blood per rectum. Evaluation of a patient should include vitals assessment to ensure hemodynamic stability. Initial investigation of complete blood count, liver function test, coagulation studies, and renal function test is usually required to know the severity of anemia and diagnose any underlying medical condition associated with bleeding such as end-stage renal disease, congenital or acquired coagulation disorders such as in cirrhosis. Because angiodysplasia is omnipresent throughout the GI tract, a combination of studies with endoscopy may be necessary.

Upper GI endoscopy and colonoscopy are common initial diagnostic tools. Angiodysplasia on direct visualization from endoscopy or colonoscopy looks like 5 to 10 mm flat cherry-red fern-like projecting vessels originating from a central artery.[30] Estimates of the sensitivity of colonoscopy to diagnose angiodysplasia are at around 80 percent and a positive predictive value of about 90%.[31]

Small bowel angiodysplasia as a source of obscure GI bleeding may require further evaluation with wireless video capsule endoscopy or deep bowel enteroscopy (single or double-balloon enteroscopy) if the initial workup is negative.

Radionuclide scanning images are the most sensitive radiologic diagnostic tool during active bleeding, which can detect bleeding up to 0.1 to 0.5 ml/min. It is done with two types of nuclear scans 99m Tc pertechnetate autologous red blood cell and technetium sulfur colloid. Technetium red cell scintigraphy is now commonly used because of its longer half-life allow to obtain imaging at definite time interval up to 24 hours after initial injection increasing its yield to diagnose intermittent active bleeding compared to technetium sulfur colloid test.[32] The biggest drawback of radionuclide scanning is that it generally shows active bleeding extravasation on a localized area of general abdominal imaging, which may not correlate to the specific site of bleeding because of the peristaltic nature of intestine.

CT angiography and magnetic resonance angiography are also useful investigative tools to investigate further if the conventional investigation does not show bleeding sources. Helical CT angiography sensitivity and specificity are 70 and 100 percent, respectively. However, it yields more results during active bleeding, with a minimum rate of bleeding is 0.3 to 0.5 ml/min.[33]

Angiography is usually necessary for actively bleeding unstable hemodynamically patients or patients in whom the active source of bleeding remains unidentified with conventional diagnostic methods. Angiography requires 0.5 to 1 ml/min blood loss to diagnose the active source of bleeding and also provides the benefit of therapeutic intervention at the same time.[34]

Intraoperative enteroscopy is useful when both endoscopic and radiological investigation fails to detect the source of bleeding. It is done by inserting an endoscopy by oral, rectal, or enterotomy route during surgery. The diagnostic yield is estimated to be 60 to 88 percent. Intraoperative enteroscopy is rarely used and only done when there is no source identified in an active bleeding patient. Complication includes perforation, serosal, mesentery or vessel tears, azotemia, and prolonged ileus.[35][36]

Treatment / Management

Angiodysplasia is more commonly diagnosed as an incidental finding for endoscopy for different reasons and can divide into incidental angiodysplasia, nonbleeding angiodysplasia in a patient with GI bleeding, and an actively bleeding angiodysplasia with GI bleeding. Clinicians should base treatment decisions on these factors.

Incidental angiodysplasia- Incidental angiodysplasia should not have treatment if there is no history of GI bleeding or unexplained iron deficiency anemia. The future risk of incidental angiodysplasia-related bleeding is unknown, and the recommendation is based solely on expert opinions.

Nonbleeding angiodysplasia in a patient with GI bleeding - In these patients, angiodysplasia should have treatment, which again has its basis on expert opinions.

Actively bleeding angiodysplasia- In most patient’s management should follow a similar path as in managing upper and lower GI bleeding for other reasons, which is hemodynamic resuscitation, frequent complete blood count monitoring, and blood transfusion if needed. Treatment decisions should be dependent on hemodynamic stability and whether the patient is actively bleeding or not.

Hemodynamically unstable patient - In an unstable patient with active bleeding intravenous fluid resuscitation should be started immediately. If the patient is obtunded with a thready pulse, hypoxic, having active hematemesis, and unable to protect the airway, then they need to be intubated and admitted in the intensive care unit for frequent CBC monitoring and blood transfusion as required. An endoscopy or colonoscopy should be done if possible, but it may not be possible if the patient is actively bleeding. In that case, surgery or radiology intervention with angiography is usually required.

Hemodynamically stable patient - In patients with stable vitals, an endoscopy or colonoscopy should be done within 24 hours based on characteristics of bleeding. If the test reveals no identified source, then the next diagnostic modality is chosen on the fact whether the bleeding is active or not. 

Endoscopy or colonoscopy - If angiodysplasia is present on endoscopy or colonoscopy then different techniques can be used to treat angiodysplasia which is as follows 

  • Argon plasma coagulation ablation - Most commonly used intervention.[37] High-frequency energy transmitted to tissues by ionized gas. It requires thorough bowel preparation to avoid a colonic gas explosion.[38] It has comparatively more risk of bowel perforation in the upper GI tract.
  • Electrocoagulation - Uses bipolar or heater probe coagulation. It is more suitable for the lower GI tract.
  • Endoscopic clips and band ligation - These are mechanical methods to treat angiodysplasia. Band ligation is an option in the stomach and small bowel angiodysplasia treatment.
  • Injection sclerotherapy - It includes injecting a sclerosant to obliterate angiodysplasia and other vascular lesions of the upper and lower GI tract. Commonly used sclerosants are ethanolamine or sodium tetradecyl sulfate. Endoscopic ligation, endoscopic resection, and photocoagulation are also some other techniques that are being used in the treatment of angiodysplasia endoscopically.[39][40][41][40]

Endoscopy with push enteroscopy is used to investigate and treat with endoscopic intervention in OGIB.

Angiography- Usually done in patients with active bleeding who have failed other treatment mentioned above, patients who are poor surgical candidates, and to localize bleeding sites as a preoperative investigation before surgical resection. The therapeutic intervention involves either temporary absorbable gelatin sponge, local infusion of vasopressin, or permanent such embolization with micro-coils, particles, or glue.  Major complication includes bowel ischemia or infarction along with complication of arteriography itself. The initial success rate of achieving hemostasis with embolization in lower GI bleed is 95% and 64% to 89% in upper GI bleeding.[42][43] Estimates of lower GI bleed embolization rebleeding rates are 22% to 48%.[44][45]

Surgery - Surgical resection is required eventually in patients with heavy active bleeding requiring multiple blood unit transfusion with failed all other measures described above.[46] Rebleeding after surgery could be secondary to inadequate resection or missed lesion. Preoperative workup with push enteroscopy, intraoperative enteroscopy, and angiography can better localize the bleeding site to reduce rebleeding rate. Endoscopy or colonoscopy also can be done preoperatively and can inject dye or put an endoclip to demarcate the lesion for better localization during surgery. Intraoperative enteroscopy can also help in localization of the unidentified lesions. Aortic valve replacement in a patient with associated aortic stenosis may improve angiodysplasia-related bleeding.[16]

Angiogenesis inhibitors - Thalidomide and bevacizumab have been described with success in the treatment of gastrointestinal vascular malformation, including angiodysplasia.[25][26][47] In one clinical trial, an effective response rate, which was described GI bleeding cessation by over 50% by the end of the year, was 71.6% in the thalidomide treated group compared to the control group 3.7%.[48] Even though thalidomide has shown some promise in refractory angiodysplasia-related GI bleeding and transfusion-dependent patients, thalidomide use requires caution in this patient population because of extensive side effects, including teratogenicity.  Another angiogenesis inhibitor bevacizumab is a human monoclonal antibody again vascular endothelial growth factor and has been used in some case reports and series for the treatment of refractory GI bleeding related to angiodysplasia but because of the paucity of data should be used as last resort.[47]

Hormone therapy - Few studies have evaluated treatment with estrogen with or without progesterone in chronic obscure GI bleeding.[49] However, other studies, including a randomized controlled trial, did not show any benefit of hormonal therapy in the prevention of angiodysplasia-related GI bleeding.[50]

Octreotide – Octreotide seems to be effective in the treatment of refractory angiodysplasia related GI bleeding, as mentioned in some case series and meta-analysis. Octreotide with twice-daily subcutaneous injections with dose 50 to 100 mcg and long-acting form, octreotide-LAR, which is given intramuscularly once a month is an option. The studies which evaluated octreotide showed 73 to 76% of patients showed response in terms of bleeding events, transfusion requirement, and mean hemoglobin.[51] [52][53][54] Based on the results of these studies, octreotide may be an option in patients with refractory angiodysplasia-related bleeding.

Differential Diagnosis

Symptomatic angiodysplasia usually presents with symptoms similar to upper and lower GI bleeding, which is either unexplained iron deficiency anemia or GI bleeding. Differential diagnosis includes common causes of both upper and lower GI bleeding. 

  • Peptic ulcer disease
  • Diverticulosis 
  • Colitis (ischemic, inflammatory bowel disease and radiation-induced, infectious )
  • Hemorrhoidal bleeding
  • GI malignancies, such as colon and rectal cancer.[55]

Prognosis

Patients with angiodysplasia have a good prognosis because the bleeding subsides automatically in most cases. Patients with ten or more angiodysplasia lesions or lesions larger than 10 mm, may have a worse prognosis, lower hemoglobin level, and require more blood transfusions.[56]

Complications

Chronic occult bleeding and iron deficiency anemia is the most common complication and presenting symptoms of symptomatic angiodysplasia. Rarely symptomatic angiodysplasia may present as massive bleeding and can cause hemodynamic instability. 

Consultations

Gastroenterologist consultation is necessary for patients with symptomatic angiodysplasia for confirmation of diagnosis and further treatment with a combination of different endoscopic methods. Patients with symptomatic angiodysplasia with an unconfirmed source of bleeding after initial investigations may require an interventional radiology consultation for angiography for diagnosis as well as the opportunity for treatment. Cases with uncontrolled bleeding after attempts to control it fails with all other intervention will require surgery.

Deterrence and Patient Education

Patient reassurance is recommended in most cases of incidental angiodysplasia since it is usually asymptomatic. The decision for therapy by endoscopy is usually based on clinical presentation and the presence of GI bleeding or unexplained iron deficiency anemia.

Enhancing Healthcare Team Outcomes

The majority of patients with bleeding angiodysplasia present to the emergency department, and hence the nursing staff and triage need to be aware of the management of these patients. Because the diagnosis is not simple, numerous specialists may be involved. For those who are unstable, resuscitation is vital. Once stable, imaging studies are required to locate the angiodysplasia for more definitive treatment. Acutely bleeding patients must be monitored in an intensive care setting and be aware of the potential complications.

When choosing medical treatment, the specialist should work closely with a board-certified pharmacotherapy pharmacist to optimize drug selection and dosing. A gastroenterology specialty nurse can also verify patient compliance, provide patient counsel, and evaluate therapeutic effectiveness, irrespective of the treatment path chosen. Close communication and collaboration between specialists and all members of the interprofessional team are vital for improving outcomes; this includes ED physicians, specialists, pharmacists, and nursing. [Level V]

A recent case-control study with 270 patients diagnosed between 2010 and 2015 with angiodysplasia and 5594 controls demonstrated that the risk factors for incidental angiodysplasia are anticoagulants, autoimmune disease, chronic obstructive pulmonary disease, male gender, and thyroid dysfunction. They showed that risk factors related to symptomatic angiodysplasia are advanced age, diabetes mellitus, hyperlipidemia, and valvular heart disease. The risk factors for symptomatic angiodysplasia are different and more significant than incidental angiodysplasia, which may help in a proper treatment plan of a patient with angiodysplasia.[57]



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References

[1] Gordon FH,Watkinson A,Hodgson H, Vascular malformations of the gastrointestinal tract. Best practice     [PubMed PMID: 11355900]
[2] Poralla T, Angiodysplasia in the renal patient: how to diagnose and how to treat? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 1998 Sep;     [PubMed PMID: 9761492]
[3] Chong J,Tagle M,Barkin JS,Reiner DK, Small bowel push-type fiberoptic enteroscopy for patients with occult gastrointestinal bleeding or suspected small bowel pathology. The American journal of gastroenterology. 1994 Dec;     [PubMed PMID: 7977230]
[4] Sami SS,Al-Araji SA,Ragunath K, Review article: gastrointestinal angiodysplasia - pathogenesis, diagnosis and management. Alimentary pharmacology     [PubMed PMID: 24138285]
[5] Schwartz J,Rozenfeld V,Habot B, Cessation of recurrent bleeding from gastrointestinal angiodysplasia, after beta blocker treatment in a patient with hypertrophic subaortic stenosis--a case history. Angiology. 1992 Mar;     [PubMed PMID: 1575371]
[6] Pate GE,Chandavimol M,Naiman SC,Webb JG, Heyde's syndrome: a review. The Journal of heart valve disease. 2004 Sep;     [PubMed PMID: 15473466]
[7] Gola W,Lelonek M, Clinical implication of gastrointestinal bleeding in degenerative aortic stenosis: an update. Cardiology journal. 2010;     [PubMed PMID: 20690087]
[8] Foutch PG,Rex DK,Lieberman DA, Prevalence and natural history of colonic angiodysplasia among healthy asymptomatic people. The American journal of gastroenterology. 1995 Apr;     [PubMed PMID: 7717311]
[9] Dodda G,Trotman BW, Gastrointestinal angiodysplasia. Journal of the Association for Academic Minority Physicians : the official publication of the Association for Academic Minority Physicians. 1997;     [PubMed PMID: 9048468]
[10] Foutch PG, Angiodysplasia of the gastrointestinal tract. The American journal of gastroenterology. 1993 Jun;     [PubMed PMID: 8389094]
[11] Cheng CL,Lee CS,Liu NJ,Chen PC,Chiu CT,Wu CS, Overlooked lesions at emergency endoscopy for acute nonvariceal upper gastrointestinal bleeding. Endoscopy. 2002 Jul;     [PubMed PMID: 12170402]
[12] Raju GS,Gerson L,Das A,Lewis B, American Gastroenterological Association (AGA) Institute technical review on obscure gastrointestinal bleeding. Gastroenterology. 2007 Nov;     [PubMed PMID: 17983812]
[13] Ueno S,Nakase H,Kasahara K,Uza N,Kitamura H,Inoue S,Mikami S,Matsuura M,Chiba T, Clinical features of Japanese patients with colonic angiodysplasia. Journal of gastroenterology and hepatology. 2008 Aug;     [PubMed PMID: 17725595]
[14] Chalasani N,Cotsonis G,Wilcox CM, Upper gastrointestinal bleeding in patients with chronic renal failure: role of vascular ectasia. The American journal of gastroenterology. 1996 Nov;     [PubMed PMID: 8931412]
[15] Zuckerman GR,Cornette GL,Clouse RE,Harter HR, Upper gastrointestinal bleeding in patients with chronic renal failure. Annals of internal medicine. 1985 May     [PubMed PMID: 3872616]
[16] King RM,Pluth JR,Giuliani ER, The association of unexplained gastrointestinal bleeding with calcific aortic stenosis. The Annals of thoracic surgery. 1987 Nov     [PubMed PMID: 3499881]
[17] Cappell MS,Lebwohl O, Cessation of recurrent bleeding from gastrointestinal angiodysplasias after aortic valve replacement. Annals of internal medicine. 1986 Jul     [PubMed PMID: 3487267]
[18] Vincentelli A,Susen S,Le Tourneau T,Six I,Fabre O,Juthier F,Bauters A,Decoene C,Goudemand J,Prat A,Jude B, Acquired von Willebrand syndrome in aortic stenosis. The New England journal of medicine. 2003 Jul 24     [PubMed PMID: 12878741]
[19] Marie I,Ducrotte P,Antonietti M,Herve S,Levesque H, Watermelon stomach in systemic sclerosis: its incidence and management. Alimentary pharmacology     [PubMed PMID: 18498445]
[20] Demirozu ZT,Radovancevic R,Hochman LF,Gregoric ID,Letsou GV,Kar B,Bogaev RC,Frazier OH, Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011 Aug;     [PubMed PMID: 21530318]
[21] Kushnir VM,Sharma S,Ewald GA,Seccombe J,Novak E,Wang IW,Joseph SM,Gyawali CP, Evaluation of GI bleeding after implantation of left ventricular assist device. Gastrointestinal endoscopy. 2012 May;     [PubMed PMID: 22341716]
[22] Brock AS,Cook JL,Ranney N,Rockey DC, Clinical problem-solving. A not-so-obscure cause of gastrointestinal bleeding. The New England journal of medicine. 2015 Feb 5;     [PubMed PMID: 25651250]
[23] Singh G,Albeldawi M,Kalra SS,Mehta PP,Lopez R,Vargo JJ, Features of patients with gastrointestinal bleeding after implantation of ventricular assist devices. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2015 Jan;     [PubMed PMID: 24858705]
[24] Ghdes O,Gaja A,Blel A,Jarraya H,Mnif N, Ileal angiodysplasia presentation as a bowel obstruction: A case report. International journal of surgery case reports. 2017;     [PubMed PMID: 28892784]
[25] Chen HM,Ge ZZ,Liu WZ,Lu H,Xu CH,Fang JY,Xiao SD, [The mechanisms of thalidomide in treatment of angiodysplasia due to hypoxia]. Zhonghua nei ke za zhi. 2009 Apr     [PubMed PMID: 19576118]
[26] Fujita H,Momoi M,Chuganji Y,Tomiyama J, Increased plasma vascular endothelial growth factor levels in patients with angiodysplasia. Journal of internal medicine. 2000 Sep     [PubMed PMID: 10971796]
[27] Starke RD,Ferraro F,Paschalaki KE,Dryden NH,McKinnon TA,Sutton RE,Payne EM,Haskard DO,Hughes AD,Cutler DF,Laffan MA,Randi AM, Endothelial von Willebrand factor regulates angiogenesis. Blood. 2011 Jan 20     [PubMed PMID: 21048155]
[28] Mudhar HS,Balsitis M, Colonic angiodysplasia and true diverticula: is there an association? Histopathology. 2005 Jan     [PubMed PMID: 15656890]
[29] Boley SJ,DiBiase A,Brandt LJ,Sammartano RJ, Lower intestinal bleeding in the elderly. American journal of surgery. 1979 Jan     [PubMed PMID: 310250]
[30] Rodrigues JP,Chivia J,Figueiredo PC, Fleeting Angiodysplasia. GE Portuguese journal of gastroenterology. 2018 Jun;     [PubMed PMID: 29998169]
[31] Richter JM,Hedberg SE,Athanasoulis CA,Schapiro RH, Angiodysplasia. Clinical presentation and colonoscopic diagnosis. Digestive diseases and sciences. 1984 Jun     [PubMed PMID: 6609803]
[32] Dusold R,Burke K,Carpentier W,Dyck WP, The accuracy of technetium-99m-labeled red cell scintigraphy in localizing gastrointestinal bleeding. The American journal of gastroenterology. 1994 Mar     [PubMed PMID: 8122642]
[33] Kuhle WG,Sheiman RG, Detection of active colonic hemorrhage with use of helical CT: findings in a swine model. Radiology. 2003 Sep     [PubMed PMID: 12954894]
[34] Walker TG, Acute gastrointestinal hemorrhage. Techniques in vascular and interventional radiology. 2009 Jun     [PubMed PMID: 19853226]
[35] Ress AM,Benacci JC,Sarr MG, Efficacy of intraoperative enteroscopy in diagnosis and prevention of recurrent, occult gastrointestinal bleeding. American journal of surgery. 1992 Jan     [PubMed PMID: 1733380]
[36] Raju GS,Gerson L,Das A,Lewis B, American Gastroenterological Association (AGA) Institute medical position statement on obscure gastrointestinal bleeding. Gastroenterology. 2007 Nov     [PubMed PMID: 17983811]
[37] Vargo JJ, Clinical applications of the argon plasma coagulator. Gastrointestinal endoscopy. 2004 Jan     [PubMed PMID: 14722558]
[38] Ladas SD,Karamanolis G,Ben-Soussan E, Colonic gas explosion during therapeutic colonoscopy with electrocautery. World journal of gastroenterology. 2007 Oct 28     [PubMed PMID: 17879396]
[39] Ertekin C,Taviloglu K,Barbaros U,Guloglu R,Dolay K, Endoscopic band ligation: alternative treatment method in nonvariceal upper gastrointestinal hemorrhage. Journal of laparoendoscopic     [PubMed PMID: 11905861]
[40] Kobeissy A,Mallat M,Jamali F,Yaghi S,Jabbour M,Shabb N,Soweid A, Endoscopic removal of a bleeding colonic polypoid angiodysplasia: case report. Acta gastro-enterologica Belgica. 2010 Jul-Sep;     [PubMed PMID: 21086949]
[41] Selinger RR,McDonald GB,Hockenbery DM,Steinbach G,Kimmey MB, Efficacy of neodymium:YAG laser therapy for gastric antral vascular ectasia (GAVE) following hematopoietic cell transplant. Bone marrow transplantation. 2006 Jan     [PubMed PMID: 16284614]
[42] Weldon DT,Burke SJ,Sun S,Mimura H,Golzarian J, Interventional management of lower gastrointestinal bleeding. European radiology. 2008 May     [PubMed PMID: 18185932]
[43] Mirsadraee S,Tirukonda P,Nicholson A,Everett SM,McPherson SJ, Embolization for non-variceal upper gastrointestinal tract haemorrhage: a systematic review. Clinical radiology. 2011 Jun     [PubMed PMID: 21371695]
[44] Neuman HB,Zarzaur BL,Meyer AA,Cairns BA,Rich PB, Superselective catheterization and embolization as first-line therapy for lower gastrointestinal bleeding. The American surgeon. 2005 Jul     [PubMed PMID: 16089115]
[45] DeBarros J,Rosas L,Cohen J,Vignati P,Sardella W,Hallisey M, The changing paradigm for the treatment of colonic hemorrhage: superselective angiographic embolization. Diseases of the colon and rectum. 2002 Jun     [PubMed PMID: 12072634]
[46] Czymek R,Kempf A,Roblick UJ,Bader FG,Habermann J,Kujath P,Bruch HP,Fischer F, Surgical treatment concepts for acute lower gastrointestinal bleeding. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2008 Dec;     [PubMed PMID: 18636299]
[47] Marlu R,Barthelon J,Durand A,Mathieu N,Barro C,Granger V,Tatu A,Pernod G,Polack B,Bonaz B, Long-term therapy with bevacizumab in a patient with Glanzmann's thrombasthenia and recurrent digestive bleeding due to gastrointestinal angiodysplastic lesions. The American journal of gastroenterology. 2015 Feb;     [PubMed PMID: 25646919]
[48] Ge ZZ,Chen HM,Gao YJ,Liu WZ,Xu CH,Tan HH,Chen HY,Wei W,Fang JY,Xiao SD, Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology. 2011 Nov     [PubMed PMID: 21784047]
[49] Barkin JS,Ross BS, Medical therapy for chronic gastrointestinal bleeding of obscure origin. The American journal of gastroenterology. 1998 Aug     [PubMed PMID: 9707046]
[50] Junquera F,Feu F,Papo M,Videla S,Armengol JR,Bordas JM,Saperas E,Piqu� JM,Malagelada JR, A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology. 2001 Nov;     [PubMed PMID: 11677198]
[51] Szilagyi A,Ghali MP, Pharmacological therapy of vascular malformations of the gastrointestinal tract. Canadian journal of gastroenterology = Journal canadien de gastroenterologie. 2006 Mar;     [PubMed PMID: 16550261]
[52] Brown C,Subramanian V,Wilcox CM,Peter S, Somatostatin analogues in the treatment of recurrent bleeding from gastrointestinal vascular malformations: an overview and systematic review of prospective observational studies. Digestive diseases and sciences. 2010 Aug     [PubMed PMID: 20393879]
[53] Bon C,Aparicio T,Vincent M,Mavros M,Bejou B,Raynaud JJ,Zampeli E,Airinei G,Sautereau D,Benamouzig R,Michopoulos S, Long-acting somatostatin analogues decrease blood transfusion requirements in patients with refractory gastrointestinal bleeding associated with angiodysplasia. Alimentary pharmacology & therapeutics. 2012 Sep     [PubMed PMID: 22831465]
[54] Nardone G,Compare D,Scarpignato C,Rocco A, Long acting release-octreotide as "rescue" therapy to control angiodysplasia bleeding: A retrospective study of 98 cases. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2014 Aug     [PubMed PMID: 24893688]
[55] Strate LL, Lower GI bleeding: epidemiology and diagnosis. Gastroenterology clinics of North America. 2005 Dec;     [PubMed PMID: 16303575]
[56] Redondo-Cerezo E,G�mez-Ruiz CJ,S�nchez-Manjavacas N,Vi�uelas M,Jimeno C,P�rez-Vigara G,Morillas J,P�rez-Garc�a JI,Garc�a-Cano J,P�rez-Sola A, Long-term follow-up of patients with small-bowel angiodysplasia on capsule endoscopy. Determinants of a higher clinical impact and rebleeding rate. Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva. 2008 Apr;     [PubMed PMID: 18563976]
[57] Grooteman KV,Dalloyaux S,van den Bemt MCP,de Graaf J,Verbeek ALM,Jackson CS,van Geenen EJM,Drenth JPH, Risk factors for incidentally detected and symptomatic angiodysplasias: a case-control study with the general population as reference. European journal of gastroenterology     [PubMed PMID: 30562184]