Disappearance of Angiodysplasia Following Transcatheter Aortic Valve Implantation in a Patient with Heyde's Syndrome: A Case Report and Review of the Literature.

An 83-year-old woman with severe aortic stenosis was admitted to our hospital due to heart failure with refractory anemia requiring blood transfusions. She had repetitive bleeding episodes from endoscopically proven angiodysplasia in the stomach. Moreover, she repeatedly underwent endoscopic argon plasma coagulation for hemostasis. Importantly, she had a deficiency of the high-molecular-weight (HMW) multimers of von Willebrand factor (VWF), and she was diagnosed with Heyde's syndrome.After she underwent transcatheter aortic valve implantation (TAVI), aortic valve area and mean left ventricular aorta pressure gradient improved. Notably, endoscopy showed cessation of bleeding at 10 days after TAVI and the disappearance of angiodysplasia at 4 months after TAVI. Even at 2 years after TAVI, follow-up endoscopy showed remaining free of angiodysplasia in the stomach. She experienced no episodes of anemia since TAVI procedure. Additionally, analysis of HMW multimers demonstrated immediate and lasting recovery after TAVI.Recovery of HMW multimers of VWF with cessation of gastrointestinal bleeding following aortic valve replacement has been previously reported in a patient diagnosed with Heyde's syndrome. To the best our knowledge, this is the first case to demonstrate that angiodysplasia disappears after TAVI for a long term with endoscopic images in a patient with Heyde's syndrome. Here, we summarized case reports of patients with Heyde's syndrome that required aortic valve intervention. Cessation of gastrointestinal bleeding and anemia after aortic valve intervention for severe aortic stenosis may be attributed not only to recovery of HMW multimers of VWF but also to the disappearance of angiodysplasia.

Clinical and In Vitro Evidence That Left Ventricular Assist Device-Induced von Willebrand Factor Degradation Alters Angiogenesis.

Background Gastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia. Methods and Results Clinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm2, n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers ( P<0.0001) into low-molecular-weight VWF multimers ( P<0.0001) and VWF fragments ( P<0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated ( P=0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders ( P=0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length ( P=0.04) and migration ( P=0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length ( P<0.001) and migration ( P=0.01). Conclusions LVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.

Expression of Angiogenic Factors in Patients With Sporadic Small Bowel Angiodysplasia.

GOALS: To identify putative angiogenic factors associated with sporadic small bowel angiodysplasia (SBA). BACKGROUND: SBAs account for 50% of obscure gastrointestinal bleeding and due to delays in diagnosis and ineffective treatments, are associated with high levels of morbidity and mortality. Treatment development is impeded by a limited knowledge of the pathophysiology behind SBA formation. STUDY: We identified patients with definite sporadic SBA, and fecal immunochemical-negative controls were recruited from our institution's colorectal cancer screening program. Serum levels of VEGF, endoglin, Angiopoietin-2 (Ang-2), PDGF, Angiopoietin-1 (Ang-1), and TNF-α were measured using commercially available enzyme-linked immunosorbent assay kits. On the basis of serum results, we measured gene expression of target angiogenic factors in small bowel biopsy samples from angiodysplasias and unaffected tissue by quantitative PCR assessment. RESULTS: Serum samples were analyzed from 40 SBA patients and 40 controls. Median serum levels of Ang-2 were significantly higher in patients than controls with levels of Ang-1 and TNF-α significantly lower. There were no differences in serum levels of VEGF, endoglin, or PDGF. Gene expression levels of Ang-1, Ang-2, and their receptor Tie2 were all significantly higher in biopsies from areas of angiodysplasia compared with normal small bowel. CONCLUSIONS: This study, the first to explore the role of angiogenic factors in SBA, has identified a positive association between SBA and the Angiopoietin pathway, with increased serum and mucosal expression of Ang-2, which could potentially be used as a serum biomarker and future therapeutic target to improve outcome in affected patients.

Gastrointestinal angiodysplasia and bleeding in von Willebrand disease.

Von Willebrand disease (VWD), the most common genetic bleeding disorder, is characterised by a quantitative or qualitative defect of von Willebrand factor (VWF). Patients with VWD suffer from mucocutaneous bleeding, of severity usually proportional to the degree of VWF defect. In particular, gastrointestinal bleeding associated with angiodysplasia is often a severe symptom of difficult management. This review focuses on the pathophysiology, diagnosis and treatment of VWD-associated gastrointestinal angiodysplasia and related bleeding.

Long acting release-octreotide as "rescue" therapy to control angiodysplasia bleeding: A retrospective study of 98 cases.

BACKGROUND: Gastrointestinal angiodysplasias are an important cause of difficult to manage bleeding, especially in older patients. AIM: To retrospectively evaluate the long-term efficacy of long acting release-octreotide in controlling angiodysplasia bleeding. METHODS: 98 patients with a history of bleeding due to gastrointestinal angiodysplasias lasting over 2 years were retrospectively selected among those treated from January 2000 to December 2008. All patients had received octreotide 0.1mg tid for 28 days and, then from day 14, long acting release-octreotide 20mg monthly, for 6 months. RESULTS: The mean follow-up was 78 months. In all patients mean haemoglobin levels significantly increased and the number of bleeding episodes, hospitalizations, patients requiring blood transfusions and units of transfused red cells significantly decreased, compared to the two-year observation period before starting therapy. According to outcome patients were classified as: 40 full responders (40.8%), 32 relapsers (32.6%) and 26 poor responders (26.5%). At multivariate analysis age >65 years, male sex, chronic antiplatelet therapy, chronic obstructive pulmonary disease and chronic renal failure were the only covariates independently associated with poor response to therapy. CONCLUSION: Our study suggests that long acting release-octreotide could be used as rescue therapy to control bleeding due to gastrointestinal angiodysplasias in patients not suitable for endoscopic or surgical treatments.

Refractory bleeding from intestinal angiodysplasias successfully treated with danazol in three patients with von Willebrand disease.

von Willebrand disease (VWD) is associated with development of gastrointestinal (GI) vascular malformations that lead to chronic GI bleeding. Conventional management, including von Willebrand factor concentrate replacement and endoscopic ablation or bowel resection, does not consistently reduce hemorrhage. We describe three patients with VWD for whom conventional management failed to control GI bleeding. We retrospectively reviewed medical records of patients with VWD and GI bleeding. After patients began treatment with danazol, we observed long-term reductions in GI bleeding and packed red blood cell transfusion requirements. One patient had severe liver toxicity and was found to have concomitant primary biliary cirrhosis. Danazol use may be considered in patients with VWD and GI bleeding due to angiodysplasia that otherwise fails to respond to conventional treatment; the primary aim of treatment is to reduce transfusion dependence. The benefits are variable and possibly transient. Monitoring for toxicity is important when this treatment is pursued.

Bleeding from gastrointestinal angioectasias is not related to bleeding disorders - a case control study.

BACKGROUND: Angioectasias in the gastrointestinal tract can be found in up to 3% of the population. They are typically asymptomatic but may sometimes result in severe bleeding. The reasons for why some patients bleed from their angioectasias are not fully understood but it has been reported that it may be explained by an acquired von Willebrand syndrome (AVWS). This condition has similar laboratory findings to congenital von Willebrand disease with selective loss of large von Willebrand multimers. The aim of this study was to find out if AVWS or any other bleeding disorder was more common in patients with bleeding from angioectasias than in a control group. METHODS: We compared bleeding tests and coagulation parameters, including von Willebrand multimers, from a group of 23 patients with anemia caused by bleeding from angioectasias, with the results from a control group lacking angioectasias. RESULTS: No significant differences between the two groups were found in coagulation parameters, bleeding time or von Willebrand multimer levels. CONCLUSION: These results do not support a need for routine bleeding tests in cases of bleeding from angioectasias and do not show an overall increased risk of AVWS among these patients.

Clinical implication of gastrointestinal bleeding in degenerative aortic stenosis: an update.

Gastrointestinal (GI) bleeding due to colonic angiodysplasias can be associated with calcifying aortic stenosis (AS). GI angiodysplasias and AS are defined as chronic degenerative disorders, and the prevalence of both diseases increases with age. Moreover, degenerative AS is associated with increased destruction of high molecular weight multimers of von Willebrand factor which can promote bleeding from intestinal angiodysplasias. The coincidence of gastrointestinal bleeding angiodysplasias and AS has been known for many years as Heyde's syndrome. Aortic valve replacement is the first line therapy for advanced stage AS-patients, but can also be an effective treatment for co-existent bleeding angiodysplasias and acquired von Willebrand disease. In this study, we tried to collect as well as systemized data about the etiopathogenesis of AS coagulation abnormalities and diagnostic, clinical and therapeutic implications of AS-patient with GI angiodysplasias.

[Angiodysplasia and hemorrhages of the gastrointestinal tract as a particular manifestation of the connective tissue dysplasia].

The clinical case of hemorrhagic syndrome associated with alterations of gastrointestinal tract small vessels in the patient with connective tissue dysplasia, magnesium deficiency and with pathological addiction to alcohol is represented in this article.

Unexplained iron deficiency anaemia: Is it worthwhile to perform capsule endoscopy?

BACKGROUND: In around 30% of iron deficiency anaemia (IDA) cases a definite diagnosis cannot be made. AIM: To investigate the role of capsule endoscopy (CE) in detecting lesions in patients with unexplained IDA after a negative endoscopic, serologic and haematologic diagnostic work up and its possible role in influencing clinical outcome. METHODS: 138 patients suffering from IDA were identified among 650 consecutive patients undergoing CE at our unit. RESULTS: CE revealed the following positive findings in 91/138 patients: angiodysplasias in 51 patients; jejunal and/or ileal micro-ulcerations in 12; tumours/polyps in 9; erosive gastritis in 4; Crohn's disease in 5; jejunal villous atrophy in 5; a solitary ileal ulcer in 1 and active bleeding in the last 4 patients. Follow up data were available for 80/91 patients (87.9%). In 15 out of 46 patients with angiodysplasias IDA spontaneously resolved without any treatment; 9 patients required iron supplementation; 10 patients healed after lanreotide administration; APC was performed in 9 out of 46 patients and 3 patients underwent regular blood transfusion without any success on IDA. 10 out of the 12 patients with small bowel micro-ulcers spontaneously recovered from IDA whilst 2 patients after iron supplementation. All 9 patients affected by tumours/polyps were surgically addressed. In all erosive gastritis cases, patients recovered from IDA after PPI and Helicobacter pylori eradication. Four patients with Crohn's disease diagnosis restored to health with medical therapy. One out of the 4 patients with jejunal villous atrophy and the sole patient with a solitary ileal ulcer spontaneously healed. In 1 out of 3 patients with active bleeding IDA resolved without further treatment after blood transfusion whilst 2 patients were referred for surgical treatment. At follow up, complete resolution of IDA was achieved in 96.25%. CONCLUSIONS: Small bowel investigation is a matter of great importance in IDA patients after negative upper and lower gastrointestinal endoscopy.

Increased plasma fibrinolytic activity in bleeding gastrointestinal angiodysplasia.

OBJECTIVE: Gastrointestinal angiodysplasia is a major cause of recurrent bleeding. Haemostatic abnormalities have been implicated in the haemorrhage from these common vascular lesions but their precise contribution remains to be established. Our aim was to investigate whether bleeding angiodysplasia is associated with any specific coagulation disorder. METHODS: Clinical features and blood samples were prospectively obtained from 21 patients with bleeding gastrointestinal angiodysplasia 3 months after the last episode of haemorrhage. Plasma levels of von Willebrand factor, D-dimer, plasminogen activator inhibitor type 1 (PAI-1), tissue-plasminogen activator activity, tissue factor pathway inhibitor and activated factor VII (FVIIa-rTF) were measured. A group of 14 patients with bleeding duodenal ulcer were similarly studied as controls. RESULTS: Mean plasma von Willebrand factor levels were higher in angiodysplasia patients (208+/-12%) than in controls (143+/-11%) (P<0.05). D-dimer levels (661+/-80 ng/ml) and tissue-plasminogen activator activity levels (2.04+/-0.14 IU/ml) were also higher than in controls: 395+/-99 ng/ml and 1.6+/-0.1 IU/ml, respectively (P<0.05), whereas levels of PAI-1, FVIIa-rTF and tissue factor pathway inhibitor were similar in both groups. However, PAI-1 levels (31.5+/-11 ng/ml) were lower in high-bleeding-rate angiodysplasia (more than two bleeding episodes/year) than in low-bleeding-rate angiodysplasia (< or = 2 bleeding episodes/year) (PAI-1 47+/-14 ng/ml) (P<0.05). In a multivariate regression analysis, the plasma level of PAI-1 was a predictor of haemorrhage from angiodysplasia (P<0.05). CONCLUSIONS: Increased plasma fibrinolytic activity may contribute to bleeding from angiodysplasia. Low plasma PAI-1 levels constitute a risk factor for bleeding tendency in patients with angiodysplasia.

Changing epidemiology of gastrointestinal angiodysplasia with increasing recognition of clinically milder cases: angiodysplasia tend to produce mild chronic gastrointestinal bleeding in a study of 47 consecutive patients admitted from 1980-1989.

It is important to recognize patients with gastrointestinal bleeding who are at high risk of having angiodysplasia, because these patients should be evaluated by endoscopy rather than barium studies. Sixty-two clinical and epidemiologic parameters were compared between 47 consecutive patients bleeding from angiodysplasia and 47 consecutive controls bleeding from other lesions admitted to two university teaching hospitals from 1980 through 1989. This study demonstrated statistically significant differences between these two groups. The patients with angiodysplasia generally presented with symptoms and clinical findings compatible with hemodynamically well-compensated, chronic bleeding: they were more likely than other gastrointestinal bleeders to experience weakness or fatigue, less likely to experience dizziness or syncope, and less likely to be orthostatic or hypotensive. They had more prior admissions for gastrointestinal bleeding, particularly for gastrointestinal bleeding of undetermined etiology. They were more likely than other gastrointestinal bleeders to be smokers. Patients with angiodysplasia had a milder hospital course: they had fewer transfusions of packed erythrocytes, shorter hospitalizations, and a lower mortality. The in-hospital mortality of patients bleeding from angiodysplasia was 2.1%. Despite the futility of diagnosing angiodysplasia by barium studies, patients ultimately diagnosed as having angiodysplasia were more often initially evaluated by barium studies than the other gastrointestinal bleeders. The currently identified risk factors for bleeding from angiodysplasia should help to select which gastrointestinal bleeders should be evaluated initially by endoscopy.

Primary biliary cirrhosis associated with recurrent angiodysplastic lesions in the gastrointestinal tract, the lupus anticoagulant and eosinophilic colitis.

A patient is described with stable primary biliary cirrhosis and recurrent gastrointestinal bleeding due to angiodysplasias in the gastrointestinal tract. This is a very rare disease association. In addition this patient showed two other disease associations, not known in the literature. She also suffered from eosinophilic colitis and had the lupus anticoagulant. These associations have not yet been described in the literature.