Background: Heyde syndrome is a rare condition characterized by the triad of severe aortic stenosis, gastrointestinal bleeding, and acquired type 2A von Willebrand syndrome. This case report highlights the diagnostic and therapeutic approach for a 72-year-old woman presenting with exertional chest pain, dyspnea, fatigue, and a history of melena. Methods: The diagnostic workup revealed severe microcytic anemia and a reduced vWF ristocetin-to-antigen ratio. Imaging confirmed severe degenerative aortic stenosis, while video capsule endoscopy identified angiodysplasia and telangiectasias in the small bowel as the source of gastrointestinal bleeding. Following evaluation by a multidisciplinary Heart Team, the patient underwent transcatheter aortic valve replacement (TAVR) with an Evolut Fx self-expanding prosthesis. Results: Post-procedural echocardiography showed mild paravalvular regurgitation. The patient's clinical course was favorable, with resolution of anemia and no further gastrointestinal bleeding episodes. Conclusions: Heyde syndrome requires a high index of suspicion for diagnosis in patients with severe aortic stenosis and unexplained anemia or gastrointestinal bleeding. TAVR offers an effective treatment option that not only resolves valvular pathology, but also mitigates associated bleeding risks.

The association between aortic stenosis and increased gastrointestinal arteriovenous malformations is known as Heyde's syndrome. An acquired von Willebrand deficiency mediates the connection between these two seemingly dispersed pathologies. As von Willebrand factor passes through a stenosed aorta, it is broken down and can no longer inhibit angiogenesis, leading to angiodysplasias. Heyde's syndrome can manifest with chronic, refractory anemia requiring multiple hospitalizations for symptomatic gastrointestinal bleeding and transfusion. Hitherto, Heyde's syndrome has been considered exceptionally rare, with 1-3% of populations with aortic stenosis. However, given that 31.7% of patients with gastrointestinal angioplasty have aortic stenosis and gastrointestinal arteriovenous malformations are not screened for in patients without anemia, the prevalence of Heyde's syndrome is most likely higher than currently reflected in the literature. Also, the prevalence of Heyde's syndrome in populations who are predisposed to angiodysplasias, such as those on hemodialysis, is understudied. We aim to impart a need for increased research on the prevalence of Heyde's syndrome, especially in high-risk patients. This case report presents a patient with severe Heyde's syndrome on hemodialysis, showing an unconsidered risk factor for Heyde's syndrome in need of further research.

Heyde's syndrome is a multisystem disorder describing the association between calcified aortic stenosis, gastrointestinal tract bleeding from arteriovenous malformations, and acquired von Willebrand syndrome. Several studies have reported an increase in prevalence of gastrointestinal arteriovenous malformation in patients with aortic stenosis and vice versa; however, the incidence of Heyde's syndrome remains controversial. In general, the syndrome is prevalent in the elderly population. The pathogenesis and management remain controversial as well. Our review, provides a unique case to highlight the diagnosis and management of Heyde's syndrome while also briefly describing the prevalence, etiology, diagnosis, and management of calcific aortic valve disease in general.

Gastrointestinal angiodysplasias (GIADs), also called angioectasias, are the most frequent vascular lesions. Its precise prevalence is unknown since most of them are asymptomatic. However, the incidence may be increasing since GIADs affect individuals aged more than 60 years and population life expectancy is globally increasing worldwide. They are responsible of about 5% to 10% of all gastrointestinal bleeding (GIB) cases. Most GIADs are placed in small bowel, where are the cause of 50 to 60% of obscure GIB diagnosed with video capsule endoscopy. They may be the cause of fatal severe bleeding episodes; nevertheless, recurrent overt or occult bleeding episodes requiring repeated expensive treatments and disturbing patient's quality-of-life are more frequently observed. Diagnosis and treatment of GIADs (particularly those placed in small bowel) are a great challenge due to insidious disease behavior, inaccessibility to affected sites and limitations of available diagnostic procedures. Hemorrhagic causality out of the actively bleeding lesions detected by diagnostic procedures may be difficult to establish. No treatment guidelines are currently available, so there is a high variability in the management of these patients. In this review, the epidemiology and pathophysiology of GIADs and the status in the diagnosis and treatment, with special emphasis on small bowel angiodysplasias based on multiple publications, are critically discussed. In addition, a classification of GIADs based on their endoscopic characteristics is proposed. Finally, some aspects that need to be clarified in future research studies are highlighted.

Angiodyplasia and aortic stenosis are both conditions that are highly prevalent in elderly people and can often co-exist. Recent studies suggest that this association is related to subtle alterations in plasma coagulation factors. The von Willebrand factor is the strongest link between aortic stenosis and bleeding associated with gastrointestinal angiodysplasia. With an ageing population, the disease burden of aortic stenosis and its association with angiodysplasia of the bowel makes this an incredibly underdiagnosed yet important condition. Clinicians should be aware of this association when dealing with elderly patients presenting either with unexplained anemia, gastrointestinal bleeding or with aortic stenosis. A high index of suspicion and appropriate diagnostic techniques followed by appropriate and prompt treatment could be life-saving. No clear guidelines exist on management but surgical aortic valve replacement is thought to offer the best hope for long-term resolution of bleeding. With a growing number of technological armamentarium in the management of such patients, especially with the advent of transcatheter aortic valve implantation, new options can be offered even to elderly patients with comorbidities for whom conventional surgery would have been impossible.

Several important physiological processes, from permeability to inflammation to hemostasis, take place at the vessel wall and are regulated by endothelial cells (ECs). Thus, proteins that have been identified as regulators of one process are increasingly found to be involved in other vascular functions. Such is the case for von Willebrand factor (VWF), a large glycoprotein best known for its critical role in hemostasis. In vitro and in vivo studies have shown that lack of VWF causes enhanced vascularization, both constitutively and following ischemia. This evidence is supported by studies on blood outgrowth EC (BOEC) from patients with lack of VWF synthesis (type 3 von Willebrand disease [VWD]). The molecular pathways are likely to involve VWF binding partners, such as integrin αvβ3, and components of Weibel-Palade bodies, such as angiopoietin-2 and galectin-3, whose storage is regulated by VWF; these converge on the master regulator of angiogenesis and endothelial homeostasis, vascular endothelial growth factor signaling. Recent studies suggest that the roles of VWF may be tissue specific. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal bleeding resulting from vascular malformations. In this article, we review the evidence showing that VWF is involved in blood vessel formation, discuss the role of VWF high-molecular-weight multimers in regulating angiogenesis, and review the value of studies on BOEC in developing a precision medicine approach to validate novel treatments for angiodysplasia in congenital VWD and acquired von Willebrand syndrome.

Gastrointestinal angiodysplasias (GIADs) could be responsible for recurrent bleeding and severe anemia. Somatostatin analogs could reduce transfusion requirements in these patients but no randomized controlled study is available. The main objective of the ANGIOPAS phase II double-blinded randomized, noncomparative study was to assess the effectiveness of pasireotide-LAR in reducing transfusion requirements in patients with refractory GIADs bleeding.

A total of 22 patients with transfusion requirements ⩾6 units of packed red blood cells (pRBCs) during the 6 months prior to inclusion were randomized to receive pasireotide-LAR 60 mg (n = 10) or placebo (n = 12) every 28 days for 6 months. Patients were then followed for an additional 6 months after stopping treatment.

The pasireotide-LAR and placebo groups were equivalent for age, sex, comorbidities and transfusion requirement during the reference period (median 13 and 9.5 pRBCs). A 50 and 83% success rate (success defined as a decrease of at least 30% of transfused pRBCs) was observed in the pasireotide-LAR arm in the Intent to Treat (ITT) and per protocol (PP) analysis respectively. The need for transfusion during the intervention period was 3 pRBC units in the pasireotide-LAR group (range 0-26) and 11.5 pRBC units in the placebo group (range 0-23). Overall, three cases with glycemic control impairment were observed in the pasireotide-LAR group including one de novo diabetes.

This double-blinded noncomparative randomized phase II study suggests, for the first time, the effectiveness of pasireotide-LAR 60 mg every 28 days to decrease the transfusion requirement in patients with recurrent bleeding due to GIADs.

Gastric antral vascular ectasia (GAVE), also known as "watermelon stomach", is an uncommon condition, which can cause gastrointestinal bleeding due to rupture of blood vessels that line the stomach. The pathogenesis of GAVE remains unclear; however it is thought that hemodynamic changes, mechanical stress, and autoimmune factors all have a part to play. A range of conditions are also commonly associated with the syndrome, such as portal hypertensive gastropathy, liver cirrhosis, and autoimmune disorders. Less commonly, chronic renal failure, cardiac diseases, and bone marrow transplantation have coexisted with GAVE. The diagnosis is usually based on visualization of the tissue upon endoscopy; however, histology plays a role in uncertain cases. The typical "watermelon" appearance relates to the tissue having a striped appearance radiating out from the pylorus. Medical treatment has failed to show satisfactory results and surgery is usually considered as a last resort, due to its increased risk for complications and mortality. Lasers and argon plasma coagulation have been used recently, and been shown to be as effective as surgery and a safer option. We present three cases of gastric antral vascular ectasia treated at our institution with radiofrequency ablation and review the literature on treatment modalities for GAVE.

Gastrointestinal angiodysplasia are rare but clinically important vascular aberrations found within the gastrointestinal mucosa and submucosa. Their clinical impact varies from being an asymptomatic incidental finding, to causing life threatening bleeding. In this review we critically appraise the key findings from the current literature on the pathology, clinical presentation and management of these lesions.

Angiodysplasia (AD) of the gastrointestinal (GI) tract is an important condition that can cause significant morbidity and -rarely - mortality.

To provide an up-to-date comprehensive summary of the literature evaluating this disease entity with a particular focus on pathogenesis as well as current and emerging diagnostic and therapeutic modalities. Recommendations for treatment will be made on the basis of the current available evidence and consensus opinion of the authors.

A systematic literature search was performed. The search strategy used the keywords 'angiodysplasia' or 'arteriovenous malformation' or 'angioectasia' or 'vascular ectasia' or 'vascular lesions' or 'vascular abnormalities' or 'vascular malformations' in the title or abstract.

Most AD lesions (54-81.9%) are detected in the caecum and ascending colon. They may develop secondary to chronic low-grade intermittent obstruction of submucosal veins coupled with increased vascular endothelial growth factor-dependent proliferation. Endotherapy with argon plasma coagulation resolves bleeding in 85% of patients with colonic AD. In patients who fail (or are not suitable for) other interventions, treatment with thalidomide or octreotide can lead to a clinically meaningful response in 71.4% and 77% of patients respectively.

Angiodysplasia is a rare, but important, cause of both overt and occult GI bleeding especially in the older patients. Advances in endoscopic imaging and therapeutic techniques have led to improved outcomes in these patients. The choice of treatment should be decided on a patient-by-patient basis. Further research is required to better understand the pathogenesis and identify potential therapeutic targets.

Anaemia may be multifactorial in origin. We present a woman with autoimmune hepatitis and secondary warm autoimmune haemolytic anaemia and most likely also concomitant anaemia of chronic disease. A relapse of autoimmune haemolysis was successfully treated with steroids and high-dose intravenous immunoglobulin. At the same time, bleeding from angiodysplasia in the coecum was masked by unauthorised perorally administrated iron. No other cause of bleeding was found. During that period, she required extensive blood transfusions, up to several times per month. Surgical or endoscopic treatment of the bleeding angiodysplasia was not possible. Alloimmunisation developed as a complication to the large number of transfusions, despite the use of steroids. Treatment with somatostatin analogue markedly reduced the need of our patient for blood transfusions for a follow-up period of more than one year, and she has not experienced any side effects. We do not know how long the haemostasis achieved will last, however, we believe that this treatment may be an alternative for other patients as bleeding from angiodysplasia is not uncommon and is often difficult to eradicate.

Transfusion-dependent anaemia and portal hypertension are recognised complications of hereditary haemorrhagic telangiectasia (HHT). The anaemia is a result of chronic bleeding from gastrointestinal telangiectasias, which are usually multiple and located throughout the gastrointestinal tract. As a result, treatment with argon plasma coagulation via gastroscopy and or colonoscopy is often insufficient to prevent ongoing blood loss. Portal hypertension in HHT occurs as a result of blood shunting between the hepatic artery and the portal vein within the liver. The somatostatin analogue octreotide has been used as a treatment for bleeding angiodysplasia; however, its possible role as a treatment for diuretic intractable ascites secondary to portal hypertension has not been previously established. The authors report a case that apparently illustrates a dual benefit of long-acting octreotide in the management of both occult bleeding and refractory ascites in a patient with HHT.

Gastrointestinal angiodysplasia (GIAD) may either be asymptomatic or induce overt or obscure bleeding with a high risk of recurrence. Numerous therapeutic options are available but evidence bases are lacking.

We conducted a comprehensive review of pharmacological and endoscopic treatments for previous or active bleeding GIAD and established the unmet needs of the clinicians.

Clinical trials, series, and reports, having been selected through PubMed inquiry, manual searching, and reference list reviewing, were classified by levels of evidence.

Controlled studies focusing on GIAD treatment, excluding other GI vascular malformations, are rare. Endoscopic destruction, preferably using non-contact endoscopic techniques, is most often proposed as a first-line treatment for GIAD (expert level). In addition, APC is preferred over Nd:Yag laser due to the lower risk of perforation (expert level). Pharmacological treatments for GIAD are considered either when endoscopy fails to access the AD or in order to prevent rebleeding for "chronic bleeding patients." Octreotide and oestroprogestative treatments are the best evaluated drugs; however, no appropriate comparison on cost-effectiveness and tolerance has been performed.

The most effective therapeutic strategy for bleeding GIAD is currently inconclusive, and new trials should be performed to address unmet needs.

Gastrointestinal (GI) bleeding in ventricular assist devices (VADs) has been reported with rotary devices. The pathophysiological mechanisms and treatments are in evolution. We performed a retrospective review of GI bleeding episodes for all VADs implanted at our institution. Five male patients experienced GI bleeding-age 63.6 ± 3.64 years. VAD type VentrAssist n = 1, Jarvik 2000 n = 2, and HeartWare n = 2. All patients were anticoagulated as per protocol with antiplatelet agents (aspirin and/or clopidogrel bisulfate [Plavix] and warfarin (therapeutic international normalized ratio 2.0-3.5). There was no prior history of gastric bleeding in this group. Ten episodes of bleeding requiring blood transfusion occurred in five patients. Some patients had multiple episodes (1 × 5, 1 × 2, 3 × 1). The events occurred at varying times post-VAD implantation (days 14, 21, 26, 107, 152, 189, 476, 582, 669, and 839). Octreotide (a long-acting somatostatin analogue that reduces splanchnic arterial and portal blood flow) was administered subcutaneously or intravenously. Three patients received infusions of adrenaline at 1 µg/min to enhance pulsatility. Anticoagulation was interrupted during bleeding episodes but successfully introduced post bleeding event. GI bleeding is a significant complication of VAD therapy. In this article, we discuss diagnosis and management options.

The case of a postmenopausal woman with a congenital aortic stenosis is presented. She presented with severe iron deficiency anemia. After negative extensive gastrointestinal analysis, she was treated with octreotide for six months. After cessation of octreotide, anemia rapidly recurred. A second capsule endoscopy and a double balloon enteroscopy were performed, and an intestinal vascular malformation was found. After surgical segment resection, the patient had stable, normal levels of hemoglobin and no complaints after 14 months of follow-up.

Preliminary studies suggested that octreotide may be therapeutic in bleeding angiodysplasia. Our aim was to investigate the efficacy of long-term octreotide therapy in the prevention of rebleeding from gastrointestinal angiodysplasia.

A cohort of 32 patients diagnosed with bleeding from angiodysplasia was treated with octreotide 50 mu 12 h subcutaneously for a 1-2 yr period. This cohort was compared with an external control group (38 patients who had received placebo [1 tablet/day] in a concurrent randomized clinical trial for the same period.

Two patients of the octreotide group were lost to follow-up. Treatment failure occurred in seven of 30 (23%) patients in the octreotide group and in 17 of 35 (48%) in the placebo group (three dropouts before first visit) (P= 0.043). The actuarial probability of remaining free of rebleeding at 1 and 2 yr of follow-up was 77% and 68%, respectively, for the octreotide group and 55% and 36%, respectively, for the placebo group (log rank P= 0.030). Multivariate proportional hazards-regression analysis showed that octreotide therapy and previous bleeding episodes were positive and negative predictors of efficacy, respectively. No significant differences between the groups were observed according to number of bleeding episodes (0.4 +/- 0.7 vs 0.9 +/- 1.5, P= 0.070) and transfusion requirements (1.1 +/- 2.6 vs 0.7 +/- 1.5 units); however, iron requirements were lower in the octreotide than in the placebo group (22 +/- 62 vs 166 +/- 267 units; P < 0.001). Likewise, major adverse events (1 vs 1) and mortality (0 vs 1) were similar between groups.

This study suggests that octreotide treatment may be beneficial in preventing rebleeding from gastrointestinal angiodysplasia.

Vascular malformation (AVM) in the gastrointestinal tract is an uncommon, but not rare, cause of bleeding and iron deficiency anemia, especially in an aging population. While endoscopic coagulative therapy is the method of choice for controlling bleeding, a substantial number of cases require additional therapy. Adjunctive or even primary phamacotherapy may be indicated in recurrent bleeding. However, there is little evidence-based proof of efficacy for any agent. The bulk of support is derived from anecdotal reports or case series. The present review compares the outcome of AVM after no intervention, coagulative therapy or focus on pharmacological agents. Most of the literature encompasses two common AVMs, angiodysplasia and hereditary hemorrhagic telangiectasia. Similarly, the bulk of information evaluates two therapies, hormones (estrogen and progesterone) and the somatostatin analogue octreotide. Of these, the former is the only therapy evaluated in randomized trials, and the results are conflicting without clear guidelines. The latter therapy has been reported only as case reports and case series without prospective trials. In addition, other anecdotally used medications are discussed.

Small bowel bleeding is infrequent and presents a challenge to the clinician. Approximately 30-40% of gastrointestinal bleeding localized in the small bowel is due to angiodysplasia, a vascular malformation. We present the case of a patient with multiple angiodysplasia of the small bowel who required push enteroscopy and capsule endoscopy to establish the diagnosis. Treatment with subcutaneous octreotide was successful. In conclusion, in doubtful cases or in patients with persistent hemorrhage, capsule endoscopy can improve the diagnostic yield of enteroscopy in bleeding gastrointestinal vascular lesions such as angiodysplasia. Endoscopic treatment (laser coagulation) and drug therapy (somatostatin or analogs) are valid alternatives in inoperable or non-resectable cases.

Recent evidence points to isolated deficiency of the largest multimers of von Willebrand factor (VWF)-known as von Willebrand syndrome type 2A (VWS-2A)-as a risk factor for bleeding from gastrointestinal (GI) angiodysplasia. This disorder is not widely recognized, perhaps because most patients do not exhibit generalized hemostatic impairment (bleeding is generally restricted to GI angiodysplasia) and because all but the largest multimers of VWF remain detectable in the plasma (thus, routine screening tests for VWS-2A are usually normal). The "Rosetta stone" for elucidating this syndrome was the enigma of Heyde's syndrome (aortic stenosis plus bleeding GI angiodysplasia), particularly the striking observation that aortic valve replacement generally cures GI bleeding and that preoperative deficiency of the largest VWF multimers undergoes long-term normalization after valve replacement. We critically review the evidence implicating VWS-2A as a risk factor for bleeding GI angiodysplasia. We hypothesize that VWS-2A secondary to cardiovascular disease other than severe aortic stenosis, such as peripheral arterial occlusive disease, could explain why elderly patients often develop recurrent GI bleeding or iron deficiency anemia from GI angiodysplasia.

Management of bleeding angiodysplasia of the gastrointestinal tract is often a major clinical problem. Lesions are frequently multiple, not detectable or missed during conventional endoscopy and patients are sometimes at high risk for complications because of advanced age and serious concomitant disorders.

To determine the efficacy of a new formulation of somatostatin analogue (octreotide long-acting) in management of recurrent bleeding angiodysplasia in patients resistant to endoscopic treatment and not suitable for surgery.

Three patients with recurrent bleeding angiodysplasia of gastrointestinal tract were treated with long-acting octreotide administered intramuscularly 20 mg monthly to each individual. The number of admissions for acute bleeding, hospital stay and number of blood units transfused before and after treatment (followup: 15-17 months) were regularly monitored.

In each patient, a relevant decrease in number of hospital admissions, duration of hospital stay, number of administered blood units was seen and mean haemoglobin values significantly increased in all of them after introducing long-acting octreotide therapy.

This is the first report on use of long-acting octreotide in bleeding angiodysplasia of gastrointestinal tract. Data suggest that long-acting octreotide is a safe drug and is successful in controlling recurrent gastrointestinal bleeding due to angiodysplasia in elderly patients not eligible for surgical or endoscopic therapy.

Two cases of von Willebrand's disease and angiodysplasia with intractable gastrointestinal bleeding are presented. Replacement therapy with cryoprecipitate and variable purity von Willebrand factor (VWF) was ineffective, as were other treatments including steroids, immunoglobulin and hormonal replacement. Both patients required massive blood transfusion and product support. The efficacy of somatostatin and an analogue is described. In one patient, we observed a rise in von Willebrand factor activity after octreotide infusion.

The treatment of angiodysplasia and watermelon stomach, vascular abnormalities implicated in gastrointestinal bleeding of obscure origin, is a major clinical problem.

To determine the efficacy of octreotide in patients with long-standing gastrointestinal bleeding due to acquired angiodysplasia and watermelon stomach, resistant to previous treatments and not suitable for surgery because of old age and/or concomitant disorders.

We treated 17 patients (seven had isolated angiodysplasia, seven had multiple upper and lower gastrointestinal angiodysplasia, and three had watermelon stomach) with octreotide (0. 1 mg subcutaneous t.d.s. for 6 months). Six of the patients had liver cirrhosis, one had Glanzmann-type platelet derangement, two had cardiovascular diseases and one had chronic uraemia.

Octreotide treatment stopped bleeding in 10 patients. A transient improvement was observed in four, who needed subsequent cyclical retreatment to correct low haemoglobin levels. No effect was observed in three, probably due to the severity of the concomitant disorders.

Octreotide is a safe drug that may be useful to control the recurrent gastrointestinal bleeding due to acquired angiodysplasia and watermelon stomach, especially in patients who are not candidates for surgery due to old age and/or concomitant disorders.