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.

Overview of small bowel angioectasias: clinical presentation and treatment options.

INTRODUCTION: Elderly patients with multiple co-morbidities are at an increased risk of developing small bowel angioectasias. Treating these lesions can be both challenging and costly with patients requiring extensive investigations and recurrent admissions for iron infusions and blood transfusions as well as invasive procedures. This review presents treatment options and describes in detail drugs that should be considered whilst taking into account their effectiveness and their safety profile. Areas covered: A PubMed search was carried out using the following keywords: small bowel angiodysplasias, small bowel angioectasias, small bowel bleeding and obscure gastrointestinal bleeding to assess existing evidence. The pathophysiology and risk factors are covered in this review together with appropriate methods of investigation and management. Treatment options discussed are endoscopic measures, surgical options and pharmacotherapy. The role of serum biomarkers is also discussed. Expert commentary: Future work should be directed at alternative drugs with a good safety profile that target biomarkers. Novel pharmacotherapy directed at biomarkers could potentially provide a non-invasive treatment option for angioectasias particularly in the elderly where management can be challenging.

Decreased health-related quality of life in angiodysplasia patients: A cross-sectional cohort.

Gastrointestinal angiodysplasias may cause anemia. Quality of life (QoL) is a valid patient reported outcome and improvement of QoL represents an important treatment goal. There is a paucity of data on the effect of angiodysplasias on QoL. Therefore, we aim to evaluate QoL and fatigue in angiodysplasia patients. We performed a cross-sectional patient-reported outcome study. We included patients with endoscopy proven angiodysplasias and measured QoL with Short Form-36 and level of fatigue using Multi Fatigue Inventory-20. We distinguished three subgroups of patients according to disease severity: 1) with treatment for angiodysplasias, 2) without treatment for angiodysplasias and 3) without recent hospital visits. The primary outcome was the physical component summary (PCS) score on the SF-36. Multivariate regression analysis were performed to correct for differences at baseline. A total of 144 patients completed the questionnaires (response rate = 62%; mean age 68 years; 65% men). Angiodysplasia patients have a significant lower PCS compared to the age-matched general population (respectively 41.0 vs. 43.3, p = 0.01). Disease severity is independently associated with a negative outcome on QoL (ß -4.6, 95% CI -7.8--1.3). Similarly patients score lower on multiple QoL subdomains, i.e. role limitations due to physical health problems (40.8 vs. 44.0, p<0.01), general health (39.7 vs. 47.3, p<0.01). Angiodysplasia patients are more fatigued compared to the general population (male 56.1 vs. 48.5, p<0.01, female 59.2 vs. 51.5, p = 0.01). In conclusion, angiodysplasias are independently associated with clinically significant impairments in multiple domains of health-related QoL, especially in measures of functional limitation.

Multimodal Assessment Reveals Late-Onset Hemispheric Shift of Language in a Child with Meningocerebral Dysplasia.

We report on a girl with progressive left frontal tissue destruction starting at the age of almost 8 years. She manifested acutely with epileptic seizures accompanied by Broca aphasia as well as transient right hemiparesis. Due to refractory epilepsy developing over the next years, which originated from the left frontal lobe, the decision was made to proceed to epilepsy surgery. By then, her language functions had recovered despite progressive left frontal tissue-destruction, raising the possibility of a hemispheric shift of language. Clinical functional magnetic resonance imaging (fMRI) was conducted to localize brain regions involved in language production. A complex pattern of clear right-hemispheric dominance, but with some left-sided contribution was found. However, a Wada test suggested the left hemisphere to be critical, seemingly contradicting fMRI. Invasive electroencephalogram recordings could reconcile these results by identifying the fMRI-detected, residual left-sided activation as being relevant for speech production. Only by combining the localizing information from fMRI with the information obtained by two invasive procedures could the unusual pattern of late-onset language reorganization be uncovered. This allowed for extensive left frontal resection, with histology confirming meningocerebral angiodysplasia. Postoperatively, language functions were preserved and seizure outcome was excellent. The implications of our findings for presurgical assessments in children are discussed.

Importance of Heparin Provocation and SPECT/CT in Detecting Obscure Gastrointestinal Bleeding on 99mTc-RBC Scintigraphy: A Case Report.

We presented a pediatric case with a history of intermittent melena for 3 years because of angiodyplasia of small intestine. The results of frequent upper gastrointestinal endoscopies and colonoscopies as well as both Tc-red blood cell (RBC) and Meckel's scintigraphies for several times were negative in detection of bleeding site. However, Tc-RBC scintigraphy with single-photon emission computed tomography (SPECT)/computed tomography (CT) after heparin augmentation detected a site of bleeding in the distal ileum which later was confirmed during surgery with final diagnosis of angiodysplasia.It could be stated that heparin provocation of bleeding before Tc-RBC scintigraphy accompanied by fused SPECT/CT images should be kept in mind for management of intestinal bleeding especially in difficult cases.

[MASSIVE RECTORRHAGIA MIMICKING POSSIBLE GENITAL HAEMORRHAGE].

A case is presented of a 76-year-old woman who was initially considered to have massive genital hemorrhage, but exclusion examination and treatment proved it to be massive rectorrhagia. The patient died due to irreversible hemorrhagic shock and rupture of rectal angiodysplasia was proved on autopsy.

Heyde's syndrome: exploring the link between aortic stenosis and an acquired bleeding disorder.

Heyde's syndrome was first proposed in 1958. It refers to gastrointestinal haemorrhage resulting from a combination of aortic stenosis with angiodysplasia. This report explores the case of a 93-year-old lady who was admitted to hospital following a neck of femur fracture. She suffered from multiple comorbidities including renal failure and congestive heart failure secondary to critical aortic stenosis. As an inpatient she suffered an exacerbation of both her heart and renal failure postoperatively. A week later she suffered from heavy upper gastro-intestinal bleeding, which failed to respond to pharmacological and endoscopic therapies as well as angiographic embolisation. The pathophysiology of Heyde's syndrome: an acquired von Willebrand deficiency syndrome has a much wider impact than was commonly thought, both in terms of how common it is and in how the association may be extrapolated to a wide range of bleeding disorders, rather than simply angiodysplasia associated gastrointestinal haemorrhage.

[Lymphedema: anatomy, physiology and pathophysiology of lymphedema, definition and classification of lymphedema and lymphatic vascular malformations]. / Das Lymphödem - Anatomie, Physiologie und Pathophysiologie des Lymphödems, Definition und Klassifizierung des Lymphödems und lymphatischer Gefäßmalformationen.

Lymphedema is a chronic disease associated with a congenital or acquired disorder of the lymphatic vessels or lymph nodes. Untreated lymphedema can lead to complications and disability. Clinical Lymphology deals not only with lymphedema of the extremities but also of the head, the genitals and the internal organs (lymphostatic enteropathy, chylaskos, chylothorax, chylopericard etc). Symptoms of this disorder are often misdiagnosed or not recognized. Ignorance and trivialization of lymphedema causes insufficient treatment, which then is not carried out to the extent as it is possible today by scientific findings. Even today delayed or not optimal treatment causes a long ordeal for many patients.The fact that lymphedema for those affected is a major psychological and social burden, which is limiting the quality of life, has also often been unregarded. The knowledge of anatomy, physiology and pathophysiology as well as the knowledge of causes are necessary for diagnosis, so that early treatment can be initiated.

Small bowel lymphangiectasia and angiodysplasia: a positive association; novel clinical marker or shared pathophysiology?

INTRODUCTION: Small bowel angiodysplasia accounts for 30 to 40% of cases of obscure gastrointestinal bleeding and is associated with significant morbidity and mortality. Identifying lesions can be difficult. Small bowel capsule endoscopy (SBCE) is a significant advance on earlier diagnostic techniques. The cause of angiodysplasia is unknown and the natural history poorly understood. Many lesions are thought to arise from a degenerative process associated with ageing, local vascular anomalies, and tissue hypoxia. Nonpathologic lymphangiectasias are commonly seen throughout the small bowel and are considered a normal finding. AIMS: To determine whether there is an association between lymphangiectasias, angiodysplasia, and atherosclerosis related conditions. METHODS: Relevant information was collected from a dedicated SBCE database. Logistic regression analysis was used to examine associations between angiodysplasia, lymphangiectasia, patient demographics, and comorbidity. RESULTS: In all, 180 patients underwent SBCE during the study period, 46 (25%) had angiodysplasia and 47 (26%) lymphangiectasia. Lymphangiectasia were seen in 24 (52%) of 46 with angiodysplasia, in 16 (19%) of 84 with obscure gastrointestinal bleeding without angiodysplasia and in 7 (14%) of 50 without gastrointestinal bleeding. Logistic regression analysis confirmed a strong positive association between angiodysplasia and lymphangiectasia; odds ratio 4.42, P<0.003. Angiodysplasias were also associated with increasing age; odds ratio 1.1. There was no correlation with any other patient characteristic. CONCLUSIONS: Lymphangiectasia are strongly associated with the presence of small intestinal angiodysplasia and may represent a useful clinical marker for this condition. Angiodysplasia are also associated with increasing age. Conditions associated with systemic atherosclerosis did not increase the risk of angiodysplasia.

Intestinal angiodysplasia and aortic valve stenosis: let's not close the book on this association.

The association between gastrointestinal (GI) bleeding due to angiodysplasia of the large intestine and calcific aortic stenosis (AS) has been a matter of debate. Recent studies suggest that this association is related to subtle alterations in plasma coagulation factors. von Willebrand factor is the strongest possible link between aortic stenosis and bleeding associated with GI angiodysplasia. Physicians should be aware of this entity when dealing with elderly patients presenting either with GI bleeding or with AS. A high index of suspicion and appropriate diagnostic procedures followed by prompt treatment could be life saving. Several questions related to the pathogenesis and optimal management remain unanswered. Aortic valve replacement appears to offer the best hope of long-term resolution of the bleeding, and should be considered in most cases. The association between chronic gastrointestinal bleeding in elderly patients and aortic stenosis becomes more relevant with the advent of transcatheter aortic valve implantation which can be offered even to elderly patients with comorbidities which could make conventional surgery impossible.

Angiogenesis and vascular malformations: antiangiogenic drugs for treatment of gastrointestinal bleeding.

Treatment of gastrointestinal bleeding in patients with angiodysplasias and Osler's disease (hereditary hemorrhagic teleangiectasia) is clinically challenging. Frequently, vascular malformations occur as multiple disseminated lesions, making local treatment an unfavorable choice or impossible. After local therapy, lesions often recur at other sites of the intestine. However, as there are few therapeutic alternatives, repeated endoscopic coagulations or surgical resections are still performed to prevent recurrent bleeding. Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective. Therefore, new therapeutic strategies are required. Understanding of the pathophysiology of angiogenesis and vascular malformations has recently substantially increased. Currently, multiple inhibitors of angiogenesis are under development for treatment of malignant diseases. Experimental and clinical data suggest that antiangiogenic substances, which were originally developed for treatment of malignant diseases, may also represent long-awaited specific drugs for the treatment of vascular malformations. However, antiangiogenics display significantly different actions and side-effects. Although antiangiogenics like thalidomide seem to inhibit gastrointestinal bleeding, other substances like bevacizumab can cause mucosal bleeding. Therefore differential and cautious evaluation of this therapeutic strategy is necessary.