Hereditary Hemorrhagic Telangectasia Research Articles

Inhibition of endothelial cell proliferation as a potential therapeutic approach in hereditary hemorrhagic telangectasia.

Inhibition of endothelial cell proliferation as a potential therapeutic approach in hereditary hemorrhagic telangectasia.

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial.

Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. clinicaltrials.gov Identifier: NCT02106520.

Endoglin regulates mural cell adhesion in the circulatory system.

The circulatory system is walled off by different cell types, including vascular mural cells and podocytes. The interaction and interplay between endothelial cells (ECs) and mural cells, such as vascular smooth muscle cells or pericytes, play a pivotal role in vascular biology. Endoglin is an RGD-containing counter-receptor for β1 integrins and is highly expressed by ECs during angiogenesis. We find that the adhesion between vascular ECs and mural cells is enhanced by integrin activators and inhibited upon suppression of membrane endoglin or β1-integrin, as well as by addition of soluble endoglin (SolEng), anti-integrin α5β1 antibody or an RGD peptide. Analysis of different endoglin mutants, allowed the mapping of the endoglin RGD motif as involved in the adhesion process. In Eng+/− mice, a model for hereditary hemorrhagic telangectasia type 1, endoglin haploinsufficiency induces a pericyte-dependent increase in vascular permeability. Also, transgenic mice overexpressing SolEng, an animal model for preeclampsia, show podocyturia, suggesting that SolEng is responsible for podocytes detachment from glomerular capillaries. These results suggest a critical role for endoglin in integrin-mediated adhesion of mural cells and provide a better understanding on the mechanisms of vessel maturation in normal physiology as well as in pathologies such as preeclampsia or hereditary hemorrhagic telangiectasia.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-2099-4) contains supplementary material, which is available to authorized users.

Endovascular treatment of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia.

To assess the efficiency and complication rates of vaso-occlusion of pulmonary arteriovenous malformations (PAVMs) in Rendu-Osler-Weber disease (hereditary haemorrhagic telangectasia; HHT). Seventy-two patients were investigated in our institution for HHT between March 2000 and November 2011. Sixteen presented PAVMs (22.2%), and 11 (68.8%) were treated with vaso-occlusion for a total of 18 procedures. Procedures included coils, plugs and combined approaches. Immediate success and recurrence rate, complication were recorded, as well as persistent and new PAVMs during clinical and computed tomography (CT) follow-up. Eighteen procedures were performed and a total of 37 PAVMs were treated, 19 with coils, 16 with plugs and 2 with combined treatment. Mean CT follow-up time was 41 months (1‒164). No major complication was observed. One distal translocation was treated during the same intervention. Two PAVMs persisted after treatment (5.7%), both treated by means of plug embolisation. One new PAVM was observed during follow-up CT. PAVMs with an afferent artery of less than 3mm or asymptomatic PAVMs were not treated. Recent studies have demonstrated that vaso-occlusion has become the gold standard treatment for PAVM. This study is in accordance with previous results and shows a minimal complication rate and little recurrence, whether by coils, plugs, or combined treatments.

A postal survey of hereditary hemorrhagic telangectasia in the northeast of England.

The aim of this study is to identify the demographics and epistaxis burden of hereditary hemorrhagic telangiectasia (HHT). A questionnaire was sent to participants with HHT who were recruited from a prospectively maintained respiratory clinic data base in a tertiary hospital. Details on demographics, HHT symptoms, family history, epistaxis severity, and treatment received were recorded. There were 34 of 60 responses (57%). Two responses were from families of the deceased. Of the 32 evaluable patients (men, 14; women 18), the average age was 51 years (range, 23–78 years). The average age of HHT diagnosis was 31 years (range, 3–61 years). The diagnosis of HHT was made by the respiratory team in 13 patients; neurologist (2); ear, nose, and throat (ENT) specialist (4); general practitioner (5); hematologist (4); gastroenterologist (1); and not mentioned in two patients. Twenty-seven of 32 patients (84%) had a positive family history of HHT. Only 13 patients had formal genetic testing (4 endoglin, 1 activin receptor–like kinase, 8 unknown gene). All patients who presented to the respiratory clinic had a background of epistaxis, which was noted on presentation. The average age at initial epistaxis was 14 years (range, 2–50 years). The frequency of epistaxis was daily 63% (n = 20), weekly 9% (3), monthly 16% (5), and a few times a year 10% (3), and unstated in one patient. Nine of 32 patients (28%) required a transfusion. Six patients thought that they were unable to perform daily activities due to epistaxis. Only 15 of 32 patients (47%) were under the care of an ENT specialist. The treatment plan for epistaxis management was deemed good by 7 patients, adequate in 8, poor in 6, and not stated by 11 patients. In conclusion, this survey is the first to quantify the epistaxis burden within the northeast of England. The management of epistaxis needs specific education and treatment to optimize the quality of life among these patients.

Rendu-Osler-Weber Syndrome: A Case Report

Hereditary hemorrhagic telangectasia (HHT) or Rendu-Osler-Weber syndrome, is a rare genetic disorder with autosomal dominance and variable penetrance. The typical findings of the disease are telangiectasias in skin and mucous membranes, and arteriovenous malformations presenting in the organs like lung, intestine, brain and liver. It is characterized by the classic triad of recurrent epistaxis, mucocutaneous telangiectasias and visceral hemorrhages, with familial occurrence. This article describes a case of HHT of an adult patient, associated with multiple angiodysplasic injuries in the nasal mucosa, upper gastrointestinal tract, lungs and who presents continuous blood loss, resulting iron deficiency anemia. Based on clinical and diagnostic findings, we diagnosed this case as HHT, which has rarely been reported in our literature.

Rendu-Osler-Weber Syndrome: A Case Report

Hereditary hemorrhagic telangectasia (HHT) or Rendu-Osler-Weber syndrome, is a rare genetic disorder with autosomal dominance and variable penetrance. The typical findings of the disease are telangiectasias in skin and mucous membranes, and arteriovenous malformations presenting in the organs like lung, intestine, brain and liver. It is characterized by the classic triad of recurrent epistaxis, mucocutaneous telangiectasias and visceral hemorrhages, with familial occurrence. This article describes a case of HHT of an adult patient, associated with multiple angiodysplasic injuries in the nasal mucosa, upper gastrointestinal tract, lungs and who presents continuous blood loss, resulting iron deficiency anemia. Based on clinical and diagnostic findings, we diagnosed this case as HHT, which has rarely been reported in our literature.

Spontaneous superior ophthalmic vein thrombosis: a rare entity with potentially devastating consequences

Spontaneous superior ophthalmic vein thrombosis (SOVT) is a rare entity. We describe three patients with spontaneous ophthalmic vein thrombosis, each with various risk factors. A retrospective review of three patients with a diagnosis of superior ophthalmic vein thrombosis. Clinical characteristics, radiographic features, management techniques and outcomes are described. All patients presented with unilateral painful proptosis. Two patients had intact light perception, whereas one patient presented with absent light perception. All patients had identifiable risk factors for thrombosis, which included sickle cell trait, hereditary hemorrhagic telangectasia and colon cancer with recurrent deep vein thrombosis. Anticoagulation was initiated in two patients. Resolution of proptosis was seen in all patients, with no recovery of vision in one patient. Risk factors for spontaneous superior ophthalmic vein thrombosis are multifactorial. MRI and MRV confirm the diagnosis of SOVT. Despite urgent intervention devastating visual loss may occur.

Abstract 5079: Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies.

Abstract Endoglin (ENG), a co-receptor for several TGFβ-family cytokines, is expressed in activated endothelial cells alongside ALK1, the ACVRL1 gene product. ENG and ACVRL1 are both required for angiogenesis and mutations in either gene are associated with Hereditary Hemorrhagic Telangectasia, a rare genetic vascular disorder. ENG and ALK1 function in the same genetic pathway but the relative contribution of TGFβ and BMP9 to SMAD1/5/8 activation and the requirement of ENG as a co-mediator of SMAD phosphorylation in endothelial cells remain debated. Here, we show that BMP9 and TGFβ1 induce distinct SMAD phosphorylation responses in primary human endothelial cells and that, unlike BMP9, TGFβ1 only induces SMAD1/5/8 phosphorylation in a subset of immortalized mouse endothelial cell lines, but not in primary human endothelial cells. We also demonstrate, using siRNA depletion of ENG and novel neutralizing anti-ENG antibodies, that ENG is required for BMP9/pSMAD1 signaling in all human and mouse endothelial cells tested. Finally, anti-ENG antibodies that interfere with BMP9/pSMAD1 signaling, but not with TGFβ1/pSMAD3 signaling, including the TRC105 clinical candidate, also decrease in vitro HUVEC endothelial tube formation and inhibit BMP9 binding to recombinant ENG in vitro. Our data demonstrate that BMP9 signaling inhibition is a key and previously unreported mechanism of action of TRC105, an anti-angiogenic anti-ENG antibody currently evaluated in clinical trials. Citation Format: Olivier P. Nolan-Stevaux, Wendy Zhong, Dineli Wickramasinghe, Astrid Ruefli-Brasse. Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-Endoglin antibodies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5079. doi:10.1158/1538-7445.AM2013-5079

Endoglin requirement for BMP9 signaling in endothelial cells reveals new mechanism of action for selective anti-endoglin antibodies.

Endoglin (ENG), a co-receptor for several TGFβ-family cytokines, is expressed in dividing endothelial cells alongside ALK1, the ACVRL1 gene product. ENG and ACVRL1 are both required for angiogenesis and mutations in either gene are associated with Hereditary Hemorrhagic Telangectasia, a rare genetic vascular disorder. ENG and ALK1 function in the same genetic pathway but the relative contribution of TGFβ and BMP9 to SMAD1/5/8 activation and the requirement of ENG as a co-mediator of SMAD phosphorylation in endothelial cells remain debated. Here, we show that BMP9 and TGFβ1 induce distinct SMAD phosphorylation responses in primary human endothelial cells and that, unlike BMP9, TGFβ only induces SMAD1/5/8 phosphorylation in a subset of immortalized mouse endothelial cell lines, but not in primary human endothelial cells. We also demonstrate, using siRNA depletion of ENG and novel anti-ENG antibodies, that ENG is required for BMP9/pSMAD1 signaling in all human and mouse endothelial cells tested. Finally, anti-ENG antibodies that interfere with BMP9/pSMAD1 signaling, but not with TGFβ1/pSMAD3 signaling, also decrease in vitro HUVEC endothelial tube formation and inhibit BMP9 binding to recombinant ENG in vitro. Our data demonstrate that BMP9 signaling inhibition is a key and previously unreported mechanism of action of TRC105, an anti-angiogenic anti-Endoglin antibody currently evaluated in clinical trials.

Key Role for Otolaryngology in a Hereditary Hemorrhagic Telangectasia Center of Excellence

Objective: 1) Learn about the initial experiences of a Hereditary Hemorrhagic Telangectasia (HHT) Center of Excellence. 2) Understand which HHT patients require otolaryngologic evaluation and interventions, and review other common clinical manifestations of the disease. Method: We performed a retrospective review of all patients from the Southwestern United States referred to our HHT Center of Excellence from its inception in May 2010 through February 2012. Clinical presentation, radiographic imaging, genetic testing, otolaryngologic treatments, and other operative interventions were analyzed. Results: In 2010 a dedicated center was started at our tertiary medical center to manage patients with HHT, an autosomal dominant disease with a prevalence of 1:5000. Of the 159 patients referred, 86 have HHT based on genetic testing or Curacao clinical criteria. Seventy-three do not have HHT or are undergoing further workup. Fourteen patients have sought otolaryngologic evaluation for relentless epistaxis or oral bleeding, with 50% of these requiring KTP laser ablation for symptomatic nasal and oral telangectasias. Additionally, 21 patients have required embolization, neurosurgical clipping, or radiation for enlarging or symptomatic arteriovenous malformations in the lung, brain, and abdomen. Conclusion: An HHT Center of Excellence is important in providing comprehensive care for patients with this rare disease with significant clinical sequelae. Otolaryngologists are critical members of this multidisciplinary team performing interventions in the clinic and operating room to improve quality of life for these patients.

Pulmonary arteriovenous malformation: a rare anterior mediastinal mass

Pulmonary arteriovenous malformations are rare pulmonary vascular lesions which are associated with Osler Weber Rendu syndrome (hereditary haemorrhagic telangectasia). They act as right-to-left shunts and have cardiovascular and embolic complications. We present a patient with an apparent anterior mediastinal mass secondary to a pulmonary arteriovenous malformations which was successfully treated percutaneously.

Abstract 3169: Reduced PDGFR-beta Expression After Regional Alk1 Deletion and VEGF Stimulation in the Brain is Associated with Reduced Mural Cell Coverage

Background and Purpose: About 2% of brain arteriovenous malformations (bAVM) are attributable to Hereditary Hemorrhagic Telangectasia (HHT). Previously we created a bAVM model in the adult mouse using regional Alk1 (the causal gene in HHT2) deletion and VEGF stimulation, and reported that the dysplastic vessels in this model have less smooth muscle cell coverage than the normal cerebrovasculature. We hypothesized that VEGF stimulation in the setting of Alk1 loss-of-function leads to impaired mural cell coverage through reduction of platelet-derived growth factor receptor (PDGFR) signaling, and is associated with impaired cerebrovascular integrity. Methods: Brain AVM formation was induced by injection of 2X107 PFU adenoviral vector expressing cre-recombinase (AdCre) and 2X109 genome copies of adeno-associated viral vector (AAV) expressing VEGF (AAV-VEGF) into the basal ganglia of Alk1-floxed mice (loxP sites flanking Exons 4-6). The brain samples were collected 8 weeks after vector injection. Intra-parenchymal hemorrhage, microglial/macrophage counts, Alk1 and PDGFR/PDGFB protein expression were evaluated using Prussian blue staining, Iba1 staining and Western blot. Results: We found a 66±27% reduction in Alk1 protein expression around the injection site of the AdCre and AAV-VEGF-treated group compared with the control vector treated group (p=0.002, ANOVA). Fresh red blood cells (RBCs) were detected in the extravascular space in the Alk1-deficient brain parenchyma (Ad-Cre-treated Alk1-floxed mice), with ≈10-fold increase of Prussian blue coverage area compared to the brain with intact Alk1 gene (Ad-GFP-treated Alk1-floxed mice; p=0.016, rank sum test; or AdCre-treated wild-type mice, p=0.010, rank sum test) after VEGF stimulation. The area of Prussian blue coverage was positively correlated with the number of Iba1+ cells (R2=0.39, p<0.05). Alk1 deletion resulted in a 26±10% reduction of PDGFR-beta expression compared to controls (p<0.001; ANOVA) after VEGF stimulation. However, Alk1 deletion did not affect the level of one of the PDGFR-beta ligands, PDGF-B. Conclusions: These results indicate an important role for Alk1 in maintaining cerebrovascular integrity as shown by its effect on pericyte function through interaction with PDGFR-beta signaling. Alk1 deletion plus VEGF stimulation reduced vessel wall integrity that was associated with an inflammatory response. Altered pericyte-endothelial cell interaction may play a causal role in the pathogenesis of human bAVM, possibly involving a local inflammatory response associated with RBC extravasation.

Abstract A1: Phase 1 study of PF-03446962, a fully human mAb against activin receptor-like kinase 1 (ALK 1), a TGFβ receptor involved in tumor angiogenesis.

Abstract Background: Transforming Growth Factor β (TGF β) is a cytokine able to regulate many biological processes in cancer. At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), triggering a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of proangiogenic factors. ALK-1 deficiency is related to a clinical syndrome called hereditary hemorrhagic telangectasia. PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated preclinically in human tumour xenografts. Mechanistic studies indicated that ALK 1 and VEGF signalling pathways may promote angiogenesis in a collaborative manner. Methods: We conducted a Phase 1 trial in patients (pts) with solid tumors. Primary objectives: identify MTD and a recommended phase 2 dose (RP2D); secondary objectives included safety profile, PK, antitumor activity, soluble proteins TGFβ related and blood flow by contrast enhanced ultrasound (CE-US). Results: 44 pts have been enrolled on 8 dose levels (0.5–15 mg/kg). PF-03446962 is administered iv on Day 1, 29 and then q 2 weeks. 15 mg/kg was defined as maximum administered dose, with DLTs represented by G3 thrombocytopenia and increase in pancreatic enzymes in 2/6 pts. Noteworthy 3 pts developed telangectasia suggesting an in vivo knock-out of the ALK-1 function. The dose of 6.75 mg/kg was defined as RP2D and PK data support the proposed regimen with drug concentration above the estimated therapeutic concentrations during each cycles. 3 PRs were observed, one hepatocellular carcinoma (HCC) resistant to anti-VEGF therapy, one NSCLC and one RCC (both NSCLC and RCC still ongoing). SD lasting for at least 16 weeks was observed in 7/44 pts, with 2 patients (adrenocortical ca. and mesothelioma) lasting for approximately 12 months from treatment start. 2/5 HCC pts showed a TTP of 5.5–6 months similar to those observed with sorafenib in first line. Of note all patients with PR and most of SDs were treated with prior antiangiogenic therapy. In preclinical models, PF-03446962 exerted antitumor activity in tumors resistant to VEGFRTKIs thus suggesting ALK 1 as potential mechanism of escape from VEGF blockade. CE-US showed changes consistent with reduced blood flow in 2/3 pts assessed at this time. Conclusions: PF-03446962 is a first in class mAb anti ALK-1, safe and with manageable toxicities, mainly characterized by asymptomatic elevation of pancreatic enzymes and transient platelet decreases. Based on clinical activity, anti ALK 1 may be a promising novel antiangiogenic strategy with particular interest for pts who failed anti VEGF/VEGFRTKI in clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A1.

Intracardiac defect demonstrated by cardiac CTA

A 50-year-old woman with history of multiple pulmonary arteriovenous malformation embolisations caused by hereditary haemorrhagic telangectasia (Rendu-Osler-Weber syndrome), complained of atypical chest pain and dyspnea. Electrcardiographic (ECG) findings were normal and the bicycle stress test was equivocal. ECG-gated 64-row cardiac multidetector computed tomography (MDCT) showed no significant coronary stenosis, but a membranous ventricular septal defect (VSD) (Fig. A, B). Patient responded well to a treatment with beta-adrenergic blocker (Carvedilol 3.125 mg/day), and considering the surgical risks, no attempt to close the VSD was performed.

Imaging modalities for retrieval of a migrated coil from the left ventricle, after pulmonary arterio-venous malformation embolisation

We present a case of a 62-year-old lady who was a known case of hereditary haemorrhagic telangectasia (Rendu-Osler-Weber syndrome) and had pulmonary arteriovenous malformations (AVMs). She had multiple embolisations of pulmonary AVMs. During the last embolisation therapy, one of the coils migrated into the heart. This could not be located by transoesophageal echocardiography, however, was identified in the left ventricle by computerised tomogram scan. It was removed successfully using cardiopulmonary bypass.

Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells

Mutations in transforming growth factor-beta (TGF-beta) receptor superfamily members underlie conditions characterized by vascular dysplasia. Mutations in endoglin and activin-like kinase receptor 1 (ALK1) cause hereditary hemorrhagic telangiectasia, whereas bone morphogenetic protein type II receptor (BMPR-II) mutations underlie familial pulmonary arterial hypertension. To understand the functional roles of these receptors, we examined their relative contributions to BMP signaling in human pulmonary artery endothelial cells (HPAECs). BMP9 potently and selectively induced Smad1/5 phosphorylation and Id gene expression in HPAECs. Contrary to expectations, BMP9 also stimulated Smad2 activation. Furthermore, BMP9 induced the expression of interleukin 8 and E-selectin. Using small interfering RNA, we demonstrate that the type I receptor, ALK1, is essential for these responses. However, small interfering RNA and inhibitor studies showed no involvement of ALK5 or endoglin. We further demonstrate that, of the candidate type II receptors, BMPR-II predominantly mediated IL-8 and E-selectin induction and mitogenic inhibition by BMP9. Conversely, activin receptor type II (ActR-II) contributed more to BMP9-mediated Smad2 activation. Only abolition of both type II receptors significantly reduced the Smad1/5 and Id responses. Both ALK1 and BMPR-II contributed to growth inhibition of HPAECs, whereas ActR-II was not involved. Taken together, our findings demonstrate the critical role of type II receptors in balancing BMP9 signaling via ALK1 and emphasize the essential role for BMPR-II in a subset of BMP9 responses (interleukin 8, E-selectin, and proliferation). This differential signaling may contribute to the contrasting pathologies of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.

Hereditary hemorrhagic telangectasia and spinal cord infarct: Case report with a review of the neurological complications of HHT

Hereditary hemorrhagic telangectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant vascular dysplasia with high penetrance and variable expressivity. A wide variety of neurological complications have been reported in association with this condition. We report the first case of spinal cord infarction likely due to paradoxical embolization with HHT and review the literature on the neurological complications of this disorder. MEDLINE was employed to identify all published reports of HHT with neurological complications. We identified 44 references with a total of 436 cases of neurological complications of HHT. The most common complication was ischemic stroke and the main etiology for the vascular neurological complications in patients with HHT was pulmonary arteriovenous malformation. HHT should be considered in the differential diagnosis of any patient with cutaneous or mucosal telangiectasia or a history of unexplained epistaxis. HHT is associated with a diverse array of neurological disorders; most commonly ischemic and hemorrhagic stroke, transient ischemic attack, and brain abscess. While myelopathy secondary to arteriovenous malformation with HHT has been previously reported, this is the first instance of spinal cord infarction due to paradoxical embolization in this disorder.

DIC as a Complication of HHT or Osler-Weber-Rendu Syndrome

The possibility of disseminated intravascular coagulopathy (DIC) as a complication of hereditary hemorrhagic telangectasia (HHT) has been described in the past[1]. However, due to the low incidence of HHT, information on the topic is scarce. We present a case of HHT complicated by DIC to support the clinical awareness needed with regards to DIC resulting in bleeding as a presentation of HHT. A 72 year old female presented with a severe episode of epistaxis and was found to be in DIC. She had been suffering from recurrent episodes of epistaxis for over 5 years. Her past medical history included pulmonary embolus, COPD, hypertension and diverticulosis. Her family history included recurrent epistaxis in her father and son. Physical examination on presentation demonstrated a telangectetic lesion on the tongue and fingertips and dried blood in her right nares. Laboratory data revealed WBC 7.67, HCT 37, MCV 86.2, Platelets 114, PT 24, INR 2.1, Fibrinogen < 70, and DDimer >5250. BUN 8, Cr 0.8. Endoscopy performed for hematemesis confirmed gastric arterio-venous malformations (AVMs). CT angio of abdomen and chest demonstrated pulmonary, liver, and gastrointestinal tract AVMs. Small bowel capsule study confirmed gastric AVMs with no small bowel AVMs. Genetic testing demonstrates single nucleotid (A) deletion at position 364 of the ALK-1 gene causing a truncated ALK-1 protein. A clinical diagnosis of HHT was confirmed. This case adds to the literature in support of the clinical relevance of DIC as a complication of HHT. Furthermore, in this case it was a part of the acute presentation which led to the diagnosis of HHT. [1] Ann N Y Acad Sci, 1981;370:851–4

Transcatheter closure of pulmonary arteriovenous malformations with Amplatzer devices

To review the authors' experience with transcatheter closure of pulmonary arteriovenous malformations (PAVMs) using amplatzer duct occluder (ADO) devices and vascular plugs (AGA Medical, Golden Valley, MN) and present a novel technique for delivery sheath placement and device delivery. PAVMs can cause cyanosis, fatigue, polycythemia, and thromboembolic phenomena. Transcatheter closure using coils, detachable balloons, and various devices has replaced surgery as the preferred therapy. Between January 2001 and December 2004, five patients (2M, 3F) of median age 33 years (14-49) were referred for transcatheter closure of multiple PAVMs. All patients were diagnosed previously with hereditary hemorrhagic telangectasia. The procedures were performed with sedation using a percutaneous transcatheter technique via the femoral vein under fluoroscopic guidance. A total of 14 PAVMs (11 ADO and 3 plugs) were closed in five patients. Three patients required two procedures after developing additional PAVMs. All attempts at PAVM closure were successful. Oxygen saturation increased from 88.4 +/- 6.1 to 96.4 +/- 0.5 (P < 0.05). No complications, including air or thromboembolism, hemoptysis, or chest pain, occurred. At median follow-up of 3.4 years (1.4-3.6), all patients are alive and have suffered no embolic phenomena or infection. Amplatzer patent ductus arteriosus occluders and vascular plugs are safe and effective in the closure of PAVMs in the acute setting and at intermediate follow-up. Placement of a long delivery sheath can be facilitated by the methods outlined. Though promising, further clinical evaluation of these devices is required. Their apparent advantages must be compared to other techniques and devices for transcatheter PAVM closure.