Pulmonary gas exchange in hereditary hemorrhagic telangiectasia patients with liver arteriovenous malformations.

BACKGROUND: The severity of Hereditary Hemorrhagic Telangiectasia (HHT) disease is generally related to vascular visceral involvement represented by arteriovenous malformations (AVMs). Pulmonary function tests (PFTs) remain normal in HHT patients without Pulmonary AVMs (PAVMs) and respiratory comorbidity. The aim of our study was to compare the diffusing capacity of the lung for carbon monoxide (DLCO) and nitric oxide (DLNO) and its 2 components: the pulmonary capillary blood volume (Vc) and the alveolar-capillary membrane conductance (Dm), in HHT patients with PAVMs, PAVMs and liver AVMs (LAVMs), LAVMs without PAVM, no PAVM and LAVM, and controls. METHODS: Sixty one consecutive adult patients (HHT without PAVM and LAVM: n = 7; HHT with PAVMs: n = 8; HHT with PAVMs and LAVMs: n = 25; HHT with LAVMs: n = 21) and controls matched for age and sex ratio without respiratory, heart and liver pathology (n = 15) were non-invasively evaluated using PFTs, combined DLCO/DLNO, arterial blood gas at rest, contrast echocardiography and enhanced computed tomography scan of the liver and chest the day of pulmonary function testing. RESULTS: We found that patients with LAVMs but without PAVMs exhibited increased Vc/Dm ratio. Interestingly, HHT patients with hepatic artery enlargement showed higher Vc/Dm ratio than HHT patients with normal hepatic artery diameter. CONCLUSION: Vc/Dm ratio may have practical impact in HHT patients' management to detect precociously the occurrence of LVAMs. However, further studies are needed to assess the accuracy and potential prognostic value of pulmonary gas exchange measurements in HHT patients with LVAMs.

Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. RESULTS: Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1-3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1-3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). CONCLUSIONS: With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.

Liver Transplantation Trends and Outcomes for Hereditary Hemorrhagic Telangiectasia in the United States.

BACKGROUND: Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. METHODS: Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. RESULTS: Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. CONCLUSIONS: Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease.

PURPOSE: To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. METHODS: Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy-two eyes from 86 patients who had a comparable scan protocol of at least 30 µm interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. RESULTS: From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 ± 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 µm (range 15 µm-80 µm). CONCLUSION: Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Müller cell dysfunction in this disorder.

Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report.

CASE DESCRIPTION: Five-year-old female patient with hereditary hemorrhagic telangiectasia. CLINICAL FINDINGS: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. TREATMENT AND OUTCOME: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. CLINICAL RELEVANCE: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome.

DESCRIPCIÓN DEL CASO: Paciente de cinco años de sexo femenino con telangiectasia hemorrágica hereditaria. HALLAZGOS CLÍNICOS: Deterioro de la función cardiopulmonar con mayores requerimientos de oxígeno secundario a shunt pulmonar arteriovenoso, epistaxis. TRATAMIENTO Y RESULTADO: La paciente fue tratada con el anticuerpo monoclonal bevacizumab, que inhibe el factor de crecimiento endotelial vascular, con buen resultado clínico. RELEVANCIA CLÍNICA: La telangiectasia hemorrágica hereditaria es un trastorno autosómico dominante caracterizado por malformaciones arteriovenosas en diferentes órganos, lo que hace que sus presentaciones clínicas varíen. Las opciones terapéuticas sistémicas para la enfermedad generalizada son limitadas. El anticuerpo monoclonal bevacizumab, parece ser una buena opción en este trastorno. Aunque se ha reportado como exitoso en la población adulta, su uso en población pediátrica aún no ha sido reportado. Aquí se informa el uso de bevacizumab en una paciente de 5 años de edad con telangiectasia hemorrágica hereditaria, mostrando beneficios clínicos y buen resultado.

Deregulated TGF-ß/BMP Signaling in Vascular Malformations.

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-ß/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-ß/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-ß/BMP receptor complex and the second to increased signaling sensitivity to TGF-ß/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia.

INTRODUCTION: Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor ß (TGF-ß) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level. Areas covered: Pathogenic mutations in genes coding for the TGF-ß receptors endoglin (ENG) (HHT1) or the activin receptor-like kinase-1 (ACVRL1 or ALK1) (HHT2), are responsible for more than 80% of patients with HHT. Therefore, ENG and ALK1 are the main potential therapeutic targets for HHT and the focus of this review. The current status of the preclinical and clinical studies, including the anti-angiogenic strategy, have been addressed. Expert opinion: Endoglin and ALK1 are attractive therapeutic targets in HHT. Because haploinsufficiency is the pathogenic mechanism in HHT, several therapeutic approaches able to enhance protein expression and/or function of endoglin and ALK1 are keys to find novel and efficient treatments for the disease.

Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report / Bevacizumab como tratamiento para telangiectasia hemorrágica hereditaria en niños: Reporte de caso

Abstract Case description: Five-year-old female patient with hereditary hemorrhagic telangiectasia. Clinical Findings: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. Treatment and Outcome: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. Clinical Relevance: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome.

Resumen Descripción del caso: Paciente de cinco años de sexo femenino con telangiectasia hemorrágica hereditaria. Hallazgos Clínicos: Deterioro de la función cardiopulmonar con mayores requerimientos de oxígeno secundario a shunt pulmonar arteriovenoso, epistaxis. Tratamiento y resultado: La paciente fue tratada con el anticuerpo monoclonal bevacizumab, que inhibe el factor de crecimiento endotelial vascular, con buen resultado clínico. Relevancia clínica: La telangiectasia hemorrágica hereditaria es un trastorno autosómico dominante caracterizado por malformaciones arteriovenosas en diferentes órganos, lo que hace que sus presentaciones clínicas varíen. Las opciones terapéuticas sistémicas para la enfermedad generalizada son limitadas. El anticuerpo monoclonal bevacizumab, parece ser una buena opción en este trastorno. Aunque se ha reportado como exitoso en la población adulta, su uso en población pediátrica aún no ha sido reportado. Aquí se informa el uso de bevacizumab en una paciente de 5 años de edad con telangiectasia hemorrágica hereditaria, mostrando beneficios clínicos y buen resultado.

Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations.

Background: Cerebral abscess is a recognized complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Methods: Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with computed tomography-confirmed PAVMs (including 403 [90.5%] with hereditary hemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression was performed and detailed periabscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier nonoverlapping series. Results: Thirty-seven of the 445 (8.3%) patients experienced a cerebral abscess at a median age of 50 years (range, 19-76 years). The rate adjusted for ascertainment bias was 27 of 435 (6.2%). Twenty-nine of 37 (78.4%) patients with abscess had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. Twenty-one of 37 (56.7%) suffered residual neurological deficits (most commonly memory/cognition impairment), hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events, emphasized potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio, 5.4 [95% confidence interval, 1.4-21.1]); male sex; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Conclusions: Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower oxygen saturation and intravenous iron may be modifiable risk factors.

Comprehensive management of hereditary hemorrhagic telangiectasia.

PURPOSE OF REVIEW: Hereditary hemorrhagic telangiectasia (HHT), or Osler Weber-Rendu disease, is a rare inherited disorder of fibrovascular tissue affecting various organs. Epistaxis is the most common symptom of HHT but as the disease affects multiple organs, a multisystem and multidisciplinary approach to management is required. The purpose of this article is to provide an overview of the multidisciplinary approach to HHT for the otolaryngologist and to discuss the current pharmacologic and procedural treatment options available for HHT-related epistaxis. RECENT FINDINGS: Multidisciplinary expert guidelines have better defined what screening tests are advised for the multisystem evaluation of the HHT patient. New pharmacologic therapies including bevacizumab (Avastin) used submucosally or topically have shown promise as in-office treatment modalities. Sclerotherapy of telangiectasia, including in-office applications, has recently proven safe and effective. SUMMARY: HHT remains a difficult disease to treat. Being aware of the common organ systems involved by the disease will help the practicing otolaryngologist to ensure the patient receives appropriate multidisciplinary care. For HHT-related epistaxis, new medical and surgical options allow for a wider range of treatments than were previously available.

[A rare cardiomegaly]. / Una rara cardiomegalia.

We present the case of a patient who came to our attention for enlargement of the cardiac silhouette on chest X-ray. Echocardiography showed moderate diastolic overload of both ventricles with enhanced cardiac output without valvular disease or cardiac shunt that could account for this cardiomegaly. A subsequent abdominal echocardiographic exploration showed an angiomatous transformation of the liver due to diffuse lacunar enlargement of hepatic portal vein branches and arterial-venous shunts. Computed tomography and magnetic resonance imaging confirmed the echocardiographic findings. The imaging findings coupled with cutaneous and nasopharyngeal lesions were suggestive of hereditary hemorrhagic telangiectasia (HHT) and the diagnosis was confirmed after the identification of a mutation in the ACVRL1 gene on chromosome 12. HHT is a rare but underestimated vascular disease that can affect different organs, in particular the liver, leading to organ failure requiring transplantation as occurred in our patient. Echocardiography is a useful imaging tool to exclude cardiac abnormalities as a cause of cardiomegaly and to guide the correct diagnosis of a peripheral origin of high cardiac output.

Open arterial reconstruction of multiple hepatic artery aneurysms in a patient with hereditary hemorrhagic telangiectasia: A case report.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is characterized by mucocutaneous telangiectasia and visceral vascular malformations (VMs). Liver involvement with VMs may lead to high-output cardiac failure, portal hypertension, and biliary disease. There is no curative treatment for the disease, and liver transplantation is indicated for life-threatening complications. Herein, we report a case of multiple hepatic artery aneurysms (HAAs) in a patient with HHT in which open arterial reconstruction was performed. There have only been a few case reports on HAA occurring with HHT. Thus, this case provides important information for the management of HHT-associated HAAs. CASE SUMMARY: A 62-year-old female with known HHT was referred to our facility to seek further treatment for a giant HAA. She denied any symptoms except recurrent epistaxis. A computed tomography (CT) scan revealed a right HAA with a diameter of 72 mm, in addition to 2 other minor HAAs. The CT scan also revealed the VMs that were scattered in the liver, and a continuously dilated and tortuous artery existing from the celiac trunk to the right and left hepatic arteries. We performed open arterial reconstruction of the HAAs. Her postoperative course was uneventful. CONCLUSIONS: When treating HAAs, there are a variety of options. However, hepatic VMs might affect HHT patients in various ways postprocedurally. Ligation and embolization of the hepatic artery may lead to complications, such as massive hepatic necrosis. Hepatectomy should be avoided if possible, because a postoperative hyperperfusive state in the remaining liver can cause adverse events. We believe that arterial reconstruction of HHT-associated HAAs might reduce the risk of postprocedural complications with minimal hemodynamic changes in the liver, thus obviating the need for hepatectomy or liver transplantation.

Clinical Outcomes of Patients with Severe Hepatic Hereditary Hemorrhagic Telangiectasia After Banding of the Hepatic Artery and Banding/Ligation of Branches of the Hepatic Artery.

OBJECTIVE/BACKGROUND: To evaluate the effectiveness of double banding/ligation of hepatic arteries in treating patients with hepatic hereditary hemorrhagic telangiectasia (HHHT). METHODS: From January 2004 to December 2013, 35 patients were diagnosed with HHHT, among whom 11 woman and two men with a mean ± SD age of 44 ± 9 years were treated by double hepatic artery banding/ligation for cardiac insufficiency and/or portal hypertension. The outcomes were evaluated prospectively by measuring clinical manifestations, imaging features, liver and cardiac function, pulmonary arterial systolic pressure, and post-operative complications. Quality of life was evaluated with the Short Form Health Survey questionnaire. RESULTS: For each patient, the common hepatic artery and one branch of the left and/or right hepatic artery were banded, and other significantly dilated hepatic artery branches were ligated. No patient died after surgery. Clinical symptoms were improved in all patients, although ischemic cholangitis was observed in two patients and treated conservatively. Cardiac function, classified per the New York Heart Association (NYHA) cardiac functional grading, improved (NYHA III-IV vs. NYHA I-II); pulmonary arterial systolic pressure significantly decreased in all patients (48 ± 8 mmHg vs. 24 ± 4 mmHg; P < .001) and remained in the normal range (26 ± 3 mmHg) at the end of follow up. The levels of γ-glutamyl transpeptidase and alkaline phosphatase decreased in 11 patients (144 ± 94 U/L vs. 71 ± 34 U/L; P = .003) and 10 patients (207 ± 71 U/L vs. 105 ± 32 U/L; P = .001), respectively. Patients were followed up for 50 ± 28 months (range 6-113 months); one death resulted from causes unrelated to surgery and all dimensions of quality of life improved in all surviving patients. CONCLUSIONS: This study helps to establish double hepatic artery banding/ligation as an effective therapy for selected patients with HHHT.

Structural causes of ischemic and hemorrhagic stroke in children: moyamoya and arteriovenous malformations.

PURPOSE OF REVIEW: Moyamoya and arteriovenous malformations represent, respectively, significant sources of ischemic and hemorrhagic stroke in children after the first year of life. Although rarely encountered in routine pediatric practice, the potential severe morbidity of these entities, coupled with the typical acuity of their presentation, merit ongoing awareness of current relevant diagnostic and therapeutic strategies. RECENT FINDINGS: Mutations in RNF213, ACTA2, and GUCY are implicated in moyamoya. Several common pediatric conditions - trisomy 21, sickle-cell disease, and neurofibromatosis type I - demonstrate an increased risk of moyamoya development. Advances in imaging have improved the diagnosis of moyamoya and surgical revascularization has been further supported as the primary treatment.Genetic associations with arteriovenous malformations (AVMs) are few outside of hereditary hemorrhagic telangiectasia. Within this population, the majority harbor mutations in ENG and ACVRL. Once screened, if no AVM is found, repeat scanning may not be needed for 5 years. Trauma and infection may not be 'triggers' for inducing hemorrhage in patients with untreated AVMs. If found in children, evidence supports the treatment of the AVM, ideally with surgery. SUMMARY: Moyamoya and AVMs are rare but important causes of stroke in children. If identified, it is important to refer the children to pediatric centers with experienced neurovascular teams. Surgical revascularization of moyamoya and resection of AVMs should be strongly considered, including incidentally discovered asymptomatic disease.

Life-Threatening Oral Bleed­A Rare Presentation of Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder of fibrovascular tissues. Patients with HHT often develop life-threatening bleeds from telangiectasias in the nasal or gastrointestinal mucosa or from visceral arteriovenous malformations. Recurrent oral bleeds are rare presentations in these patients and are seldom reported. This report describes a rare case of 72-year-old man with a known history of HHT who presented with a recurrent life-threatening oral bleed from telangiectasia of the palate and reviews the literature for current trends of medical and dental management. This study is an effort to draw the attention of oral physicians and surgeons to such drastic complications of the disease and various current treatment modalities.

Coincidence of Glanzmann's thrombasthenia with hereditary haemorrhagic telengiectasia in a man with gastrointestinal bleeding.

Here we report a case of a 57-year-old man referred to our hospital with weakness, lethargy, melena, and rectorrhalgia. His physical examination and past medical history showed gingival bleeding, several episodes of epistaxis and post-surgery bleeding. Primary laboratory evaluation revealed only anaemia. Gastrointestinal findings including upper endoscopy and colonoscopy documented normal status, but balloon endoscopy illustrated telengiectasia-like lesions in the mid-jejunum. The case was suspected to be haemophilia due to the past medical history, although complete haemostatic evaluation demonstrated Glanzmann's thrombasthenia. The diagnosis of co-occurrence of hereditary haemorrhagic telengiectasia and Glanzmann's thrombasthenia was confirmed. This case revealed the coincidence of two bleeding tendencies, which, although rare, is a possible phenomenon. We recommend carrying out both primary and secondary haemostatic profiles for every patient with bleeding diathesis.

Osler-Weber-Rendu syndrome during pregnancy.

Osler-Weber-Rendu syndrome is a very rare systemic fibrovascular dysplasia. Rupture of angiomas can cause haemorrhages, which sometimes can be severe with difficult bleeding control. The main manifestation is recurrent epistaxis. Treatment of this disorder is symptomatic. During pregnancy, there may be an increased risk of complications. We describe a case of a pregnant woman with Osler-Weber-Rendu syndrome. Besides frequent epistaxis and microcytic hypochromic anaemia that resolved with oral iron treatment, she had a normal pregnancy, vaginal delivery and puerperium without complications.

MiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF-beta signaling pathways in endothelial cells.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-ß pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-ß balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR-205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype.