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Background Hereditary haemorrhagic telangiectasia (HHT) is a rare disease characterized by a multisystemic vascular dysplasia and epistaxis, that is the most common cause of disability and social impairment. Patient management strictly depends on the severity of this symptom; therefore, it is of paramount importance for the clinicians to effectively grade epistaxis severity. The aim of this report was to validate the Frequency, Intensity and Duration score (FID) for grading epistaxis severity in patients with HHT; we studied repeatability and external validity comparing FID score with Epistaxis Severity Score (ESS). Methods This is a descriptive, observational study that included 264 adult HHT patients with epistaxis. Diagnosis of HHT was established with Curacao criteria or positivity at genetic testing. Nosebleed severity was evaluated according to the FID score and the ESS. The first 30 patients were included in the validation of the FID score, which was graded on days 0, 1, 3 and 7. In the remaining 234 patients, a comparison between the ESS and FID score was performed. Results The statistical analysis performed in order to validate the FID score showed very good agreement between scores calculated on different days; analysis comparing the FID score with the ESS revealed a high correlation between the two grading systems. Conclusions The FID score is a quick, easy and precise tool for evaluating HHT-related epistaxis and could be a possible alternative to the ESS. The FID score meets the need for an intuitive and smart grading system that is easy to manage in clinicians’ hands.

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an “AVM” bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.

A 25-year-old gravida 3 para 3 with a history of hereditary haemorrhagic telangiectasia (HHT) and embolised pulmonary arteriovenous malformations (PAVMs) was admitted at 36 weeks gestation with haemoptysis, epistaxis and CT evidence of recent alveolar haemorrhage. An urgent caesarean section was planned. Both previous pregnancies had been delivered by elective lower segment caesarean section (LSCS) under subarachnoid block (SAB) at term. Preanaesthetic planning involved consultation with our tertiary maternity referral centre, the national HHT centre and our tertiary adult referral centre, which has interventional radiology and cardiothoracic capabilities. A whole spine MRI was carried out to rule out vascular malformation. Following multidisciplinary discussion, the decision was made to proceed with caesarean section in our hospital under SAB. Wide bore intravenous access was sited and blood product availability was ensured in case of acute pulmonary haemorrhage. The LSCS was uneventful. Postoperatively following discharge from the hospital, the patient experienced recurrent episodes of small volume haemoptysis, and had further PAVM embolisation in the national HHT centre. This report highlights the difficulties in managing complex parturients in a non-tertiary referral centre and underlines the importance of communication and multidisciplinary team discussion to determine the most appropriate management.

La telangiectasia hemorrágica hereditaria (HHT) o síndrome de Rendu-Osler-Weber es una enfermedad genética de baja prevalencia caracterizada por malformaciones vasculares con riesgo de sangrado. Objetivo: Describir las características clínicas, genéticas y epidemiológicas de la población cántabra diagnosticada. Material y métodos: Entre el 1 de enero de 2003 y el 31 de diciembre de 2017 se estudiaron 252 pacientes cántabros con sospecha de HHT en la unidad especializada del Hospital Sierrallana. Se les realizó estudio genético y protocolo de exploración para descartar afectación orgánica.Resultados: De los 252 pacientes, 121 fueron diagnosticados de HHT. El tipo genético predominante fue HHT2 y la clínica principal la epistaxis. El órgano más afectado fue el pulmón. En HHT1 predominaron la afectación cerebral y la pulmonar y en HHT2, la hepática. La capilaroscopia fue patológica en el 66,67%, predominando en HHT1. La prevalencia para Cantabria fue 1:4960. Varios municipios tuvieron prevalencias superiores a 1:2000, en rango de enfermedad no minoritaria. Discusión: La HHT es una enfermedad minoritaria en Cantabria pero con áreas de agregación elevada (prevalencia > 1:2000). Las tasas de afectación orgánica son similares a las de estudios previos, objetivándose una relación significativa entre afectación pulmonar y HHT1. Entre los diagnosticados, predominaron los HHT2. Hereditary haemorrhagic telangiectasia (HHT) or Rendu Osler Weber syndrome is a rare genetic disease characterized by an anomalous vessel development with potential risk of bleeding. Aim: To describe clinical, genetic and epidemiological characteristics of the Cantabrian diagnosed population. Material and methods: Between 1st january 2003 and 31st december 2017, 252 Cantabrian patients with suspected HHT were evaluated at the specialized unit in Hospital Sierrallana. Genetic test and screening to disclose organ affection were performed. Results: The diagnosis was confirmed in 121 individuals of the 252 suspected cases. There was a predominance of HHT2, the main clinical presentation was epistaxis. The most affected organ was the lung. In HHT1 brain and lung affectation was predominant, whereas in HHT2, it was hepatic affectation. Capillaroscopy found pathologies 66, 67% of the time, being HHT1 the most predominant. Prevalence in Cantabria was 1:4960. Many municipalities had prevalences higher tan 1:2000, in a range of non-rare diseases. Discussion: HHT is a rare disease in Cantabria, but in some areas there is high aggregation (prevalence > 1:2000). Organic affectation rates are similar to those of previous studies, showing a significant connection between pulmonary affectation and HHT1. Among the diagnosed patients, there was a predominance of HHT2. Grado en Medicina

Aim: To describe epidemiological characteristics of a wide cohort of Spanish patients with hereditary hemorrhagic telangiectasia (HHT)/ Rendu-Osler-Weber disease. Methods and Results: Between 1 January 2002 and 31 December 2013, 667 Spanish patients with suspected HHT were evaluated in the reference HHT Unit in Hospital Sierrallana and 449 were diagnosed by clinical Curacao criteria and/or genetic test. The diagnostic sensitivity of Curacao clinical criteria in the population studied was 94.59%. Prevalence was 1:5,936 people and lethality rate of 0.16%. Type 2 HHT was the most prevalent and in total 147 different mutations was identified. Epistaxis was the most prevalent symptom (96.88% of cases) while 95.18% of patients showed typical telangiectasias. Pulmonary involvement was present in 28.25% of patients (by computed tomography) mainly in women and HHT1 cases while liver infection was more prevalent in HHT2 cases. Brain involvement was disclosed in 28.35% of cases. Telangiectasias in conjuctival mucose were very frequent mainly in HHT1 elderly patients. Conclusion: This is the first representative series of epidemiological data on a non-previously evaluated population, showing results about prevalence, genetic distribution and organ infection and disclosing new observations that can help guide the diagnostic and screening procedures for these patients.

Kjeldsen AD, Oxhoj H, Andersen PE, Green A, Vase P (Odense University and Odense University Hospital, Odense; University of Aarhus, Aarhus; and the Department of Otorhinolaryngology, Svendborg, Denmark). Prevalence of pulmonary arteriovenous malformations (PAVMs) and occurrence of neurological symptoms in patients with hereditary haemorrhagic telangiectasia (HHT). J Intern Med 2000; 248: 255–262. Background. Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. Objective. To estimate (i) the prevalence of PAVM, and (ii) the occurrence of neurological symptoms in a geographical well-defined population of HHT patients. Methods. HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for pulmonary arteriovenous malformations and neurological evaluation. Two groups served as controls: (i) first-degree relatives without any signs of HHT; and (ii) age- and gender-matched controls. Setting. Odense University Hospital. Subjects. HHT patients identified in a cross-sectional family survey carried out in the County of Fyn, Denmark. Results. Included in the study were 169 HHT family members representing 24 families. They included both HHT patients and their first-degree relatives. The criteria of HHT were fulfilled in 75 participants; of these, 59 had a screening procedure performed, and PAVMs were demonstrated at pulmonary angiography (PA) in 18. Seven of the HHT patients had a history of cerebral stroke, compared with none of their healthy first-degree relatives. Conclusion. The prevalence of PAVM was 24% amongst HHT patients. The study confirmed an increased prevalence of neurological symptoms amongst HHT patients; the odds ratio was estimated to be 7.6. In order to enable prevention of these complications, screening for PAVM should become an integral part of the medical care for HHT patients.

Hereditary Haemorrhagic Telangiectasia (HHT) or Rendu-Osler-Weber syndrome, is an autosomal dominant rare disease characterized by localized angiodysplasia. This is manifested as epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations in the pulmonary, cerebral or hepatic circulation. The prevalence is between 1 in 5,000 to 8,000, although it is higher in some regions. The most frequent clinical manifestation of HHT is epistaxis, normally from light to moderate from the 4th decade of life. However, many patients show severe epistaxis which may interfere with their quality of life. The epistaxis is due to telangiectasia on the nasal mucosa. These are focally dilated postcapilar venules, which in advanced phases show many layers of smooth muscle cells without elastic fibers, and very frequently directly connect with dilated arterioles. As a consequence of these vascular alterations, telangiectases are very sensitive to slight trauma and even to the friction with the air when breathing, which gives rise to nose bleeds. Unfortunately, there is no optimal pharmacological treatment for the epistaxis in HHT. The use of antifibrinolytic agents for the treatment of HHT has been studied recently by our group as an effective relief for nasal and gastric haemorrhages. This work represents a systematic review and the begining of a systematic laboratory work we are now conducting in our lab to screen for “orphan drugs” as therapeutic agents in HHT. In this context, the use of hormones, immunosuppresants and anti-angiogenic agents are under preclinical study in our laboratory

20 p.-7 fig., Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploinsufficiency of ENG and ALK1, This work was supported by grants from Ministerio de Ciencia e Innovacion (SAF05–01090 and AF08–01218 to LMB, and SAF2007–61827 to CB), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII-CIBER CB/06/07/0038), Fundacion Ramón Areces of Spain, and Instituto Fundación Marqués de Valdecilla (IFIMAV)

Introduction: Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. Methods To identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHT-affected individuals. Results In the pilot study, Factor VIII (FVIII) and Von Willebrand Factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p0.0013, Mann-Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent ill-health, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (PAVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), and VTE: VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36-71)yr. Four VTE occurred in Factor V Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10-132 months from VTE (odds ratio 2.41 (95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. Conclusions HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in the management of individuals with HHT.

9 páginas, 5 figuras, 2 tablas -- PAGS nros. 254-262, Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment is difficult. Our objective was to assess the use of tranexamic acid (TA), an antifibrinolytic drug, for the treatment of epistaxis in HHT patients and to investigate in vitro the effects of TA over endoglin and ALK-1 expression and activity in endothelial cells.A prospective study was carried out on patients with epistaxis treated with oral TA in the HHT Unit of Sierrallana Hospital (Cantabria, Spain). Primary cultures of endothelial cells were treated with TA to measure the levels of endoglin and ALK-1 at the cell surface by flow cytometry. RNA levels were also measured by real-time PCR, and the transcriptional effects ofTA on reporters for endoglin, ALK-1 and the endoglin/ALK-1 TGF beta pathway were assessed.The results showed that the fourteen HHT patients treated orally withTA improved, and the frequency and severity of their epistaxis were decreased. No complications derived from the treatment were observed. Cultured endothelial cells incubated with TA exhibited increased levels of endoglin and ALK-1 at the protein and mRNA levels, enhanced TGF-β signaling, and improved endothelial cell functions like tubulogenesis and migration. In summary, oral administration of TA proved beneficial for epistaxis treatment in selected patients with HHT. In addition to its already reported antifibrinolytic effects, TA stimulates the expression ofALK-1 and endoglin,as well as the activity of the ALK-1/endoglin pathway, Grants from Fondo de Investigacion Sanitaria (PI020200) to CB and MEC (SAF05–01090 to LB and SAF2004–01390 to CB).

Background: The frequency of haemorrhage in individuals with hereditary haemorrhagic telangiectasia (HHT), 10% of whom will have cerebral arteriovenous (AV) malformations, could be high enough to justify screening. This would allow presymptomatic treatment to prevent early onset stroke in a condition that affects at least 1 in 8000 individuals. This is an important issue in view of the contrast between transatlantic management approaches, the worldwide dissemination of patient information, and the ethical implications of the diagnosis for the untreated patient. Objectives: To define the annual incidence of haemorrhagic stroke in individuals with HHT. Methods: Retrospective study on stroke incidence in individuals with HHT and their immediate families (n = 674; 22 061 HHT patient years), specifically analysing patients under 46 years of age (17 515 patient years). The results were compared with stroke risk in the general population. Results: In the majority of cases, the haemorrhage was the first significant neurological event. Overcorrecting for any bias towards overestimation that would be introduced in excluding non-penetrant family members, cerebral haemorrhages were more than 20 times more common in male HHT subjects under the age of 45 years than in the general population (standardised ratio 22.99; 95% confidence interval, 13.14 to 37.33). Haemorrhages were also six times more common in female HHT subjects (6.18; 2.27 to 13.45). The incidence ratio of cerebral haemorrhage in male patients (1.84; 1.05 to 2.99) yielded a haemorrhage rate in individuals with cerebral AV malformations of 1.4–2.0% per annum, comparable to figures in the non-HHT cerebral AV malformation population. Conclusions: These data contradict accepted wisdom in many countries that asymptomatic HHT patients are at a low (and acceptable) risk of haemorrhage. The data justify a more aggressive screening approach to identify small causative lesions amenable to treatment.

Introduction. Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable and include epistaxis, gastrointestinal bleeding, pulmonary arteriovenous malformations and cerebral arteriovenous malformations. Early death due to these complications has been described.Design. We report a study on the prevalence and mortality of HHT in a Danish population based on two cross-sectional surveys in combination with a long-term follow-up study.Settings and subjects. Prevalent cases of HHT as of 1 January 1974 in the County of Fyn, Denmark, were identified. In 1995–97 a follow-up study of mortality was performed of the initial patient sample, and a new point prevalence rate of HHT as of 1 January 1995 was calculated. All live patients and their families were invited to attend a detailed clinical examination.Results. The prevalence of HHT in the County of Fyn was 13.8 per 100 000 on 1 January 1974 and 15.6 per 100 000 on 1 January 1995. In the HHT group as a whole, we found a slightly increased mortality; however, amongst the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality could be fully explained by severe HHT symptoms.Conclusion. This study suggests that HHT is more prevalent than previously believed. In young patients the disease is associated with an excess mortality which is fully attributable to HHT. Future research should aim at the identification of HHT patients at particular risk of developing severe complications.

Cerebral arteriovenous malformations (CAVM) can be associated with Hereditary Haemorrhagic Telangiectasia (HHT), adominantly inherited vascular disorder with variable penetrance and expressivity. The presentation and angiographic features were analysed retrospectively. The purpose is to point to special groups of AVM patients within the overall CAVMs and to discuss the issue of screening. We reviewed 34 cases of HHT -related CAVM from the data bank in Bicêtre from 1985–2003. In Spinal cor d AVM (SCAVM) there were 194 patients with 5 HHT. HHT was diagnosed when at least two criteria were met; cutaneous telangiectasia, epistaxis, visceral AVMs, angiographic findings of AVF and first degree family history. Intracranial haemorrhage was the presenting symptom in 8.8% and the risk of haemorrhage in the natural history was 0.7% per year. The commonest angiographic features in adults are nidus (81.8%) and multiplicity (45.5%), while in the paediatric group venous ectasia and giant pouches (91.3%), AVF (69.6%) and multiplicity (52.2%). In spinal cor d lesions macrofistulas are demonstrated in 83% of HHT with no multiplicity. HHT-related CAVMs present as multiple lesions, cortical in location, micro AVMs or AVF. HHT in SCAVM is expressed as single macro AVF, especially in the paediatric group. AVF in children are highly suggestive of HHT. We do not recommend screening in HHT adult patients for CAVM, while in the paediatric population, screening could be recommended at six months of age for cerebrospinal localization. These patients should be screened for Pulmonary AVF, which needs to be treated in priority.

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training. Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement. In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers. Electronic supplementary material The online version of this article (10.1186/s13023-018-0850-2) contains supplementary material, which is available to authorized users.