Rare bleeding disorders: Advances in management.

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Hepatic manifestations of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor ß/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.

Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross-sectional population-based study.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc. METHODS: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). RESULTS: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. CONCLUSIONS: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

High risk of ischaemic stroke amongst patients with hereditary haemorrhagic telangiectasia.

BACKGROUND AND PURPOSE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disease with fragile blood vessels and vascular malformations, potentially causing neurological manifestations, including stroke and cerebral abscesses. The study aimed to investigate neurological manifestations in the Danish HHT database, focusing on pulmonary arteriovenous malformations (PAVMs) as a risk factor for cerebral events. METHODS: Retrospective analysis of the Danish HHT database was conducted, cross-referencing neurological outcomes with the Danish Apoplexy Register for accuracy. Patients were stratified by HHT type. Primary outcomes included ischaemic stroke, transient ischaemic attack and cerebral haemorrhage. Secondary outcomes comprised age, age at HHT diagnosis, age at cerebral ischaemic event, and PAVM and cerebral arteriovenous malformation status. RESULTS: Six hundred and sixty-four HHT patients were included. PAVM was diagnosed in 54% of patients, with higher prevalence in HHT type 1 (70%) compared to HHT type 2 (34%) and juvenile polyposis HHT (66%). Ischaemic stroke or transient ischaemic attack occurred in 12.5%, with a higher risk associated with macroscopic PAVM. Logistic regression showed a nearly 10 times increased risk of ischaemic stroke with macroscopic PAVM. Cerebral abscesses occurred in 3.2% of patients, all with macroscopic PAVM. Incomplete PAVM closure increased cerebral abscess risk. CONCLUSION: This study provides valuable insights into the prevalence of neurological manifestations and vascular events in HHT patients. The presence of PAVM was associated with an increased risk of ischaemic stroke, highlighting the importance of early screening and intervention. The findings emphasize the need for comprehensive management strategies targeting both vascular and neurological complications in HHT patients, especially regarding secondary stroke prevention.

Hereditary haemorrhagic telangiectasia: A primer for the paediatrician.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by small telangiectasias and larger multisystem arteriovenous malformations (AVMs). Common sites of AVMs include in the nose, lungs, brain and liver. These lesions are prone to rupture, leading to complications including recurrent epistaxis and significant haemorrhage. Pulmonary hypertension (PH) can also occur. This review presents an update on the genetics, clinical manifestations, management options, and screening recommendations for children with HHT.

Fusion imaging for guidance of pulmonary arteriovenous malformation embolisation with minimal radiation and contrast exposure.

Hereditary haemorrhagic telangiectasia is an inherited disorder characterised by vascular dysplasia that leads to the development of arteriovenous malformations. Pulmonary arteriovenous malformations occur in approximately 30% of patients with haemorrhagic telangiectasia. Given the complex characteristics of haemorrhagic telangiectasia lesions, the application of three-dimensional fusion imaging holds significant promise for procedural guidance and decrease in contrast and radiation dosing. We reviewed all patients who underwent transcatheter approach for pulmonary arteriovenous malformation occlusion with fusion image guidance from June 2018 to September 2023 from a single centre. A total of nine cases with haemorrhagic telangiectasia and transcatheter occlusion of pulmonary arteriovenous malformations using fusion imaging were identified. Five (56%) were male, mean age at procedure was 15.7 years (10-28 years) and mean number of pulmonary arteriovenous malformations intervened was three per patient (1-7). Two of the cases were complex repeat embolisations. The mean fluoroscopy time was 40.6 min (10.7-68.8 min), with mean contrast dose of 28.8 mL (11-60 mL; mean of 0.51 mL/kg) and mean radiation dose of 66.3 mGy (25.6-140 mGy; mean of 40.5 mGy/m2). There were no complications reported during the procedures, with no additional interventions necessary. Fusion imaging in pulmonary arteriovenous malformations embolisation for patients with haemorrhagic telangiectasia is feasible and has the potential to reduce contrast and radiation doses. To our knowledge, we describe the lowest radiation and contrast doses per patient using fusion imaging technology reported in the literature to date.

Telangiectasias, recurrent epistaxis and a strong family history-a case of Osler- Weber-Rendu Syndrome in Pakistan.

Osler-Weber-Rendu syndrome or Hereditary Haemorrhagic Telangiectasia (HHT) is a rare condition, with very few reported cases, especially in Pakistan. As healthcare workers, we encounter multiple cases of recurrent epistaxis in the emergency as well as outpatient departments. However, patients are usually treated symptomatically without a thorough workup. HHT should be considered among the differentials for recurrent epistaxis, as a clinical diagnosis can be made with detailed family history and physical examination. Here is the case of a 58-year-old male who presented to the Gastroenterology OPD, Combined Military Hospital, Lahore, in November 2021, with complaints of generalised weakness and blood in stools. He had a history of recurrent epistaxis and telangiectasias, and further inquiry revealed a strong family history of similar symptoms. He was diagnosed as a case of Osler-Weber- Rendu Syndrome. Informed consent was taken from the patient prior to the writing of the manuscript.

Comparative Treatment of Mucocutaneous Lesions in Hereditary Haemorrhagic Telangiectasia Patients With Dual Sequential Pulsed Dye Laser and Neodymium: Yttrium-Aluminium-Garnet Versus Neodymium: Yttrium-Aluminium-Garnet Laser Alone: A Double-Blind Randomized Controlled Study With Quality-of-Life Evaluation.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. OBJECTIVE: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. METHODS: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. RESULTS: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2-4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2-3; mean 2.61) vs 2 (IQR 2-3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. CONCLUSIONS: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments.

Comparative Treatment of Mucocutaneous Lesions in Hereditary Haemorrhagic Telangiectasia Patients With Dual Sequential Pulsed Dye Laser and Neodymium: Yttrium-Aluminium-Garnet Versus Neodymium: Yttrium-Aluminium-Garnet Laser Alone: A Double-Blind Randomized Controlled Study With Quality-of-Life Evaluation. / [Artículo traducido] Tratamiento comparativo de lesiones mucocutáneas en pacientes con telangiectasia hemorrágica hereditaria con láser dual secuencial de colorante pulsado y neodimio: itrio-aluminio-granate versus neodimio: itrio-aluminio-granate solo: un estudio controlado aleatorizado doble ciego con evaluación de la calidad de vida.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is characterized by the presence of telangiectases and larger arteriovenous malformations in different organs. Mucocutaneous telangiectases can bleed and become an aesthetic concern, impairing quality of life (QoL). However, the best treatment approach has not been defined yet. OBJECTIVE: To evaluate the efficacy and safety of dual wavelength sequential 595/1064nm laser (DWSL) compared to 1064nm laser (Nd:YAG) alone. Secondarily, to evaluate QoL impairment in HHT patients, and its improvement with laser therapy. METHODS: A comparative randomized split-body double-blinded prospective study (DWSL vs Nd:YAG). Demographic, clinical and treatment characteristics were recorded. The severity and degree of improvement were evaluated by three blinded examiners who scored pre-treatment and post-treatment pictures on a 5-point scale. Patients fulfilled Skindex-29 and FACE-Q® tests and assessed procedure-associated pain and patient satisfaction. RESULTS: 111 treatment areas (55 treated with DWSL and 56 with Nd:YAG) from 26 patients were analyzed. The median number of laser sessions was 2 (interquartile range [IQR] 2-4; mean 2.90 vs 2.88, respectively). The median improvement score, irrespective of location, was significantly higher for Nd:YAG compared to DWSL: 3 (IQR 2-3; mean 2.61) vs 2 (IQR 2-3; mean 2.32), p=0.031. Both FACE-Q index and Skindex-29 test results improved significantly (p<0.001), and 92.4% patients reported a high degree of satisfaction (≥8). No severe adverse events were reported. CONCLUSIONS: DWSL and Nd:YAG laser are convenient, safe and effective treatment options for mucocutaneous telangiectases in HHT patients. However, Nd:YAG delivered better results with better tolerability. QoL was significantly improved by both treatments.

Executive summary of the 14th HHT international scientific conference.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2nd, 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

Obstetrical and neonatal complications in hereditary haemorrhagic telangiectasia: A retrospective study.

OBJECTIVE: To retrospectively describe a large series of pregnancies in women with hereditary haemorrhagic telangiectasia followed in our reference centre, plus neonatal outcomes, to better understand the risks of complications and to improve their prevention. DESIGN: A retrospective descriptive study conducted through a phone questionnaire. SETTING: Reference centre for hereditary haemorrhagic telangiectasia in Lyon, France. POPULATION: Women meeting the following criteria: (1) alive and aged ≥18 years; (2) with a definite clinical and/or genetic diagnosis of hereditary haemorrhagic telangiectasia; and (3) with at least one full-term pregnancy. MAIN OUTCOME MEASURES: Maternal and perinatal outcomes of pregnancies in women with hereditary haemorrhagic telangiectasia. RESULTS: Five hundred and sixty-two pregnancies were reported in 207 women with hereditary haemorrhagic telangiectasia. A total of 271 complications (48.2%) were registered. Of these, 149 (55%) non-specific complications, 110 (40.6%) non-severe specific complications and 12 (4.4%) severe specific complications were registered. There were four cases of haemoptysis and two cases of transient ischaemic attack related to pulmonary arteriovenous malformations. Four patients had severe decompensated dyspnoea, related to pulmonary arteriovenous malformations in three cases and to pulmonary arteriovenous malformations associated with severe hepatic arteriovenous malformations in one case. Hepatobiliary necrosis occurred in one case. Epidural or spinal anaesthesia was performed in 139 of 452 deliveries (31%), without complications. There were 12 reports of congenital anomalies in 461 live births (3%). CONCLUSIONS: Most pregnancies in hereditary haemorrhagic telangiectasia women are uneventful; complications are rare but can be severe. Women thus need to be educated about screening and possible pregnancy-related risks before becoming pregnant.

Hereditary haemorrhagic telangiectasia and SMAD4 mutation in a patient with complex single ventricle heart disease.

We report a case of hypoplastic left heart syndrome and with subsequent aortopathy and then found to have hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome due to a germline SMAD4 pathologic variant. The patient's staged palliation was complicated by the development of neoaortic aneurysms, arteriovenous malformations, and gastrointestinal bleeding thought to be secondary to Fontan circulation, but workup revealed a SMAD4 variant consistent with hereditary haemorrhagic telangiectasia/juvenile polyposis syndrome. This case underscores the importance of genetic modifiers in CHD, especially those with Fontan physiology.

Management of pulmonary arteriovenous malformations involves additional factors aside from the diameter of feeding arteries: a 3-year case-case retrospective analysis.

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) are rare but cause various manifestations. Although the diameter of feeding arteries has been linked to treatment decisions, relationships among the characteristics of PAVMs, clinical symptoms, and treatment effect remain unclear. The present study was performed to investigate how collective characteristics of PAVMs relate to clinical symptoms and to provide proper treatment recommendations for patients with PAVMs. METHODS: We retrospectively analysed 838,447 patients' radiographic data and medical records from January 2018 to December 2020. Patients were included if a PAVM was radiographically detected for the first time in our hospital. Ordered multivariable logistic regression and hierarchical multiple regression were performed to analyse the relationships between characteristics of PAVMs and various clinical symptoms. We investigated the management of PAVMs in four tertiary university hospitals. RESULTS: Detection rate of PAVMs was 0.025% (207/838,447), and 37.6% of patients (78/207) also had hereditary haemorrhagic telangiectasia. Eight patients were diagnosed with bilateral diffuse PAVMs. Two hundred thirty-six lesions were detected in 199 patients, and the mean diameter of the feeding artery was 4.13 ± 1.92 mm. Most PAVMs were the simple type and located in the peripheral pulmonary area. In total, 34.3% of patients (71/207) were symptom-free; remaining patients showed various manifestations, and respiratory symptoms were most common (dyspnoea on exertion, 47.8%). The diameter of the feeding artery and the type and the number of PAVMs were correlated with hypoxaemia (P < 0.001, P < 0.001, and P = 0.037, respectively). The collective characteristics of PAVMs were not related to the severity of central nervous system symptoms (largest diameter of feeding artery, P = 0.8; largest diameter of sac, P = 0.42; number of PAVMs, P = 0.35; type of PAVMs, P = 0.99). Various symptoms were greatly relieved after treatment. The hospital investigation showed that management of PAVMs was not generally appreciated in clinical practice. CONCLUSIONS: Our study revealed a low detection rate of PAVMs and a low degree of association with hereditary haemorrhagic telangiectasia in the general population. Considering the connection between collective characteristics of PAVMs and various clinical symptoms, clinicians should consider the type and number of PAVMs, the largest diameter of the feeding artery, and clinical symptoms when managing patients with PAVMs.

Management of epistaxis in hereditary haemorrhagic telangiectasia (HHT) patients using pulsed dye laser and the effect of withholding treatment during the COVID pandemic.

Using a patient survey, pulsed dye laser (PDL) treatment of epistaxis for hereditary haemorrhagic telangiectasia (HHT) patients was evaluated after initial referral. Subsequently, due to the COVID pandemic, a natural experimental set-up allowed assessment of an enforced withdrawal of treatment. A total of 34 subjects were identified as undergoing PDL for HHT-related epistaxis. They were surveyed to look at the effectiveness of PDL treatment after initial referral and at the effect of delay to treatment during COVID on epistaxis and the associated quality of life. The survey also examined the comparison to other available treatments. Retrospective pre-COVID Epistaxis Severity Scores (ESS) were compared to post-COVID data to assess the effect of treatment withdrawal. The patients were then followed up after resumption of their treatment to assess the ensuing change in ESS. After initial referral, frequency and severity of epistaxis decreased. Fifty-six percent of patients experienced several bleeds per day before treatment, compared to 12% after. 88% of patients had episodes of epistaxis longer than 5 min, which was halved to 44% after treatment. Average ESS pre-COVID was 4.42 compared to 5.43 post-COVID delay, with a significant statistical difference (p = 0.02). On resumption of treatment, average ESS reduced to below pre-COVID levels at 4.39 after only 2 sessions. Seventy-six percent of patients found that withdrawal of PDL during COVID diminished their quality of life. PDL treatment of nasal mucosal telangiectasia reduces the frequency and duration of epistaxis. The ESS is reduced following treatment with PDL and quality of life subjectively improved.

An update on the ophthalmic features in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary haemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber syndrome is a rare autosomal dominant disease, characterised by systemic angiodysplasia. Dysfunction of the signalling pathway of ß transforming growth factor is the main cause of HHT principally owing to mutations of the genes encoding for endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1). Clinical manifestations can range from mucocutaneous telangiectasia to organ arterio-venous malformations and recurrent epistaxis. The early clinical manifestations may sometimes be subtle, and diagnosis may be delayed. The main ophthalmic manifestations historically reported in HHT are haemorrhagic epiphora, and conjunctival telangiectasia present in 45-65% of cases, however, imaging with wide-field fluorescein angiography has recently shown peripheral retinal telangiectasia in 83% of patients. Optimal management of HHT requires both understanding of the clinical presentations and detection of early signs of disease. Advances in imaging methods in ophthalmology such as wide-field fluorescein angiography, spectral domain optical coherence tomography, and near infrared reflectance promise further insight into the ophthalmic signs of HHT towards improved diagnosis and early management of possible severe complications.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) Part I. Pathophysiology, clinical symptoms and recommend screening for vascular malformations.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes abnormal blood vessel formation. Patients with HHT may have telangiectasias and later may develop arteriovenous malformations in various organs. Pacients suffer from many complications caused by the malformations and therefore by patients with HHT must by performed screening of this arteriovenous malformations. Optimal treatment of this malformations is best delivered throught a multidisciplinary approach. Farmacological treatment is described in next paper.

Arterial endoglin does not protect against arteriovenous malformations.

INTRODUCTION: Endoglin (ENG) forms a receptor complex with ALK1 in endothelial cells (ECs) to promote BMP9/10 signalling. Loss of function mutations in either ENG or ALK1 genes lead to the inherited vascular disorder hereditary haemorrhagic telangiectasia (HHT), characterised by arteriovenous malformations (AVMs). However, the vessel-specific role of ENG and ALK1 proteins in protecting against AVMs is unclear. For example, AVMs have been described to initiate in arterioles, whereas ENG is predominantly expressed in venous ECs. To investigate whether ENG has any arterial involvement in protecting against AVM formation, we specifically depleted the Eng gene in venous and capillary endothelium whilst maintaining arterial expression, and investigated how this affected the incidence and location of AVMs in comparison with pan-endothelial Eng knockdown. METHODS: Using the mouse neonatal retinal model of angiogenesis, we first established the earliest time point at which Apj-Cre-ERT2 activity was present in venous and capillary ECs but absent from arterial ECs. We then compared the incidence of AVMs following pan-endothelial or venous/capillary-specific ENG knockout. RESULTS: Activation of Apj-Cre-ERT2 with tamoxifen from postnatal day (P) 5 ensured preservation of arterial ENG protein expression. Specific loss of ENG expression in ECs of veins and capillaries led to retinal AVMs at a similar frequency to pan-endothelial loss of ENG. AVMs occurred in the proximal as well as the distal part of the retina consistent with a defect in vascular remodelling during maturation of the vasculature. CONCLUSION: Expression of ENG is not required in arterial ECs to protect against AVM formation.

An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia.

INTRODUCTION: Systemic bevacizumab is a novel targeted therapy for severe epistaxis and chronic gastrointestinal bleeding in hereditary haemorrhagic telangiectasia (HHT), but published data are very limited. AIM: We conducted a survey-based study to characterize current treatment practices and physician-reported safety and effectiveness of systemic bevacizumab for bleeding in (HHT). METHODS: A 27-item survey was sent to physician centre directors of 31 International HHT Centers of Excellence. RESULTS: Response rate was 84%. Approximately half of centres had treated >10 HHT patients with systemic bevacizumab for chronic bleeding for a total of 291 patients treated. All centres utilize a 5 mg/kg dose for induction treatment and most administer six doses (range, 4-8) every 2 weeks. However, maintenance regimens varied considerably between centres. Bevacizumab was highly effective, with 86% reporting significant (>50%) improvement in GI bleeding and/or epistaxis and haemoglobin rise in most patients treated with bevacizumab; 52% reported haemoglobin normalization in most patients. All centres reported adverse event rates <30% and two-thirds of centres reported adverse event rates <10%. Discontinuation for adverse events or inefficacy was rare. Bleeding severity thresholds for initiation of bevacizumab were highly variable, and it is typically administered by haematologists (76% of centres). Two-thirds of centres reported obtaining insurance approval for bevacizumab for most or all patients but 48% reported difficulty in obtaining coverage. CONCLUSION: Systemic bevacizumab is widely used to treat bleeding in HHT with excellent physician-reported effectiveness and safety. There is considerable variation in maintenance treatment practices and thresholds for initiation of bevacizumab among HHT centres.

Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a rare hereditary multisystem vascular disorder causing visceral arteriovenous malformations and mucocutaneous bleeding. Chronic gastrointestinal bleeding and epistaxis often produce profound anaemia refractory to conventional treatment. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, may be effective in treatment of bleeding in HHT. METHODS: All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data collected included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, adverse events, haemoglobin, red cell transfusions, intravenous iron infusions, and other anaemia and/or bleeding-directed therapies. RESULTS: Thirteen HHT patients were treated with bevacizumab for a median of 13.9 (range 4.9-30.1) months. Compared with pretreatment values, bevacizumab treatment increased the mean haemoglobin by 4.0 g dL-1 (95% CI, 2.6-5.3 g dL-1 ) [mean (95% CI) haemoglobin 8.5 (7.8, 9.9) g dL-1 vs. 12.5 (11.2, 13.7) g dL-1 , P < 0.001)], reduced red cell units transfused by 92% [median of 6 (range 0-59) units vs. 0 (range 0-15) units, P = 0.004] and reduced quantity of iron infused by 73% [mean (95% CI) 462 (257, 668) mg month-1 vs. 126 (75, 178) mg month-1 , P = 0.002]. Epistaxis control was achieved in 85% with bevacizumab versus 0% before treatment (P < 0.001). No patient required nasal or GI procedures during the maintenance period. Two patients (15%) developed grade 3 hypertension requiring medical management. CONCLUSION: Systemic bevacizumab was highly effective to treat chronic bleeding in HHT. Further study is needed to confirm the magnitude of benefit and further define optimal dosing, treatment duration and long-term safety.

Hereditary haemorrhagic telangiectasia with multiple complications presenting in an older patient.

Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant multi-organ vascular disorder associated with bleeding and a reduced life expectancy. We present a 91-year-old woman with complications of previously undiagnosed HHT. This case demonstrates three potential complications: pulmonary arteriovenous malformation (AVM) resulting in a right to left shunt, cerebral infarctions and pericardial effusion. Despite these potentially life-threatening complications and the reduced life-expectancy associated with HHT the patient has survived to an advanced age. Due to the patient's late diagnosis and frailty, the treatment options of AVM embolization and pericardiocentesis were deemed inappropriate. The patient was treated with tranexamic acid to reduce bleeding severity and discharged home with a care package and home oxygen.