Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous (i.v.) delivery of soluble Feline McDonough Sarcoma (FMS)-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84, and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1f/f mice through i.v. followed by bAVM induction. Transduced cells in organs, vessel density, abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain endothelial cells (ECs) and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. The delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by telangiectases, which cause nasal and gastrointestinal (GI) bleeding, and visceral arteriovenous malformations. Since 2012 bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has been a promising treatment for HHT-related bleeding and was evaluated in the phase II BABH study.

To follow and describe evolution and treatments of patients with HHT post-BABH study.

This study is a 1-year, multi-centre descriptive study.

We collected clinical (nose and GI bleeding, red blood cell transfusions) and biological (haemoglobin and ferritin levels) data and treatment information.

Of 22 patients included across 4 centers, 15 received bevacizumab. Among them, 12 (86%) had a >50% decrease in the number of RBC units transfused 3 months post-treatment. Mean haemoglobin levels increased from 83.08 to 105.98 g/L.

Bevacizumab effectively reduces RBC transfusions and is efficient for treating severe bleeding in patients with HHT.

This trial was registered with the ClinicalTrials.gov Identifier #NCT06039124.

The evidence-based recommendation for the use of systemic bevacizumab to treat refractory epistaxis in hereditary hemorrhagic telangiectasia (HHT) is based on limited and historical data. An updated synthesis of the available literature is warranted.

A systematic review and meta-analysis were conducted using PRISMA guidelines to evaluate the use of systemic bevacizumab for HHT-related epistaxis. A search was conducted using three databases up to September 2024 for studies assessing the effect of systemic bevacizumab use on epistaxis outcomes in HHT. Outcome measures included epistaxis severity score (ESS), hemoglobin, red blood cell (RBC), and iron transfusion requirements and adverse effects. Random effects meta-analysis was performed for change in ESS (ΔESS) and change in hemoglobin (ΔHb). Literature quality was assessed using the Joanne Briggs Institute critical appraisal tools.

A total of 10 studies with 225 total patients were included. Systemic bevacizumab was associated with a significant posttreatment reduction in mean ESS of -3.33 (95% CI -3.62 to -3.03) and a significant increase in mean Hb of 2.38 g/dL (95% CI 1.45-3.30) compared to pretreatment. All cohort studies found a significant reduction in RBC and iron transfusions following systemic bevacizumab treatment. The most frequently reported adverse effect of systemic bevacizumab was hypertension.

Systemic bevacizumab is associated with significant improvements in epistaxis severity, hemoglobin, and transfusion requirements in HHT-related epistaxis. Adequately powered studies are required to strengthen this finding. Patient selection criteria, standardized maintenance dosing, and long-term treatment data require further study.

Bleeding in the gastrointestinal tract in patients with von Willebrand disease continues to pose a therapeutic challenge for clinicians. It is associated with significant morbidity and mortality and represents the major unmet need in this disease. Defective angiogenesis in the gut is primarily responsible, resulting in angiodysplastic malformations making bleeding notoriously refractory to standard replacement therapy. A substantial body of evidence now shows that von Willebrand factor has a role in the regulation of angiogenesis but the mechanisms responsible for the formation of vascular malformations remain incompletely understood. Data from the wider field of vascular malformations may lend insight and point to novel therapeutic approaches. Here we review evidence linking von Willebrand factor to angiodysplasia, the associated molecular mechanisms and the implications for therapy.

Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder characterised by epistaxis, mucocutaneous telangiectasias and arteriovenous malformations. Iron deficiency due to chronic bleeding events is a common manifestation that produces a range of nonspecific symptoms. We report on a patient with HHT with longstanding fatigue and exercise intolerance, which was persistently attributed to iron deficiency, who was revealed to have glycogen storage disease type V, an autosomal recessive metabolic myopathy caused by deficiency of myophosphorylase due to PYGM variants. Genetic testing revealed a pathogenic common exon mutation of one allele and a pathogenic intronic mutation of the other, possibly suggestive of a milder phenotype. We not only detail the first case of concurrent HHT and glycogen storage disease in the literature but more importantly emphasise the need for clinician awareness of the disorders to avoid perpetuating a biased clinical impression and delay in diagnosis as well as prevent potentially harmful interventions.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal multi-systemic vascular dysplasia caused by gene mutations that lead to recurrent epistaxis and other serious complications including mucocutaneous telangiectasias, gastrointestinal bleeding, and arteriovenous malformations. Treatment is limited to symptomatic relief with no approved standard therapy. Bevacizumab is a monoclonal antibody used primarily in treating metastatic malignancies and ophthalmology. Several studies have shown that bevacizumab is effective in the treatment of HHT-related epistaxis with a high safety profile.

This systematic review and network meta-analysis aims to explore the efficacy and safety of bevacizumab in the treatment of HHT epistaxis.

A comprehensive literature search was done in many databases, including PubMed, Web of Science, Scopus, and the Cochrane Library. We conducted our network meta-analysis using R version 4.2.2 and R Studio version 2022.07.2. Dichotomous data was analyzed as risk ratio and 95% confidence interval and continuous data as mean difference and 95% confidence interval.

We included four randomized clinical trials in our network meta-analysis. Different doses of bevacizumab failed to yield any statistically significant difference in reducing the epistaxis severity score, the number of epistaxis episodes, the duration of epistaxis, or improving hemoglobin levels compared to placebo or other comparators. The pooled effect sizes for all outcomes were homogenous.

Bevacizumab failed to show any significant difference compared to tranexamic acid, estriol, or placebo. These findings underscore the challenges in addressing HHT-related symptoms and highlight the ongoing need for innovative and more effective interventions.

Hereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations, commonly presenting with epistaxis and gastrointestinal (GI) bleeding. Bleeding symptoms may be difficult to manage and may become life-threatening, with many patients developing dependence on parenteral iron and/or blood transfusion. There is a growing body of evidence that antiangiogenic therapies may be effective in management of bleeding symptoms, presumably targeting pathogenic HHT pathways such as vascular endothelial growth factor receptor.

To report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptors, in 6 patients with HHT-associated epistaxis and/or GI bleeding.

A retrospective observational analysis was performed to assess the safety/efficacy of pazopanib use in patients with confirmed HHT-associated epistaxis and/or GI bleeding between January 1, 2019, and June 14, 2023. The Indiana Hemophilia and Thrombosis institutional electronic medical record was queried for HHT patients who were treated with pazopanib for ≥3 months. Patient data were obtained from patient documentation, physician/nursing notes, and on-call documentation. Institutional review board approval was obtained for data pull as an exempt study.

Our observations on the real-world use of pazopanib in 6 HHT patients with moderate-to-severe bleeding showed improvement in hemoglobin levels, with reduction in iron infusions and red blood cell transfusion requirement.

Pazopanib may be a reasonable option for patients with HHT with epistaxis or gastrointestinal bleeding that are refractory to standard treatment.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder with highly variable penetrance, affecting up to 1 in 5,000 individuals. It is characterized by the presence of abnormal blood vessels that can lead to excessive bleeding-most frequently recurrent nosebleeds (epistaxis), skin and mucosal telangiectasias (small, dilated blood vessels), as well as arteriovenous malformations (AVMs) that can form in various organs, particularly the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway, an important mediator of vascular quiescence. HHT possesses significant challenges for affected individuals, as the complications can range from mild to life-threatening events, depending on the severity and location of the vascular abnormalities. Despite this bleeding disorder being not uncommon, nowadays no specific treatment is as yet available for HHT and most current therapies include repurposed drugs. The aim of this review was to show therapeutic advances on the basis of recent promising clinical trials for HHT.

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway. Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT. In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs (causing high cardiac output). Children usually experience isolated epistaxis; in rare cases, childhood complications occur from large AVMs in the lungs or central nervous system. Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. Novel therapeutics, such as systemic antiangiogenic therapies, are actively being investigated. Although HHT is associated with increased morbidity, the appropriate screening and treatment of visceral AVMs, and the effective management of bleeding and anaemia, improves quality of life and overall survival.

Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disorder characterized by refractory recurrent epistaxis and gastrointestinal bleeding. Recent studies have reported the hemostatic effects of tyrosine kinase inhibitors on HHT-related bleeding. A 67-year-old man with HHT underwent laparoscopic radical nephrectomy for right renal cell carcinoma discovered during an investigation of anemia. Five years after surgery, pancreatic metastasis with biliary dilatation was found on computed tomography. After a biliary stent was inserted, the patient was treated with cabozantinib plus nivolumab. His hemoglobin level significantly improved from 4.8 g/dL to a maximum of 14.7 g/dL, and transfusion frequency reduced from five to one per 5 months. Despite tumor reduction after 6 months of treatment, the patient developed acute cholangitis because of biliary hemorrhage, which ultimately resulted in hepatic failure and death. This case is the first to indicate the potential of the tyrosine kinase inhibitor cabozantinib to control bleeding and tumor progression in patients with metastatic renal cell carcinoma with HHT-related bleeding.

Epistaxis greatly affects patients with hereditary hemorrhagic telangiectasia (HHT). Although few systemic treatment exist, nintedanib, is a good candidate thanks to its anti-angiogenic activity. Our main objective was to evaluate the efficacy of oral nintedanib on epistaxis duration in HHT patients with moderate to severe epistaxis. This multicenter phase 2 randomized, placebo-controlled, double-blind trial was conducted between June 2020 and February 2023. Inclusion criteria were being over 18 years old and having a confirmed HHT diagnosis with an epistaxis severity score greater than 4. Sixty patients were randomized to receive either nintedanib or placebo for 12 weeks with a 12 week follow-up. The primary endpoint was the proportion of patients achieving a reduction of at least 50% in mean monthly epistaxis duration comparing the 8 weeks before treatment to the last 8 weeks of treatment. Main secondary outcomes included monthly duration and frequency of epistaxis and hemoglobin levels. Of the 60 randomized patients, 56 completed the trial. Thirteen patients (43%) in the nintedanib group vs 8 (27%) in the placebo group met the primary endpoint (p = 0.28). We observed a significant decrease in median epistaxis (57% vs 27%, p = 0.013) and a significant increase in median hemoglobin levels (+ 18 vs - 1 g/L, p = 0.02) in the nintedanib vs the placebo group. Although we did not achieve our primary outcome, we observed a significant reduction in epistaxis duration and a significant increase in hemoglobin levels in patients treated with nintedanib. This supports the efficacy of nintedanib, and further studies are needed.

A 64-year-old woman with hereditary hemorrhagic telangiectasia (HHT) characterized by a pathological variant in ACVRL1 presents to the clinic for follow-up. Manifestations of HHT include frequent epistaxis and gastrointestinal bleeding, leading to iron-deficiency anemia. Bevacizumab is initiated, with resolution of the anemia. While maintained on a regimen of bevacizumab every 6 weeks, she continues to report frequent epistaxis and has ongoing iron-deficiency requiring periodic iron infusions. She also finds the bevacizumab infusions inconvenient. She is interested in discussing other options for managing her disease.

The last 2 decades of genetic discovery in the field of vascular anomalies have brought targeted medical therapies to the forefront of care patients with vascular anomalies and have broadened the role of hematologists/oncologists in this field. Many vascular anomalies have now been identified to be driven by somatic gain-of-function variants in the PI3K/AKT/ mTOR and Ras/MAPK intracellular signaling pathways. This has led to the introduction of various antiangiogenic agents that inhibit these pathways. Knowledge of the indications for and the safe administration of these agents in patients with vascular anomalies is now a crucial part of training for hematologists/oncologists.

To provide detailed guidance on the administration of systemic bevacizumab in patients with recurrent respiratory papillomatosis (RRP) based on a detailed review of the scientific literature and a consensus of experts with real-world clinical experience.

A bevacizumab consensus working group (N = 10) was composed of adult and pediatric otolaryngologists, adult and pediatric oncologists, and a representative from the RRP Foundation (RRPF), all with experience administering systemic bevacizumab in patients with RRP. After extensive review of the medical literature, a modified Delphi method-based survey series was utilized to establish consensus on the following key areas: clinical and patient characteristics ideal for treatment candidacy, patient perspective in treatment decisions, treatment access, initial dosing, monitoring, guidelines for tapering and discontinuation, and reintensifying therapy.

Seventy-nine statements were identified across nine critical domains, and 45 reached consensus [clinical benefits of bevacizumab (3), patient and disease characteristics for treatment consideration (7), contraindications for treatment (3), shared decision-making (incorporating the patient perspective) (5), treatment access (3), initial dosing and administration (8), monitoring (7), tapering and discontinuation (6), and reintensification (3)].

This consensus statement provides the necessary guidance for clinicians to initiate systemic administration of bevacizumab and represents a potential paradigm shift toward nonsurgical treatment options for patients with RRP.

5 Laryngoscope, 134:5041-5046, 2024.

Hereditary hemorrhagic telangiectasia (HHT) diagnostic and management approach for pediatrics underwent significant advances over the last couple of years.

In 2020, new guidelines for HHT were published that included a pediatric section thus attracting special focus into the childhood presentation.

Curacao criteria are specific, but not sensitive enough in children. Genetic testing is encouraged for all family members even if asymptomatic. Standardized scoring for epistaxis is strongly encouraged, as it allows monitoring and can stratify therapeutic approaches. Early screening for pulmonary and brain visceral arteriovenous malformations (AVMs) in pediatric patients with confirmed genetic alterations of HHT should be instituted. Graded trans-esophageal echocardiogram with agitated saline contrast can be used as screening method for pulmonary AVMs. As pulmonary AVMs can develop throughout lifetime, guidelines recommend repeated screening even in asymptomatic patients at least every 5 years. Signs of stroke in childhood are more subtle than in adults. Cerebral imaging in early childhood can identify brain AVMs that may benefit from early intervention. Embolization of high-risk pulmonary and cerebral AVMs should be performed at specialized centers even at pediatric age. One or two classic HHT telangiectasia can be considered diagnostic in children. Antibiotic prophylaxis with dental procedures continues to be recommended.

Increased endothelial cell proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Here, we report a cyclin-dependent kinase 6 (CDK6)-driven mechanism of cell cycle deregulation involved in endothelial cell proliferation and HHT pathology. Specifically, endothelial cells from the livers of HHT mice bypassed the G1/S checkpoint and progressed through the cell cycle at an accelerated pace. Phosphorylated retinoblastoma (pRB1)-a marker of G1/S transition through the restriction point-accumulated in endothelial cells from retinal AVMs of HHT mice and endothelial cells from skin telangiectasia samples from HHT patients. Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and liver, and slowed cell cycle progression in endothelial cells and endothelial cell proliferation. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT.

Vascular malformations, which arise from anomalies in angiogenesis, encompass capillary, lymphatic, venous, arteriovenous, and mixed malformations, each affecting specific vessel types. Historically, therapeutic options such as sclerotherapy and surgery have shown limited efficacy in complicated malformations. Most vascular malformations stem from hereditary or somatic mutations akin to oncogenic alterations, activating the PI3K-AKT-mTOR, RAS-MAPK-ERK, and G-protein coupled receptor pathways. Recognizing the parallels with oncogenic mutations, we emphasize the potential of targeted molecular inhibitors in the treatment of vascular malformations by repurposing anticancer drugs. This review delves into the recent development and future use of such agents for the management of slow- and fast-flow vascular malformations, including in more specific situations, such as prenatal treatment and the management of associated coagulopathies.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant, multisystem disorder that manifests with a spectrum of disease including cardiopulmonary complications. HHT is characterised by aberrant signalling via the transforming growth factor β (TGFβ) pathway, with loss of vascular integrity, angiogenesis and vascular dysplasia. The disease has an estimated prevalence of 1 in 5000 persons and the penetrance increases with increasing age. HHT commonly presents with epistaxis and telangiectasia, while visceral arteriovenous malformations are not uncommon. Mutations in the ENG, ACVRL1 and MADH4 genes account for 97% of all HHT cases, and it is recommended that genetic tests are used in combination with the clinical Curaçao criteria to confirm the diagnosis. HHT can be complicated by significant pulmonary vascular disease including pulmonary arteriovenous malformations, pulmonary arterial hypertension and high output cardiac failure. These are associated with substantial morbidity and mortality and therefore timely diagnosis is important to mitigate complications and optimise preventative strategies. This article outlines important advances in our understanding of the pathobiology of HHT and current recommendations regarding the diagnosis and screening of HHT with a specific focus on adult patients with pulmonary vascular disease. Important therapeutic advances, novel therapies on the horizon and unmet needs are also explored.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life.

We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations).

The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash.

Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Hereditary hemorrhagic telangiectasia (HHT, Rendu- Osler-Weber disease, or Osler's disease for short) is a systemic disease that can severely impair the quality of life and that requires interdisciplinary treatment. Among rare diseases, it is relatively common, with a prevalence of approximately 1/5000.

This review is based on publications retrieved by a selective literature search, including the two international guidelines on clinically relevant aspects of HHT.

On average, about two decades elapse between the initial symptoms and the diagnosis of HHT. 95% of patients have nosebleeds; these usually begin before age 20 but can occur at any time, from infancy to old age. The diagnosis is usually made on clinical grounds on the basis of the characteristic telangiectases, a positive family history, and possible involvement of the gastrointestinal tract, lungs, liver, and brain. Nosebleeds can sometimes be reduced by outpatient measures including counseling on keeping the nose moist (expert consensus), self-application of a nasal packing (which improves the quality of life, according to an online survey), and the prescription of tranexamic acid (reduction of nosebleeds from 17.3% [5.5; 27.6] to 54%). In particular, screening (expert consensus) for pulmonary vascular malformations (frequency 10-50%) can prevent many adverse outcomes. If pulmonary vascular malformations cannot be ruled out, antibiotic prophylaxis is recommended before medical procedures that can cause bacteremia (expert consensus).

Broad awareness of the condition, early diagnosis, and interdisciplinary treatment improve the quality of life and ultimate outcome of persons with HHT. Nevertheless, there are few options supported by good evidence for the appropriate treatment of this rare, often serious disease..

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 β/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.

Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) affects 1 in 5000 persons, making it the second most common inherited bleeding disorder worldwide. Telangiectatic bleeding, primarily causing recurrent epistaxis and chronic gastrointestinal bleeding, is the most common and most important manifestation of this multisystem vascular disorder. HHT-associated bleeding results in substantial psychosocial morbidity and iron deficiency anemia that may be severe. Although there remain no regulatory agency-approved therapies for HHT, multiple large studies, including randomized controlled trials, have demonstrated the safety and efficacy of antifibrinolytics for mild-to-moderate bleeding manifestations and systemic antiangiogenic drugs including pomalidomide and bevacizumab for moderate-to-severe bleeding. This has led to a recent paradigm shift away from repetitive temporizing procedural management toward effective systemic medical therapeutics to treat bleeding in HHT. In this article, 4 patient cases are used to illustrate the most common and most challenging presentations of HHT-associated bleeding that hematologists are likely to encounter in daily practice. Built on a framework of published data and supported by extensive clinical experience, guidance is given for modern evidence-based approaches to antifibrinolytic therapy, antiangiogenic therapy, and iron deficiency anemia management across the HHT disease severity spectrum.

Hereditary hemorrhagic telangiectasia (HHT) is the second-most common inherited bleeding disorder (BD) worldwide and remains without approved therapies. HHT causes serious mucosal bleeding resulting in severe iron-deficiency anemia, major psychosocial complications, and visceral arteriovenous malformations in the brain, lung, and liver, which can cause life-threatening hemorrhagic complications. No study has examined the relative morbidity of HHT and von Willebrand disease (VWD), which is the most common inherited BD in women. We performed an observational cohort study of women with HHT or VWD, comparing a representative sample of 100 randomly selected women with HHT to 100 randomly selected age-matched women with VWD. In HHT vs VWD, recurrent epistaxis and gastrointestinal bleeding were more likely (odds ratio [OR], 32.73 [95% confidence interval, 13.81-71.80]; P < .0001 and 5.69 [2.59-12.89]; P < .0001) and heavy menstrual bleeding was less likely (OR, 0.32 [0.18-0.57]; P < .0001). Iron-deficiency anemia was significantly more likely, and the lowest hemoglobin was significantly lower in HHT than in VWD. The odds of iron infusion dependence, requirement for red cell transfusion, and hemostatic surgical procedures were significantly higher-17-fold, threefold, and eightfold higher, respectively-and hospital admissions to manage disease complications were both ∼14 times more frequent in women with HHT vs those with VWD. In conclusion, much higher disease-related morbidity, mortality, and health care use were observed in women with HHT vs VWD, providing evidence that HHT may be the most clinically significant inherited BD in women. Given the vast gap in research funding for HHT compared with both hemophilia (a disease primarily of men) and VWD, these findings have significant implications for gender equity in hematology.

Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1 f/f mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1 f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.

No US Food and Drug Administration- or European Medicines Agency-approved therapies exist for bleeding due to hereditary hemorrhagic telangiectasia (HHT), the second-most common inherited bleeding disorder worldwide. The current standard of care (SOC) includes iron and red cell supplementation, alongside the necessary hemostatic procedures, none of which target underlying disease pathogenesis. Recent evidence has demonstrated that bleeding pathophysiology is amenable to systemic antiangiogenic therapy with the anti-vascular endothelial growth factor bevacizumab. Despite its high cost, the addition of longitudinal bevacizumab to the current SOC may reduce overall health care resource use and improve patient quality of life. We conducted, to our knowledge, the first cost-effectiveness analysis of IV bevacizumab in patients with HHT with the moderate-to-severe phenotype, comparing bevacizumab added to SOC vs SOC alone. The primary outcome was the incremental net monetary benefit (iNMB) reported over a lifetime time horizon and across accepted willingness-to-pay thresholds, in US dollar per quality-adjusted life year (QALY). Bevacizumab therapy accrued 9.3 QALYs while generating $428 000 in costs, compared with 8.3 QALYs and $699 000 in costs accrued in the SOC strategy. The iNMB of bevacizumab therapy vs the SOC was $433 000. No parameter variation and no scenario analysis, including choice of iron supplementation product, changed the outcome of bevacizumab being a cost-saving strategy. Bevacizumab therapy also saved patients an average of 133 hours spent receiving HHT-specific care per year of life. In probabilistic sensitivity analysis, bevacizumab was favored in 100% of all 10 000 Monte Carlo iterations across base-case and all scenario analyses. Bevacizumab should be considered for more favorable formulary placement in the care of patients with moderate-to-severe HHT.

For monogenic diseases caused by pathogenic loss-of-function DNA variants, attention focuses on dysregulated gene-specific pathways, usually considering molecular subtypes together within causal genes. To better understand phenotypic variability in hereditary hemorrhagic telangiectasia (HHT), we subcategorized pathogenic DNA variants in ENG/endoglin, ACVRL1/ALK1, and SMAD4 if they generated premature termination codons (PTCs) subject to nonsense-mediated decay. In 3 patient cohorts, a PTC-based classification system explained some previously puzzling hemorrhage variability. In blood outgrowth endothelial cells (BOECs) derived from patients with ACVRL1+/PTC, ENG+/PTC, and SMAD4+/PTC genotypes, PTC-containing RNA transcripts persisted at low levels (8%-23% expected, varying between replicate cultures); genes differentially expressed to Bonferroni P < .05 in HHT+/PTC BOECs clustered significantly only to generic protein terms (isopeptide-bond/ubiquitin-like conjugation) and pulse-chase experiments detected subtle protein maturation differences but no evidence for PTC-truncated protein. BOECs displaying highest PTC persistence were discriminated in unsupervised hierarchical clustering of near-invariant housekeeper genes, with patterns compatible with higher cellular stress in BOECs with >11% PTC persistence. To test directionality, we used a HeLa reporter system to detect induction of activating transcription factor 4 (ATF4), which controls expression of stress-adaptive genes, and showed that ENG Q436X but not ENG R93X directly induced ATF4. AlphaFold accurately modeled relevant ENG domains, with AlphaMissense suggesting that readthrough substitutions would be benign for ENG R93X and other less rare ENG nonsense variants but more damaging for Q436X. We conclude that PTCs should be distinguished from other loss-of-function variants, PTC transcript levels increase in stressed cells, and readthrough proteins and mechanisms provide promising research avenues.

Mid-gastrointestinal bleeding accounts for approximately 5%-10% of all gastrointestinal bleeding cases, and vascular lesions represent the most frequent cause. The rebleeding rate for these lesions is quite high (about 42%). We hereby recommend that scheduled outpatient management of these patients could reduce the risk of rebleeding episodes.

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.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a rare autosomal dominant disorder characterized by vascular malformations. This comprehensive review aimed to provide an overview and summarize various aspects of HHT, including the genetic abnormalities, complications associated with visceral arteriovenous malformations (AVMs), prognosis of HHT, quality of life (QOL), and treatment of epistaxis. In addition, this review highlights the challenges in diagnosing HHT and emphasizes the critical role of otolaryngologists in the early detection of HHT. Otolaryngologists can refer patients with refractory epistaxis for AVM screening to expedite intervention. Mutation of the genes involved in the transforming growth factor-β signaling pathway leads to the incidence of HHT, resulting in the formation of abnormal blood vessel formation. These vascular malformations commonly manifest as telangiectasia on the skin and mucous membranes; however, epistaxis remains the hallmark symptom of HHT. The impact of HHT goes beyond the visible symptoms and often includes the formation of life-threatening visceral AVMs in the lungs, liver, and brain. The prognosis of patients with HHT is closely related to the development of these complications, necessitating timely diagnosis and intervention. Refractory epistaxis diminishes the QOL of patients with HHT. The management of epistaxis ranges from conservative measures to advanced interventions such as prevention, conservative treatments, ablation, surgical procedures, and the administration of anti-angiogenic agents. However, effective management requires a multidisciplinary approach. The diagnosis of HHT remains challenging due to its variable presentation and lack of awareness among physicians. This review highlights the importance of reducing the duration between symptom onset and diagnosis. Otolaryngologists who are experienced in the management of refractory epistaxis can aid in identifying potential cases of HHT. They can facilitate the initiation of screening for visceral AVMs via prompt recognition of the signs and symptoms of HHT, contributing to improved patient outcomes. Early detection and intervention through screening can extend the life expectancy of patients with HHT to levels comparable with that of the general population. In conclusion, this review provides insight into various aspects of HHT and emphasizes the importance of timely diagnosis and intervention in the mitigation of the potentially life-threatening complications associated with this disorder. Otolaryngologists play a critical role in this process, serving as gatekeepers to the identification of cases of HHT and implementation of appropriate screening and management pathways, thereby improving the life expectancy and QOL of patients.

Hereditary hemorrhagic telangiectsia (HHT) is an inherited vascular disorder with highly variable expressivity, affecting up to 1 in 5,000 individuals. This disease is characterized by small arteriovenous malformations (AVMs) in mucocutaneous areas (telangiectases) and larger visceral AVMs in the lungs, liver, and brain. HHT is caused by loss-of-function mutations in the BMP9-10/ENG/ALK1/SMAD4 signaling pathway. This Review presents up-to-date insights on this mutated signaling pathway and its crosstalk with proangiogenic pathways, in particular the VEGF pathway, that has allowed the repurposing of new drugs for HHT treatment. However, despite the substantial benefits of these new treatments in terms of alleviating symptom severity, this not-so-uncommon bleeding disorder still currently lacks any FDA- or European Medicines Agency-approved (EMA-approved) therapies.

The discovery of inherited and somatic genetic mutations, along with advancements in clinical and scientific research, has improved the understanding of vascular anomalies and changed the treatment paradigm. With the aim of minimizing the need for invasive procedures and improving disease outcomes, molecularly targeted medications and anti-angiogenesis agents have become important as both adjuncts to surgery, and increasingly, as the primary treatment of vascular anomalies. This article highlights the commonly used and emerging therapeutic medications for nonmalignant vascular tumors and vascular malformations.

A 43-year-old female patient with a brain abscess and a complicated clinical course was diagnosed with hereditary haemorrhagic telangiectasia (HHT) at the Martin Zeitz Centre for Rare Diseases in Hamburg, Germany. The brain abscess was caused by pulmonary arteriovenous malformations (AVM), a typical finding in HHT. Patients with cryptogenic brain abscess should be screened for pulmonary AVM and HHT. This case report illustrates the importance of patient history and interdisciplinary exchange in patients with a broad clinical spectrum as well as interdisciplinary treatment in the case of complications of rare diseases.

Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted.

This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment.

A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm.

Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.

Glanzmann's Thrombasthenia (GT) is a rare hemorrhagic condition caused by a platelet surface receptor disorder of the glycoprotein (GP) IIb/IIIa. Symptoms of GT are various forms of hemorrhages, such as purpura, epistaxis and menorrhagia. Gastrointestinal bleeding (GIB) is a rare expression of the condition and may occur due to traumas in the GI tract or as a consequence of gastrointestinal angiodysplasia (GIADs). In this case report, we present a middle-aged woman with recurrent GIB consequent to GIADs with persistent melena and iron deficiency anemia. After several unsuccessful therapeutic interventions, the patient was studied by the hereditary hemorrhagic telangiectasia's (HHT - Osler-Weber-Rendu disease) unit, where she received bevacizumab, showing a complete improvement in symptoms as well as a reduction in her GIADs. This case shows that bevacizumab could be a possible line of treatment for patients with coagulation disorders with GIADs.

To analyze and compare the effects of epistaxis treatments for Hereditary Hemorrhagic Telangiectasia (HHT) patients.

Of total of 21 randomized controlled trials (RCT), the data from 15 RCTs (697 patients, 7 treatments: timolol, propranolol, bevacizumab, doxycycline, tacrolimus, estriol/estradiol, and tranexamic acid) were pooled for the meta-analyses while the other 6 studies (treatments: electrosurgical plasma coagulation, KTP laser, postoperative packing, tamoxifen, sclerosing agent, and estriol) were reviewed qualitatively. When compared to placebo, propranolol offered the most improved epistaxis severity score, mean difference (MD), -1.68, 95% confidence interval (95%CI) [-2.80, -0.56] followed by timolol, MD -0.40, 95%CI [-0.79, -0.02]. Tranexamic acid significantly reduced the epistaxis frequency, MD -1.93, 95%CI [-3.58, -0.28]. Other treatments had indifferent effects to placebo. Qualitative analysis highlighted the benefits of tamoxifen and estriol. The adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol were significantly reported. Propranolol, timolol, tranexamic acid, tamoxifen, and estriol were effective treatments which offered benefits to HHT patients in epistaxis management. Adverse events of tranexamic acid, tacrolimus, propranolol, and estradiol should be concerned.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder. About 80% of cases are caused by pathogenic variants in ACVRL1 (also known as ALK1) and ENG, with the remaining cases being unexplained. We identified two variants, c.-79C>T and c.-68G>A, in the 5'UTR of ENG in two unrelated patients. They create upstream AUGs at the origin of upstream overlapping open reading frames (uoORFs) ending at the same stop codon. To assess the pathogenicity of these variants, we performed functional assays based on the expression of wild-type and mutant constructs in human cells and evaluated their effect on ALK1 activity in a BMP-response element assay. This assay is mandatory for molecular diagnosis and has been so far only applied to coding ENG variants. These variants were associated with a decrease of protein levels in HeLa and HUVEC cells and a decreased ability to activate ALK1. We applied the same experiments on three additional uoORF-creating variants (c.-142A>T, c.-127C>T and c.-10C>T) located in the 5'UTR of ENG and previously reported in HHT patients. We found that all the analyzed variants alter protein levels and function. Additional experiments relying on an artificial deletion in our mutated constructs show that identified uAUGs could initiate the translation indicating that the associated effect is translation-dependent. Overall, we have identified two 5'UTR ENG variations in HHT patients and shed new light on the role of upstream ORFs on ENG regulation. Our findings contribute to the amelioration of molecular diagnosis in HHT.

Hereditary hemorrhagic telangiectasia (HHT) is a common bleeding disorder, but little is known regarding prevalence and risk factors for bleeding. Adult discharges with HHT and bleeding were identified by International Classification of Disease, 10th edition (ICD-10) codes in the National Inpatient Sample (NIS), 2016-2018. Prevalence estimates were weighted using NIS discharge-level weights to reflect national estimates. Risk factors for bleeding were determined by weighted multivariable logistic regression. Among 18 170 849 discharges, 2528 (0.01%) had HHT, of whom 648 (25.6%) had bleeding. Arteriovenous malformation (AVM) (31.9% vs 1.3%), angiodysplasia (23.5% vs 2.3%), telangiectasia (2.3% vs 0.2%), and epistaxis (17.9% vs 0.6%) were more common in HHT than in non-HHT patients (non-HHT), each P < .001. In contrast, menstrual (HMB) and postpartum bleeding (PPH) were less common in reproductive-age HHT than non-HHT, each P < .001. Anemia associated with iron deficiency (IDA), was equally common in HHT with or without bleeding (15.7% vs 16.0%), but more common than in non-HHT (7.5%), P < .001. Comorbidities, including gastroesophageal reflux (25.9% vs 20.0%) and cirrhosis (10.0% vs 3.6%) were greater in HHT than non-HHT, each P < .001. In multivariable logistic regression, peptic ulcer disease (OR, 8.86; P < .001), portal vein thrombosis (OR, 3.68; P = .006), and hepatitis C, (OR, 2.13; P = .017) were significantly associated with bleeding in HHT. In conclusion, AVM and angiodysplasia are more common and HMB and PPH less common in patients in those with HHT than non-HHT. IDA deficiency is as common in HHT with and without bleeding, suggesting ongoing blood loss and need for universal iron screening.

Endoglin, alias CD105, is a human membrane glycoprotein highly expressed in vascular endothelial cells. It is involved in angiogenesis and angiogenesis-related diseases, including the rare vascular pathology known as hereditary hemorrhagic telangiectasia type 1. Although endoglin acts as an accessory receptor for members of the transforming growth factor-β family, in recent years, emerging evidence has shown a novel functional role for this protein beyond the transforming growth factor-β system. In fact, endoglin has been found to be an integrin counterreceptor involved in endothelial cell adhesion processes during pathological inflammatory conditions and primary hemostasis. Furthermore, a circulating form of endoglin, also named as soluble endoglin, whose levels are abnormally increased in different pathological conditions, such as preeclampsia, seems to act as an antagonist of membrane-bound endoglin and as a competitor of the fibrinogen-integrin interaction in platelet-dependent thrombus formation. These studies suggest that membrane-bound endoglin and circulating endoglin are important components involved in vascular homeostasis and hemostasis.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT.

Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods.

Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes.

Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.