Hemorrhagic Telangiectasia Patients Research Articles

Red blood cell alloimmunization in transfused patients with hereditary hemorrhagic telangiectasia: A single centre retrospective study

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a genetic blood vessel disorder which may lead to chronic bleeding and red blood cell (RBC) transfusions. Data on transfusion requirements and complications in HHT patients are sparse. Study Design and MethodsRetrospective chart review was conducted at St. Michael’s Hospital (SMH) in Toronto, Canada. All adults with a definite clinical diagnosis of HHT AND inpatient hospital visits between January 1, 2011 and December 31, 2020 AND had undergone transfusion compatibility testing at SMH, were identified. Data were abstracted from electronic medical records. Simple descriptive statistics were used to analyze data. Institutional Research Ethics Board approval was obtained. Results63 HHT patients underwent compatibility testing and were subsequently transfused at SMH. Median patient age at data abstraction was 70 years (Interquartile Range [IQR]: 18) and 35 (56 %) were female. RBC alloantibodies were found in 23 transfused patients (36.5 %) and were predominantly directed against Rh and Kell antigens: Anti-E (65 %), Anti-K (39 %) and Anti-c (22 %) were most common. Excluding an outlier who received 611 RBC units during the study period, the mean number of RBC units transfused per HHT patient at SMH was 22.1 units (Standard Deviation: 40.9, IQR: 17). Six (9.5 %) transfused patients experienced at least one transfusion reaction. ConclusionRBC alloimmunization rate was 36.5 % in our cohort of transfused HHT patients; this is much higher than described in the general population and another transfused HHT cohort. The most commonly observed alloantibodies were Rh and Kell, supporting our policy of prophylactic phenotypic matching for these antigens for all transfused patients with HHT.

Pazopanib in treatment of Hereditary Hemorrhagic Telangiectasia-related epistaxis and gastrointestinal bleeding.

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a bleeding disorder characterized by arteriovenous malformations (AVMs), commonly presenting with epistaxis and gastrointestinal 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 (VEGF) receptor. ObjectivesTo report single-center, retrospective real-world use of pazopanib, an orally administered tyrosine kinase inhibitor that blocks VEGF receptors, in six patients with HHT-associated epistaxis and/or gastrointestinal (GI) bleeding. Patient/MethodsA 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 01 January 2019 and 14 June 2023The Indiana Hemophilia and Thrombosis (IHTC) institutional EMR 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 documentationInstitutional IRB approval was obtained for data pull as an exempt study Results and ConclusionsOur observations on the real-world use of pazopanib in six 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.

Molecular mechanisms and clinical manifestations of hereditary hemorrhagic telangiectasia

IntroductionHereditary Hemorrhagic Telangiectasia (HHT) is charactered by telangiectasia and arteriovenous malformations (AVMs). Recurrent visceral and mucocutaneous bleeding is frequently reported among HHT patients, while data on the prevalence of thrombosis remains limited. This study aims to describe the clinical manifestations and molecular biological characteristics of HHT patients. MethodsWe conducted a retrospective study at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. A total of 24 HHT patients, observed between January 2019 and December 2023, were included. We recorded the biological, clinical, and therapeutic events, with particular attention to bleeding and thrombotic events. Gene mutation analysis and blood constituent measurements were performed. ResultsThe prevalence of bleeding among all HHT patients was 100 %, while thrombotic events were noted in 41.70 % of cases. Hepatic arteriovenous malformations (HAVMs) were identified in six patients, pulmonary arteriovenous malformations (PAVMs) in five patients, and cerebral arteriovenous malformations (CAVMs) in one patient. For patients with thrombosis, the discontinuation rates were 23.08 % for antiplatelet therapy and 33.33 % for anticoagulant therapy due to the increased risk of bleeding. Genetic mutations related to HHT were present in 16 patients, with ACVRL1 (activin A receptor-like type 1) mutations being the most frequent at 41.67 %, followed by ENG (endoglin) mutations at 20.83 %, and GDF2 (growth differentiation factor 2) mutations at 4.17 %. The incidence of PAVMs was 75.00 % in HHT1 patients with ENG mutations and 20 % in HHT2 patients with ACVRL1 mutations, while HAVMs occurred in 0 % and 40.00 % of these groups, respectively. Patients were divided into non-AVMs and AVMs groups. Compared to normal controls, von Willebrand factor (vWF) activity was significantly increased in all HHT patients (149.10 % vs. 90.65 %, P < 0.001). In the non-AVMs group, the median level of stromal cell-derived factor-1 (SDF-1) was significantly elevated (124.31 pg/mL vs. 2413.57 pg/mL, P < 0.05), while vWF antigen levels were markedly higher in the AVMs group (165.30 % vs. 130.60 %, P = 0.021). Further grouping of HHT patients based on bleeding and thrombosis phenotypes revealed that those with thrombosis had significantly higher median percentages of schistocytes (3.50 % vs. 0 %, P = 0.002), ferritin concentrations (318.50 μg/L vs. 115.50 μg/L, P = 0.001), and lactate dehydrogenase (LDH) levels (437 U/L vs. 105 U/L, P < 0.001). There were no significant differences in the activity of vWF, protein C (PC), protein S (PS), and factor VIII (FVIII) between the two groups. ConclusionThis study highlighted the complex relationship between arteriovenous malformations and genetic mutations in HHT patients. A comprehensive assessment of bleeding and thrombosis risks should be conducted for each HHT patient, additionally, further clinical studies are needed to explore the risk factors for thrombosis and anticoagulant-related bleeding in HHT.

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

BackgroundHereditary 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. ObjectiveTo 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. MethodsA 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. Results111 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. ConclusionsDWSL 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.

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

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. 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. 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. 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.

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

BackgroundHereditary 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. ObjectiveTo 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. MethodsA 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. Results111 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. ConclusionsDWSL 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.

New genetic drivers in hemorrhagic hereditary telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. MethodsTo identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. ResultsWe identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p.(Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFβ signaling in endothelial cells. ConclusionsVariants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations.

Identifying racial disparities in hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by recurrent epistaxis (nose bleeds), mucosal telangiectasias (spider veins), and arteriovenous malformations. Although HHT affects all racial groups, few...

746 A Novel Method of Remotely Managing Complex HHT Patients via Telephone Clinic to Reduce Severity and Frequency of Nosebleeds

Abstract Introduction Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. Patients who have hereditary haemorrhagic telangiectasia can have severe debilitating manifestation of symptoms which can severely affect their quality of life. One of the severe manifestations is epistaxis, this can often lead to being anaemic, needing blood transfusion and hospital admission. Method Patient data was analysed to record number of hospital visits, A&amp;E attendances, and hospital admissions. Multidisciplinary approach to involve various teams including but not limited to specialist nurses and clinicians. Results Virtual clinics facilitate management of HHT patients with complex needs. Provision of (nurse led) specialist virtual clinic in the form of telephone consults giving advice regarding maintenance and emergency care in case of a nosebleeds. This facilitates safe pathway for emergent care and avoids hospital visit with every episode. The patients are provided with an emergency pack and a prevention pack. The emergency pack contains nasal packs, tranexamic acid mouthwash 5%, nasopore, kaltostat whereas the prevention pack contains triple therapy. Analysis of patient data suggests reduced number of hospital visits, A&amp;E attendances, and hospital admissions to seek specialist treatment. Conclusions Virtual clinics are an upcoming novel method of managing complex patients. They are beneficial for patients allowing them specialist access to medical advice to manage their symptoms at home. Improved patient care pathway allowing easy access of specialist medical advice. Safer management of complex HHT patients reducing frequent hospital visits for reasons like consultations, blood tests, admissions, and blood transfusion.

Development and validation of a quality of life measurement scale specific to hereditary hemorrhagic telangiectasia: the QoL-HHT

BackgroundHereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients’ daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT).MethodsA quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses.ResultsThe EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach’s alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test–retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores.ConclusionsWe developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support.Trial registration: ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www.clinicaltrials.gov/ct2/show/NCT03695874

Altered expressions of CXCR4 and CD26 on T-helper lymphocytes in hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes.MethodsEighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells.ResultsThe overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm3, p < 0.0001), correlated with age (r = − 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm3, p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002).ConclusionsOur findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians.MethodsUsing DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review.ResultsIn total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively.ConclusionsIn a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Resveratrol As a Novel Treatment for Recurrent Epistaxis in SMAD4+ Hereditary Hemorrhagic Telangiectasia

IntroductionHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by the development of arteriovenous malformations or telangiectasias that may affect any organ system, but are most prevalent in the nose and gastrointestinal tract. Nasal telangiectasia account for epistaxis, the most frequent manifestation of HHT, which may be frequent, debilitating and lead to decreased quality of life. Epistaxis is quantified by the Epistaxis Severity Scores (ESS), which ranges from 1-10 with higher scores associated with more severe bleeding. The diagnosis of HHT is based on clinical criteria and requires three or more of the following features: epistaxis, mucocutaneous telangiectasis, visceral AVMs, and/or a family history of HHT. HHT is associated with several mutations that may involve ENG, ACVRL1, or SMAD4; the latter occurs in only ~2% of HHT patients, which is also associated with the Juvenile Polyposis Syndrome (JPS), another autosomal dominant disorder associated with an increased risk for colorectal, stomach, small intestine, and pancreatic cancers.MethodsCase report with serial ESS scores, hemoglobin and hematocrit monitoring.ResultsA 25-year-old male was diagnosed with JPS/HHT and a c.1081C>T mutation in SMAD4 leading to an R361C missense mutation was diagnosed in 2013. The patient had a longstanding history of frequent epistaxis leading to severe iron deficiency anemia and requiring at least two 750 mg iron infusions annually (total of 14), and did not improve with oral iron supplements. In December 2020, the patient initiated a 1 g daily dose of resveratrol for general anti-aging and health benefits. His epistaxis improved immediately, and his ESS decreased from 6 (consistent with severe bleeding) to 1 (no bleeding) over a two week period. The frequency, severity and duration of epistaxis all improved dramatically (Figure). No additional iron therapy has been required since initiation of resveratrol. Recent serum iron and ferritin values (6/2021) were both within normal limits.Of interest, in parallel with the resolution of epistaxis, the patient also had a dramatic reduction in colonic polyposis after starting resveratrol.ConclusionsThere are no approved therapies for the treatment of HHT, and patients with this disorder may suffer from a markedly reduced quality of life due to unpredictable epistaxis and other manifestations. While a responses to bevacizumab have been reported in 60-70% of patients, treatment is expensive and may be associated with thromboembolic events, and patients may become refractory over time. Invasive approaches such as sclerotherapy may be initially, but only temporarily effective. Thus, there is an urgent need for better HHT therapies. [Display omitted] DisclosuresMcCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy.

Utility of modified Rankin Scale for brain vascular malformations in hereditary hemorrhagic telangiectasia

BackgroundApproximately 10% of hereditary hemorrhagic telangiectasia (HHT) patients harbour brain vascular malformations (VMs). Intracranial hemorrhage (ICH) from brain VMs can lead to death or morbidity, while treatment options for brain VMs also have associated morbidity. The modified Rankin Scale (mRS) may provide an approach to identifying HHT-brain VM patients with poor outcomes, and their predictors. We aimed to measure the relationship between mRS score and brain VM, brain VM number, as well as other aspects of HHT, at enrollment and during prospective follow-up.Methods1637 HHT patients (342 with brain VMs) were recruited from 14 HHT centres of the Brain Vascular Malformation Consortium since 2010 and followed prospectively (mean = 3.4 years). We tested whether the presence of brain VM, other HHT organ involvement, and HHT mutation genotype were associated with worse mRS scores at baseline and during follow-up, using linear mixed models, adjusting for age, sex, and year of visit.ResultsPresence of brain VMs was not associated with worse mRS score at baseline and there was no significant worsening of mRS with prospective follow-up in these patients; 92% had baseline mRS of 0–2. HHT-related gastrointestinal (GI) bleeding was associated with worse mRS scores at baseline (0.37, 95% CI 0.26–0.47, p < 0.001), as were history of anemia (0.35, 95% CI 0.27–0.43, p < 0.001) and liver VMs (0.19, 95% CI 0.09–0.30, p < 0.001). Presence of pulmonary arteriovenous malformations (AVMs) was not associated with worse mRS scores at baseline. mRS score was not associated with either HHT genotype (Endoglin vs ACVRL1). Only GI bleeding was associated with a significantly worsening mRS during prospective follow-up (0.64, 95% CI 0.21–1.08, p = 0.004).ConclusionMost HHT-brain VM patients had good functional capacity (mRS scores 0–2) at baseline that did not change significantly over 3.4 mean years of follow-up, suggesting that mRS may not be useful for predicting or measuring outcomes in these patients. However, HHT patients with GI bleeding, anemia history or liver VMs had worse mRS scores, suggesting significant impact of these manifestations on functional capacity. Our study demonstrates the insensitivity of the mRS as an outcomes measure in HHT brain VM patients and reinforces the continued need to develop outcomes measures, and their predictors, in this group.

Classification of endonasal HHT lesions using digital microscopy

BackgroundRecurrent spontaneous epistaxis is the most common clinical manifestation and the most debilitating symptom in hereditary haemorrhagic telangiectasia (HHT) patients. To this date, there exist only a classification of HHT patients by different genetic mutations. There is no standard classification for the mucocutaneous endonasal manifestations of HHT. The aim of the present study was to document the variety of endonasal HHT lesions using digital microscopy and to propose a clinical classification.MethodsWe recorded the endonasal HHT lesions of 28 patients using a digital microscope. We reconstructed the 3D images und videos recorded by digital microscope afterwards and classified the endonasal lesions of HHT in two classes: Grade A, presence of only flat telangiectasias in the mucosa level and Grade B, (additional) presence of raised berry or wart-like telangiectasia spots. We investigated also Haemoglobin level by routine laboratory procedures, plasma VEGF level by ELISA, Severity of epistaxis by epistaxis severity score (ESS) and quality of life by a linear visual analogue scale (VAS).ResultsWe found a higher quality of life and a lower severity of epistaxis in Grade A patients in comparison to Grade B patients. No difference in plasma VEGF level and in Haemoglobin between Grad A patients and Grade B patients could be detected. Plasma VEGF levels showed no gender specific differences. It could also not be correlated to the extranasal manifestation.ConclusionThe classification for endonasal manifestation of HHT proposed in this study indicates severity of epistaxis und quality of life. Digital microscopy with the ability of 3D reconstruction of images presents a useful tool for such classifications. The classification of endonasal HHT lesions using digital microscopy allows to evaluate the dynamic of HHT lesions in the course of time independent of examiner. This allows also to evaluate the efficacy of the different treatment modalities by dynamic of HHT lesions. Moreover digital microscopy is very beneficial in academic teaching of rare diseases.

Abstract MP11: Circulating Plasma Biomarkers Associated With Brain Arteriovenous Malformations

Objective: Circulating plasma protein profiling may aid in the identification of cerebrovascular disease signatures. This study aimed to identify circulating angiogenic and inflammatory biomarkers that may serve as biomarkers to differentiate sporadic brain arteriovenous malformation (bAVM) patients from other conditions with brain AVMs, including hereditary hemorrhagic telangiectasia (HHT) patients. Methods: The Quantibody Human Angiogenesis Array 1000 (Raybiotech) is an ELISA multiplex panel that was used to assess the levels of 60 proteins related to angiogenesis and inflammation in heparin plasma samples from 13 sporadic unruptured bAVM patients (69% male, mean age 51 years) and 37 patients with HHT (40% male, mean age 47 years, n=19 (51%) with bAVM). The Quantibody Q-Analyzer tool was used to calculate biomarker concentrations based on the standard curve for each marker and log-transformed marker levels were evaluated for associations between disease states using a multivariable interval regression model adjusted for age, sex, ethnicity and collection site. Statistical significance was based on Bonferroni correction for multiple testing of 60 biomarkers (P&lt; 8.3x10 - 4 ). Results: Circulating levels of two plasma proteins differed significantly between sporadic bAVM and HHT patients: PDGF-BB (P=2.6x10 -4 , PI= 3.37, 95% CI:1.76-6.46) and CCL5 (P=6.0x10 -6 , PI=3.50, 95% CI=2.04-6.03). When considering markers with a nominal p-value of less than 0.01, MMP1 and angiostatin levels also differed between patients with sporadic bAVM and HHT. Markers with nominal p-values less than 0.05 when comparing sporadic brain AVM and HHT patients also included angiostatin, IL2, VEGF, GRO, CXCL16, ITAC, and TGFB3. Among HHT patients, the circulating levels of UPAR and IL6 were elevated in patients with documented bAVMs when considering markers with nominal p-values less than 0.05. Conclusions: This study identified differential expression of two promising plasma biomarkers that differentiate sporadic bAVMs from patients with HHT. Furthermore, this study allowed us to evaluate markers that are associated with the presence of bAVMs in HHT patients, which may offer insight into mechanisms underlying bAVM pathophysiology.

Endoscopic surgical treatment of epistaxis in hereditary haemorrhagic telangiectasia: our experience.

SUMMARYObjectivesHereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterised by epistaxis. Surgical procedures for epistaxis vary from diathermocoagulation to nasal closure. The aim of this paper is to report our experience in endoscopic surgical management of epistaxis in HHT patients.MethodsThis is a descriptive, longitudinal study carried out at the Otorhinolaryngology Department of IRCCS Policlinico San Matteo in Pavia, a reference centre for the treatment and diagnosis of HHT. We retrospectively evaluated HHT patients who underwent surgery for epistaxis from 1996 to 2015, including only those treated with endoscopic surgery.ResultsAmong the 591 patients hospitalised and screened for HHT, 323 (54.7%) underwent endoscopic surgery for epistaxis, for a total of 679 procedures. General anaesthesia was used in 77.2% of procedures; argon plasma coagulation was the instrument of choice in the majority of patients, followed by lasers and quantum molecular resonance technology.ConclusionsWe report one of the largest cohorts undergoing endoscopic treatment of epistaxis in HHT patients. This mini-invasive surgical treatment allowed us to control epistaxis without major complications and nasal packaging and can be repeated over time. For these reasons, we recommend it as first choice in case of epistaxis in HHT patients.

Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia

AbstractHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.

Dietary iron intake and anemia: food frequency questionnaire in patients with hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular disease characterized by a heterogeneous clinical presentation and prognosis. Dietary evaluation is relevant in HHT patients to provide adequate iron and nutrient intake. Additionally, different dietary items have been reported to precipitate epistaxis in this setting. Our primary aim was to investigate the dietary habits of HHT patients through a food-frequency questionnaire (FFQ) to evaluate the presence of precipitants and/or protective factors for epistaxis and the occurrence of possible dietary modifications. The secondary aims were to evaluate the nutritional intake of iron in HHT patients and the self-reported effect of iron treatments on epistaxis. From April 2018 to October 2018, a 138-item FFQ was provided to HHT patients followed up at the HHT Referral Center of Crema Maggiore Hospital. The relationship between food items and epistaxis was ascertained on a separate form. Daily iron intake was calculated to establish the mean iron content of food items reported in the FFQ.ResultsOne hundred forty-nine questionnaires were evaluated [72 females, median age 54 years (12–76). Overall, 26 (18%) patients reported dietary items that improved epistaxis (mostly blueberries and red fruits, green vegetables and legumes), while 38 (26%) reported some dietary items that exacerbated epistaxis (spices, chocolate, alcohol, strawberries and ginger). Dietary modifications were reported in up to 58% of cases. In HHT patients, the mean daily iron intake was 8.46 ± 2.78 mg, and no differences were observed in the iron intake of patients reporting a diet modification and those who did not.ConclusionsIn the comprehensive management of HHT a healthy and balanced diet, with increased consumption of dietary items with a high iron content, should be encouraged.

In This Issue

HomeCirculation ResearchVol. 127, No. 9In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published8 Oct 2020https://doi.org/10.1161/RES.0000000000000443Circulation Research. 2020;127:1119is related toEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisEnhancement of ALK1 Signaling as a HHT Therapy (p 1122)Boosting activity of kinase ALK1 could be a treatment for hereditary hemorrhagic telangiectasia, say Kim et al.Download figureDownload PowerPointHereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular abnormalities called arteriovenous malformations (AVMs) in which arteries are directly connected to veins. Without intervening capillaries, blood pressure in the veins becomes excessive and can cause aneurysms and ruptures. Indeed, HHT patients often endure frequent bleeds and anemia, and sometimes suffer more severe events such as brain or pulmonary hemorrhages. HHT is caused by mutations in one of three genes—ALK1, ENG, or SMAD4—all of which encode components of a TGFβ-related growth factor signaling pathway. Because ninety percent of HHT cases are driven by ALK1 or ENG mutations, Kim et al focused on these two factors, examining how they might interact and compensate for each other. Using mice that conditionally lacked either ALK1 or ENG and had AVMs as a result, the team found that genetically increasing ALK1 production could prevent AVMs in the ENG- and ALK-lacking mice, but that increasing ENG production could only compensate for deficiency of ENG, not ALK1. Together these results suggest that ALK1 acts downstream of ENG in their shared signaling pathway and that augmenting ALK1 production could be a therapeutic approach for treating HHT.Periostin Is a Target to Treat PH (p 1138)Nie et al suggest periostin as a novel therapeutic target for treating pulmonary hypertension.Download figureDownload PowerPointPulmonary hypertension (PH) is a life threatening disease in which excess proliferation of vascular smooth muscle cells (VSMCs) and deposition of extracellular matrix (ECM) thickens the walls of the lung vasculature causing an increase in pulmonary blood pressure. Vasodilatory medications are used to treat the symptoms of the disease, but there are no available treatments that target the underlying pathologic remodeling. Nie and colleagues now suggest that drugs targeting the secreted ECM protein periostin might work. Periostin is unusually abundant in the arteries of PH patients’ lungs and is thought to be involved in cell adhesion and wound healing mechanisms such as proliferation and migration of VSMCs. The team has now confirmed the increased production of periostin in patient lungs and shown the same is true for mice with induced PH. Moreover they showed that genetic deletion of periostin attenuated PH in mice, while suppression of periostin via RNA inhibition could even reverse pathologic vessel thickening and right ventricle hypertrophy. The team went on to identify factors—HIF-1A and TrkB—that mediate periostin’s effects in cultured arterial cells, and suggest that blocking either these factors or periostin itself could be novel strategies for treating PH.Gene Regulatory Dynamics of Developing Human Heart (p e184)VanOudenhove et al examine the epigenomics and transcriptomics of the developing human heart.Download figureDownload PowerPointCongenital heart defects (CHDs) are a common form of birth abnormality. While some genes have been linked to CHDs, the majority—nearly sixty percent—have unknown etiologies. It’s thought that multiple genetic and environmental factors contribute to CHDs, one of which could be variations in regulatory regions of the genome. To find such heart-specific regulatory regions, VanOudenhove and colleagues examined heart tissue from human embryos obtained 4 to 8 weeks after conception. They performed chromatin immunoprecipitation (ChIP) experiments to scour the heart genomes for histone modifications associated with increased or decreased gene transcription. They also performed transcriptome analysis to see whether the genomic regions identified by ChIP corresponded with the activity status of nearby genes. In total, the team found more than 12 thousand previously unknown enhancers that were enriched for binding sites for heart-specific transcription factors (including GATA, MEF2 and NKX) and that tended to be close to genes activated in the heart. Many of the regions also contained sequence variations previously associated with atrial fibrillation. These newly identified sites are potential CHD candidate loci, say the authors, who have made their data freely available for study. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisJennifer VanOudenhove, et al. Circulation Research. 2020;127:e184-e209 October 9, 2020Vol 127, Issue 9Article InformationMetrics Download: 270 © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000443 Originally publishedOctober 8, 2020 PDF download