Hereditary Hemorrhagic Telangiectasia Patients Research Articles

De Novo Brain Vascular Malformations in Hereditary Hemorrhagic Telangiectasia

BackgroundApproximately 10% of people with hereditary hemorrhagic telangiectasia (HHT) have brain vascular malformations (VMs). Few reports describe de novo brain VM formation. International HHT Guidelines recommend initial brain VM screening upon HHT diagnosis in children but do not address rescreening. We aimed to confirm whether brain VMs can form de novo in patients with HHT. MethodsThe Brain Vascular Malformation Consortium HHT project is a 17-center longitudinal study enrolling patients since 2010. We analyzed the database for de novo VMs defined as those detected (1) on follow-up neuroimaging in a patient without previous brain VMs or (2) in a location distinct from previously identified brain VMs and reported those in whom a de novo VM could be confirmed on central neuroimaging review. ResultsOf 1909 patients enrolled, 409 (21%) had brain VMs. Seven patients were recorded as having de novo brain VMs, and imaging was available for central review in four. We confirmed that three (0.7% of individuals with brain VMs) had de novo brain VMs (two capillary malformations, one brain arteriovenous malformation) with intervals of six, nine, and 13 years from initial imaging. Two with de novo brain VMs were <18 years. The fourth patient, a child, did not have a de novo brain VM but had a radiologically confirmed increase in size of an existing brain arteriovenous malformation. ConclusionsBrain VMs can, albeit rarely, form de novo in patients with HHT. Given the potential risk of hemorrhage from brain VMs, regular rescreening in patients with HHT may be warranted.

Surgery or No Surgery? Exploring the Dilemma of Epistaxis Management in Patients with HHT.

Background: Epistaxis, particularly in Hereditary Hemorrhagic Telangiectasia (HHT) patients, is a common otolaryngological emergency, often requiring complex management. A hierarchy of increasingly invasive interventions, from external compression of the nasal pyramid to nostril closure, is typically proposed and applied. Methods: We conducted a retrospective study on HHT patients to assess the effectiveness and longevity of invasive procedures postoperatively. Data were collected using the Epistaxis Severity Score (ESS) questionnaire. The primary focus was on changes in the frequency and intensity of epistaxis, while the secondary focus was on the overall quality of life. Results: This study found that invasive procedures initially improved the frequency and intensity of epistaxis in HHT patients. However, within 1 to 9 months postoperatively, these benefits often diminished, with hemorrhagic symptoms recurring at similar or worsened levels. Conclusions: The findings suggest a need for a cautious and restrained approach to using invasive treatments in managing epistaxis in HHT patients. Highly invasive procedures should be reserved for cases where less invasive methods fail, due to their temporary effectiveness and the risk of causing anatomical-functional changes in the rhino-sinus area, complicating future management of severe epistaxis.

Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia from two different regions of Brazil

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized hemorrhagic diseases described in consensus clinical diagnostic criteria (Curaçao). We describe the clinical and molecular characteristics of HHT patients from two different geographic regions of Brazil (São Paulo and Manaus). Demographic and clinical data were obtained from the electronic medical records and molecular analysis was performed by Sanger sequencing. We present here the first clinical characterization concomitantly with a molecular study of patients with THH in Brazil. These clinical characterizations may reveal differences in the molecular pathophysiology of HHT in Brazil - that our phenotypic database opens the way to be studied, or indicate limitations in the care of these patients, who need a multidisciplinary attention to prevent and treat the complications of this condition. Our results, combined with our previous data with patients presenting mutation rate to 93,75% (n=15/16) in Brazilians patients with a confirmed clinical diagnosis. Also emphasize the higher numbers of intronic mutations and three large deletions 5ÙTR regions and the predominance of ACVRL1 over ENG mutations.

Stereotactic radiosurgery for brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia

ObjectiveBrain arteriovenous malformations (AVMs) in patients with hereditary hemorrhagic telangiectasia (HHT) present different characteristics from sporadic AVMs, and they have lower initial bleeding rates. Conservative management is usually preferred for the treatment of these lesions. In this case study, we present the largest series of HHT patients treated with stereotactic radiosurgery to date.MethodsWe identified eight patients with HHT and 14 AVMs. We retrospectively collected clinical, radiographic, and treatment characteristics of the patients and each AVM.ResultsMost patients in our sample presented with small AVMs. The median volume of these AVMs was 0.22 cm3 (IQR 0.08–0.59). Three out of eight patients presented with initial intracerebral hemorrhage (ICH). The majority of lesions had low (12/14) Spetzler-Martin grades (I–II). Median maximum and margin doses used for treatment were 36.2 (IQR 35.25–44.4) and 20 (IQR 18–22.5) Gy, respectively. The overall obliteration rate after SRS was 11/14, and the median time to obliteration across all 11 obliterated AVMs was 35.83 months (IQR, 17–39.99). Neurological status was favorable with all patients having a mRS of 0 or 1 at the last follow-up. Symptomatic radiation-induced changes (RIC) after SRS were low (7.1%), and there were no permanent RIC.ConclusionsPatients with HHT who present with multiple brain AVMs are generally well served by SRS. Obliteration can be achieved in the majority of HHT patients and with a low complication rate. In the current study, initial hemorrhage rates prior to SRS were noticeable which supports the decision to treat these AVMs. Future studies are needed to better address the role of SRS for HHT patients harboring ruptured and unruptured AVMs.

Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia that commonly results in bleeding but with frequent indications for therapeutic anticoagulation. Our aims were to advance the understanding of drug-specific intolerance and evaluate if there was an indication for pharmacogenomic testing. Genes encoding proteins involved in the absorption, distribution, metabolism, and excretion of warfarin, heparin, and direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran were identified and examined. Linkage disequilibrium with HHT genes was excluded, before variants within these genes were examined following whole genome sequencing of general and HHT populations. The 44 genes identified included 5/17 actionable pharmacogenes with guidelines. The 76,156 participants in the Genome Aggregation Database v3.1.2 had 28,446 variants, including 9668 missense substitutions and 1076 predicted loss-of-function (frameshift, nonsense, and consensus splice site) variants, i.e., approximately 1 in 7.9 individuals had a missense substitution, and 1 in 71 had a loss-of-function variant. Focusing on the 17 genes relevant to usually preferred DOACs, similar variant profiles were identified in HHT patients. With HHT patients at particular risk of haemorrhage when undergoing anticoagulant treatment, we explore how pre-emptive pharmacogenomic testing, alongside HHT gene testing, may prove beneficial in reducing the risk of bleeding and conclude that HHT patients are well placed to be at the vanguard of personalised prescribing.

Elevated FVIII levels in hereditary hemorrhagic telangiectasia: Implications for clinical management.

The objective of this study was twofold: to determine the prevalence of arterial and venous thromboembolic events in the Norwegian Hereditary Hemorrhagic Telangiectasia (HHT) population, and to explore potential factors linked to such events, with particular emphasis on FVIII. Patients with an HHT diagnosis attending the Otorhinolaryngology Department at Oslo University Hospital-Rikshospitalet were included consecutively between April 2021 and November 2022. We recorded the participants' medical history with an emphasis on thromboembolic events. Measurements of blood constituents, including FVIII, FIX, vWF, hemoglobin, iron, ferritin, and CRP were performed. One hundred and thirty-four patients were included in the study. The total prevalence of thromboembolic events among the participants was 23.1%. FVIII levels were high (>150 IU/dL) in the majority of HHT patients (n = 84) (68.3%) and were significantly associated with thromboembolic events (p < .001), as was age. Of the patients with high FVIII levels, 28 (33%) had experienced a thromboembolic event. Furthermore, FVIII levels were measured consecutively in 51 patients and were found to fluctuate above or below 150 IU/dL in 25% of these cases. Thromboembolic events are highly prevalent in the Norwegian HHT population and are significantly associated with FVIII levels. FVIII levels can fluctuate, and measurements should be repeated in HHT patients to assess the risk of thromboembolic events. 4.

Pro-angiogenic changes of T-helper lymphocytes in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare inherited disease due to heterozygous loss-of-function mutations on the BMP9/10 pathway (ENG, ACVRL1 or MADH4 mainly). HHT endothelial cells are prone to lose their quiescence, leading to progressive appearance of numerous telangiectases on skin and mucosa (complicated by epistaxis and anemia), and to larger arteriovenous malformations in lungs, liver and brain. HHT is also associated with T lymphocyte abnormalities, which are currently poorly understood. We quantified by flow-cytometry the main T lymphocyte circulating subsets in 40 HHT patients and 20 matched healthy controls. Immunostaining was done on 2 HHT skin telangiectases. Disruptions in T lymphocyte homeostasis was observed, characterized by increases in subsets known to promote angiogenesis: Th2 (1.38% vs 1.15%, p=0.021), Th17 (0.32% vs 0.22%, p=0.019 2) and Treg (4.94% vs 3.51%, p= 0.027). T angiogenic lymphocytes (Tang), defined as CD3+CD31+CXCR4+ T cells, were at similar levels in both groups, but the proportion of VEGF-A+ Tang after stimulation was higher in the HHT group compared to controls (68.2% vs 44.9%, p=0.012). The global HHT T lymphopenia predominantly affected the effector memory T-helper cells (200 vs 270 cells/mm3, p=0.017), and the lymphocytic infiltrate around HHT telangiectases consisted of memory T-helper cells. The Th17 circulating subset was positively correlated with the monthly epistaxis duration (r coefficient: +0,431, p=0.042), prospectively assessed. HHT T-helper lymphocytes are affected by several pro-angiogenic changes, potentially resulting from their recruitment by abnormal endothelial cells. They could constitute a biologically relevant source of VEGF-A and a valuable therapeutic target in HHT.

Tacrolimus as a Promising Drug for Epistaxis and Gastrointestinal Bleeding in HHT

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular autosomically inherited rare disease. Epistaxis (nose bleeds) is the most common symptom in HHT, leading to anemia and affecting the patient’s quality of life. In addition to epistaxis, gastrointestinal bleeding (GI), more often at older ages, may lead to severe anemia and the need for blood transfusions. Thus, finding drugs to control both types of bleeding is a primary necessity in HHT. Methods: A cross-sectional observational study was conducted in a series of 11 HHT patients treated with low tacrolimus doses (0.5–2 mg/day) on an off-label prescription basis. Patients showed refractory bleeding to previous treatments. The epistaxis severity score (ESS) and hemoglobin levels were the parameters used to evaluate the impact of tacrolimus. The occurrence of side effects was also recorded. Results: Tacrolimus was well tolerated in all of the patients except 2 (who stopped the treatment). The remaining patients tolerated the treatment, with a general improvement in their health condition. Epistaxis was significantly reduced when comparing the ESS before and after the treatment. Hemoglobin levels significantly increased, overcoming the anemia, during the course of the treatment. Conclusion: Tacrolimus at low doses should be considered as a promising treatment for epistaxis and gastrointestinal bleeding in HHT.

VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia.

Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given during four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined the angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the "second hit" theory, highlighting the role of early postnatal angiogenesis in initiating BAVM development in HHT type I mice.

Abstract 12567: A Novel Mouse Model Replicates Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Background: 1 in 5,000 people worldwide present with Hereditary Hemorrhagic Telangiectasia (HHT), a vascular disorder that is most frequently caused by mono-allelic loss of function either of the gene ALK1, or ENG . Up to 50% of patients with HHT develop Pulmonary Arteriovenous Malformations (pAVMs), abnormal connections between arteries and veins. Health consequences include stroke, or rupture of the pAVM with life threatening bleedings. How pAVMs develop is unknown and there is no cure. Aims: We here aim at generating the first mouse model with pAVMs in HHT to address how pAVMs arise and grow, and to enable preclinical drug testing. Our goal is to produce the characteristic sac-like appearance of pAVMs in random locations of the lung by replicating probable underlying genetic events of HHT patients. Methods and Results: pAVMs occur in a focal fashion, despite a systemic mono-allelic loss of function in either one of the genes ALK1 or ENG in HHT. Recently, somatic mutations causing a local bi-allelic loss of ALK1 or ENG were identified in skin vascular abnormalities of HHT patients, most likely in clonally expanding endothelial cells (ECs). To recapitulate this locally confined complete loss of function of Alk1 in the mouse lung, we generated a tamoxifen-inducible (TM) Cre-lox mouse in which bi-allelic deletion of Alk1 can be induced only in a subset of ECs of mouse pulmonary capillaries. TM was administered in P11 or P13 old mice. 5-6 days post-injection, focal sac-like structures of the pulmonary arteries with potential connections to veins were visible in random locations of the mouse lungs of Alk1 mutants, but not control lungs. Conclusion: Bi-allelic deletion of Alk1 in ECs of mouse pulmonary general capillaries closely mimics a local loss of function somatic mutation in the single functional allele of ALK1 , as uncovered in vascular abnormalities of patients with HHT. Our novel mouse model is the first to faithfully recapitulate the focal and sporadic occurrence of pAVM-like structures seen in HHT patients. This will now enable us to identify molecular drivers of pAVM formation and test therapeutics to prevent or halt pAVM development.

UAUG creating variants in the 5’UTR of ENG causing Hereditary Hemorrhagic Telangiectasia

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.

Assessing the Psychometric Validity of the Epistaxis Severity Score: Internal Consistency and Test-Retest Reliability.

The Epistaxis Severity Score (ESS) is the gold-standard patient-reported outcome measure for evaluating nosebleed severity in patients with hereditary hemorrhagic telangiectasia (HHT). To date, the ESS has been assessed only for content validity and concurrent validity. We evaluate the internal consistency and test-retest reliability of the ESS. After receiving institutional review board approval, we sent an online survey battery, including the ESS survey, to 305 (39% male) English-speaking HHT patients ≥18 years old at a single center. Of those, 140 (46%) patients completed the battery, and 110/140 (79%) reported epistaxis. Cronbach's alpha and correlation analyses were used to evaluate internal consistency. For the test-retest reliability evaluation, we recruited 69 HHT patients during HHT clinic to complete 2 self-administered ESS surveys 2 weeks apart. Participants also completed a modified Clinical Global Impression-Improvement scale with readministration of the ESS survey. We calculated the intraclass correlation coefficient in a 2-way mixed model with absolute agreement. The ESS survey demonstrated low internal consistency (Cronbach's alpha = 0.495), suggesting that it measured multiple unrelated concepts. Factor analysis revealed 3 latent factors with moderate intercorrelation, suggesting the presence of 3 related but distinct constructs underlying the ESS. However, the ESS demonstrated excellent test-retest reliability (intraclass correlation coefficient = 0.955; 95% CI, 0.91-0.98). Although the ESS demonstrates high test-retest reliability, it may not adequately assess different dimensions of nosebleed severity. Additional correlated survey questions and sub-scores may be needed to increase internal consistency to accurately measure each component of epistaxis severity. It is necessary to acknowledge epistaxis severity from different dimensions and to consider evaluating individual ESS items separately for a comprehensive understanding.

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.

Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor Improves Leukocyte Energy Metabolism in Hereditary Hemorrhagic Telangiectasia.

The interplay between hypoxia-inducible factors (HIFs) and transforming growth factor beta (TGF-β) is critical for both inflammation and angiogenesis. In hereditary hemorrhagic telangiectasia (HHT), we have previously observed that impairment of the TGF-β pathway is associated with downregulation of HIF-1α. HIF-1α accumulation is mandatory in situations of altered energy demand, such as during infection or hypoxia, by adjusting cell metabolism. Leukocytes undergo a HIF-1α-dependent switch from aerobic mitochondrial respiration to anaerobic glycolysis (glycolytic switch) after stimulation and during differentiation. We postulate that the decreased HIF-1α accumulation in HHT leads to a clinically observed immunodeficiency in these patients. Examination of HIF-1α and its target genes in freshly isolated peripheral blood mononuclear cells (PBMCs) from HHT patients revealed decreased gene expression and protein levels of HIF-1α and HIF-1α-regulated glycolytic enzymes. Treatment of these cells with the HIF-prolyl hydroxylase inhibitor, Roxadustat, rescued their ability to accumulate HIF-1α protein. Functional analysis of metabolic flux using a Seahorse FX extracellular flux analyzer showed that the extracellular acidification rate (indicator of glycolytic turnover) after Roxadustat treatment was comparable to non-HHT controls, while oxygen consumption (indicator of mitochondrial respiration) was slightly reduced. HIF stabilization may be a potential therapeutic target in HHT patients suffering from infections.

Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays. Four variants with amino acid replacement in the motifs essential for the intracellular kinase function lost SMAD-dependent signaling. Most of other variations in the kinase domain also caused marked downregulation of signaling; however, two variants behaved as the wild-type ACVRL1 did, while computational classifiers predicted their functional abnormalities. Three-dimensional structure prediction using the ColabFold program supported the significance of the L45 loop and NANDOR domain of ACVRL1 for its association with SMAD1 and BMPR2, respectively, and the variations in these motifs resulted in the reduction of SMAD signaling. On the other hand, two of the GS domain variants maintained high signal transduction capacity, which did not accord with their computational pathogenicity prediction. These results affirm the requirement of a combinatory approach using computational and experimental analyses to accurately predict the pathogenicity of ACVRL1 missense variants in the HHT patients.

Antiplatelet and anticoagulant therapies in hereditary hemorrhagic telangiectasia: A large French cohort study (RETROPLACOTEL)

BackgroundIt is unclear whether hereditary hemorrhagic telangiectasia (HHT) patients can tolerate antithrombotic therapies (AT) including antiplatelet (AP) and/or anticoagulant (AC) agents. ObjectivesPrimary endpoint was tolerance to AT in HHT. Secondary endpoints were to identify factors associated with major bleeding events (MBE) and premature discontinuation of AT. MethodsRetrospective multicenter study in French national HHT Registry patients exposed to AT. ResultsWe included 126 patients with 180 courses of AT. Median follow-up was 24 [11–52] months. Mean age was 65.6 ± 13.1 years. The first 3 months of AT exposure had an increased risk of hospitalization for hemorrhage (p < 0.001) and transfusions (p < 0.001). MBE (n = 63) occurred more frequently in the first 3 months of AT exposure (p < 0.001). Premature discontinuation of AT occurred in 61 cases. Rate of premature discontinuation was 29 % under both AP and AT therapy but significantly higher under dual AP therapy (n = 4/7, 57 % p = 0.008). Risk factors for MBE were: age ≥ 60 years (HR 2.34 [1.12;4.87], p = 0.023), prior hospitalization in the 3 months before starting AT for hemorrhage (HR 3.59 [1.93;6.66], p < 0.001) or transfusion (HR 3.15 [1.61;6.18], p = 0.001), previous history of gastro-intestinal bleeding (HR 2.71 [1.57;4.65], p < 0.001) or MBE (HR 4.62 [2.68;7.98], p < 0.001). Frequency of MBE did not differ between groups except for a higher risk in the dual AP group (HR 3.92 [1.37;11.22], p = 0.011). ConclusionTolerance of AC or AP therapy was similar in HHT population but not dual AP therapy. We identified risk factors for MBE occurrence or premature discontinuation under AT.

Unsupervised machine learning algorithms identify expected haemorrhage relationships but define unexplained coagulation profiles mapping to thrombotic phenotypes in hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) can result in challenging anaemia and thrombosis phenotypes. Clinical presentations of HHT vary for relatives with identical casual mutations, suggesting other factors may modify severity. To examine objectively, we developed unsupervised machine learning algorithms to test whether haematological data at presentation could be categorised into sub-groupings and fitted to known biological factors. With ethical approval, we examined 10 complete blood count (CBC) variables, four iron index variables, four coagulation variables and eight iron/coagulation indices combined from 336 genotyped HHT patients (40% male, 60% female, 86.5% not using iron supplementation) at a single centre. T-SNE unsupervised, dimension reduction, machine learning algorithms assigned each high-dimensional datapoint to a location in a two-dimensional plane. k-Means clustering algorithms grouped into profiles, enabling visualisation and inter-profile comparisons of patients' clinical and genetic features. The unsupervised machine learning algorithms using t-SNE and k-Means identified two distinct CBC profiles, two iron profiles, four clotting profiles and three combined profiles. Validating the methodology, profiles for CBC or iron indices fitted expected patterns for haemorrhage. Distinct coagulation profiles displayed no association with age, sex, C-reactive protein, pulmonary arteriovenous malformations (AVMs), ENG/ACVRL1 genotype or epistaxis severity. The most distinct profiles were from t-SNE/k-Means analyses of combined iron-coagulation indices and mapped to three risk states - for venous thromboembolism in HHT; for ischaemic stroke attributed to paradoxical emboli through pulmonary AVMs in HHT; and for cerebral abscess attributed to odontogenic bacteremias in immunocompetent HHT patients with right-to-left shunting through pulmonary AVMs. In conclusion, unsupervised machine learning algorithms categorise HHT haematological indices into distinct, clinically relevant profiles which are independent of age, sex or HHT genotype. Further evaluation may inform prophylaxis and management for HHT patients' haemorrhagic and thrombotic phenotypes.

Postoperative Pain Following Coblation of Sinonasal Hereditary Hemorrhagic Telangiectasias.

Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease and epistaxis is the most common symptom. This can be treated conservatively but severe cases may require operative interventions. Endoscopic endonasal coblation of HHT lesions has been used successfully but postoperative pain management has not been well described. This study aimed to assess levels of postoperative pain and opioid use among patients with HHT who underwent coblation of sinonasal lesions. This is a longitudinal, prospective cohort study of adult patients undergoing endoscopic endonasal coblation for treatment of HHT lesions with or without bevacizumab injection between November 2019 and March 2020 at a single academic university hospital. Patients were given preoperative questionnaires and contacted via telephone 48 hours after surgery. If they reported using opioids for pain control, they were called every 2 days until they no longer used these medications. Fourteen cases, including 13 unique patients, were included in this study. Opioids were ordered on discharge in 4 cases and the average morphine milligram equivalent prescribed on discharge was 41. The median pain score on postoperative day (POD) 2 was 4 of 10. Twelve patients reported using acetaminophen and 4 were using opioid pain medications. Of those using opioid pain medications, only 1 patient was using opioid pain medication by POD 4 and denied any use after POD 10. This study is the first to analyze postoperative pain management and opioid prescribing patterns in HHT patients undergoing endonasal coblation of telangiectasias. Postoperative pain was mild to moderate and most patients stopped using opioid medications by POD 4, although the majority of patients solely used acetaminophen. Future studies with increased sample size will be useful to further identify predictors of need for analgesics postoperatively and other non-opioid adjuncts for pain control.

Risk factors and clinical features associated with basal ganglia manganese deposition in patients with hereditary hemorrhagic telangiectasia

BackgroundT1-hyperintensity of the basal ganglia (BG) due to manganese deposition is a known radiologic finding in patients with hereditary hemorrhagic telangiectasia (HHT), but risk factors and associated clinical manifestations are unclear. This study conducted a quantitative analysis of the association of T1-hyperintensity in HHT patients with specific risk factors, signs, and symptoms. MethodsPatients seen at our center between 2005 and 2020 with a definitive diagnosis of HHT who had an available non-contrast T1-weighted brain MRI were included. Hyperintensity was evaluated using oval regions of interest measurements. The BG: thalamus intensity ratio was used to quantitatively evaluate T1-hyperintensity. Patient laboratory values and clinical findings were collected from electronic medical records. Hyperintensity was analyzed for its association with laboratory values, and clinical findings. Variables were analyzed through regression analysis. ResultsA total of 239 patients were included in this study. On 1.5 T scanners, values that were significant on multivariable regression analysis were age (p < .001), hepatic AVMs (p < .001), iron deficiency anemia (p = .0021), and cirrhosis (p = .016). On 3 T scanners, values that were significant on multivariable analysis were hepatic AVMs (p = .0024) and cirrhosis (p = .0056). On 3 T scanners, hyperintensity was significantly associated with tremor (OR = 1.17, p = .033), restless leg syndrome (OR = 1.22, p = .0086), and memory problems (OR = 1.17, p = .046). ConclusionsBG hyperintensity due to manganese deposition is significantly associated with hepatic risk factors on 1.5 T and 3 T scanners and iron deficiency anemia on 1.5 T scanners. On 3 T scanners, T1-hyperintensity is associated with neuropsychiatric signs and symptoms, such as tremor, restless leg syndrome, and memory problems.

Exploring effects of atmospheric conditions in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by recurrent epistaxis, telangiectasias, and visceral arteriovenous malformations. Individuals with HHT often identify low humidity and temperature as detrimental to epistaxis severity. We set out to assess the relationship between humidity and temperature on epistaxis severity in patients with HHT. Retrospective cross-sectional study at an academic hospital with an HHT center between July 1, 2014 and January 1, 2022. The primary outcome of this study was ESS. Pearson correlation analyses and multiple linear regression analyses were performed to test the association between weather variables and epistaxis severity scre (ESS). Results were reported as coefficient and 95% confidence interval (CI). Four hundred twenty-nine patients were included in the analysis. Through a Pearson correlation analysis, neither humidity (regression coefficient=-0.01; 95% CI,-0.006 to 0.003; p=0.50), daily low temperature (regression coefficient=0.01; 95% CI,-0.011 to 0.016; p=0.72), or daily high temperature (regression coefficient=0.01; 95% CI,-0.004 to 0.013; p=0.32) were significantly correlated with ESS. In a multiple linear regression analysis, adjusting for both daily low temperature and humidity, medications taken, demographics, and genotype, neither daily low temperature (regression coefficient=-0.02; 95% CI,-0.04 to 0.01; p=0.14) nor humidity (regression coefficient=0.01; 95% CI,-0.01 to 0.01; p=0.64) were significantly associated with ESS. We have shown in a large clinical sample that neither humidity nor temperature were strongly correlated with HHT patient epistaxis severity.