Search Results (116)

Background/Objectives: Air embolism on contrast-enhanced computed tomography (CECT) scans may have significant consequences, particularly if a right-to-left shunt is present, as seen in hereditary hemorrhagic telangiectasia. We sought to evaluate the frequency of CECT-associated air emboli in a single tertiary care referral center. Methods: Consecutive non-enhanced and contrast-enhanced cardiac CT studies (NECCT and CECCT, respectively) were evaluated prospectively over a 6-month period. Following the University of Alberta’s Health Research Ethics Board approval (code: Pro00042313; date: 1 May 2014), two experts reviewed all studies independently to assess for the presence and location of air emboli. The control group consisted of only NECCTs. All patients, except for the control group in this study, had an IV cannula placed. When present, the number, volume, and location of air emboli were recorded. Results: In this study, 110 subjects underwent intravenous cannula placement and both NECCT and CECCT. Of these, 27 of the NECCT studies (24.5%) and 36 of the CECCT studies (32.7%) demonstrated intravascular air emboli. Of those with air emboli, the average volume of intravascular gas was 19.22 ± 25.35 µL in the NECCT studies, with most of the intravascular air (70.4%) seen in the right atrial appendage (RAA). The average volume of intravascular air was 14.81 ± 26.54 µL in the CECCT studies, with most of the intravascular air also located within the RAA (72.2%). The incidence of intravascular air was higher in the CECCT group (28.6% increase), with lower volumes of intravascular air. None of the subjects in the control group (n = 28), who underwent NECCT without intravenous cannulation, demonstrated air emboli. Conclusions: Air emboli were present in a significant proportion of subjects undergoing intravenous cannulation and subsequent CECT. The use of CECT should be carefully considered in high-risk populations. Full article

Historically, the factor(s) that stimulate vascular malformation genesis in hereditary hemorrhagic telangiectasia (HHT) has been hotly debated. Once heterozygous loss-of-function germline mutations in ENG, ACVRL1, or SMAD4 were discovered in individuals with HHT, haploinsufficiency, a 50% reduction in the encoded protein, was proposed as the molecular mechanism of HHT. However, the focal and discrete nature of HHT-associated vascular malformations suggested to others that vascular malformation genesis requires an additional, local trigger. In this review, we discuss the evidence for the Knudsonian two-hit mutation mechanism of vascular malformation pathogenesis in HHT, where the inherited, heterozygous mutation is augmented by an acquired somatic mutation in the remaining normal copy of the gene. We consider the mechanisms of HHT–vascular malformation development in the broader context of the emerging role of somatic mutations in both sporadic and inherited vascular malformations. We discuss different mechanisms of biallelic gene inactivation in HHT, difficulties with the detection of all possible mechanisms of biallelic inactivation, and issues related to the somatic mosaic nature of the lesion. We then discuss the critical importance of non-genetic factors on the pathogenesis of HHT-associated vascular malformations. Finally, we discuss the implications of the two-hit mutation mechanism for the design of novel treatments for HHT. Full article

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by pathogenic variants in ENG (HHT1) and ACVRL1 (HHT2), with distinct phenotypic expressions. Background/Objectives: This study investigates the genotype–phenotype correlations, including comparing the quality of life by phenotype, conducting a cardiovascular risk assessment, and evaluating the impact of mutation type on its clinical manifestations and prognosis. Methods: A cross-sectional study was conducted on 85 HHT patients, stratified into HHT1 (ENG, n = 43) and HHT2 (ACVRL1, n = 42). Their clinical and biochemical parameters, arteriovenous malformations (AVMs), epistaxis severity, quality of life, and cardiovascular risk were assessed. Genetic variants were classified as truncating or non-truncating. The statistical analyses included logistic regression and survival analysis. Results: The onset of epistaxis occurred earlier in HHT1 (log-rank p = 0.011), whereas its severity (p = 0.006) and iron deficiency were greater in HHT2 (p = 0.043). Pulmonary AVMs were significantly more frequent in HHT1 (58.1% vs. 9.5%, p < 0.01), contributing to a potential decrease in survival, despite the greater hemorrhagic burden in HHT2. Truncating mutations were independently associated with anemia (p < 0.05). Cardiovascular risk (measured using the SCORE2 scale) was low to moderate, and quality of life (measured using the EQ-5D-5L scale) was most impaired in patients with severe epistaxis (p = 0.031) or anemia (p = 0.026). Truncating mutations influence the severity of anemia independently of genotype. Limitations: The principal limitations include the small sample size and the bias generated by this being a paper based on another prospective study with a methodology designed for different objectives. Conclusions: These findings underscore the need for personalized management strategies based on genotype and mutation type. Further prospective studies are warranted to validate these associations and optimize the risk stratification in HHT. Full article

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between a pulmonary artery and pulmonary vein that bypass the capillary bed, resulting in right-to-left shunting. The majority of PAVMs are associated with hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease. Asymptomatic children with either a confirmed diagnosis of HHT or who are at risk of HHT from positive family history, as well as those with signs or symptoms concerning for HHT and/or PAVMs, should undergo screening for PAVMs at the time of clinical presentation or diagnosis. Screening in children can use a conservative approach (pulse oximetry, exercise intolerance testing, and chest radiograph) or transthoracic contrast echocardiography with agitated saline (TTCE). Pediatric patients with large or physiologically significant PAVMs should be treated with transcatheter embolization. Close follow-up is required after treatment to evaluate for interval growth of other PAVMs or reperfusion of the treated PAVMs. Full article

Background/Objectives: Pathogenic variants in the growth differentiation factor 2 (GDF2) gene have been linked to a hereditary hemorrhagic telangiectasia (HHT)-like syndrome, yet their clinical significance remains under investigation. This study reports seven pediatric patients with GDF2 variants from a single center. Methods: We identified children with GDF2 pathogenic variants and variants of uncertain significance (VUS) from the Children’s Hospital of Philadelphia Comprehensive HHT Program and cross-referenced the list with a full-text query by GDF2 gene name on >53,000,000 visits to ensure complete ascertainment. Medical records were reviewed retrospectively, and variables of interest were abstracted. Results: The median age at genetic testing was 12 years (range 1.75–16). Reasons for genetic testing included telangiectasias, pulmonary hypertension, familial testing, respiratory symptoms, seizures, developmental disabilities, and lung arteriovenous malformations (AVMs). Four patients had missense VUS, including two novel VUS (c.34C>G; p.Leu12Val, c.41C>T; p.Ser14Phe), while three had pathogenic deletions. All patients experienced epistaxis, starting at a median age of 6 years (range 2–12). Three had telangiectasias. One patient had both a GDF2 VUS and a de novo partial endoglin (ENG) gene deletion. While this patient’s symptoms of HHT are likely related to her ENG variant, synergy cannot be excluded, and two first-degree family members with clinically significant epistaxis also have the same GDF2 VUS. Notably, two patients had visceral AVMs—one with a lung AVM and another with a vein of Galen malformation. Conclusions: Interpretation of GDF2 VUS and their relationship to clinical symptoms is challenging given the rarity of these genetic variants and the inadequate diagnostic utility of the current clinical criteria for HHT in the pediatric population. Further research with larger cohorts is necessary to improve the genotype–phenotype correlation in GDF2-related HHT. Carefully collected clinical information with longitudinal follow-up may also assist in refining classification of GDF2 VUS as benign or pathogenic in the future. Full article

Background/Objectives: Cerebral amyloid angiopathy (CAA) is one of the most prevalent small vessel diseases (SVDs). Its diagnostic criteria rely mainly on neuroimaging markers, in particular using Magnetic Resonance Imaging (MRI), as pathology-based diagnoses are only occasionally available. Amyloid PET is frequently used to assess parenchymal amyloid deposition in Alzheimer’s disease (AD), but amyloid tracers are not specific to vascular and parenchymal amyloids. The aim of this scoping review is to assess the usefulness of amyloid PET imaging in CAA. Methods: A systematic literature search was performed, aiming to assess amyloid PET performance in the following situations: (I) CAA-related intracerebral hemorrhage (ICH) and convexal subarachnoid hemorrhage; (II) pathology-proven CAA; (III) CAA-related inflammation; (IV) hereditary CAA. Results: A total of 52 studies were retrieved, including three systematic reviews, and from these, a specific selection was taken according to each objective, confirming the diagnostic value of amyloid PET added to MRI and clinical information in all the selected situations, although with some limitations. Conclusions: Amyloid PET reliably detects increased global and region-specific amyloid deposition in CAA patients, with a characteristic occipital-predominant pattern. Continued advancements in tracer development and imaging methodologies are needed to increase specificity. Full article

Cells respond to external mechanical cues and transduce these forces into biological signals. This process is known as mechanotransduction and requires a group of proteins called mechanosensors. This peculiar class of receptors include extracellular matrix proteins, plasma membrane proteins, the cytoskeleton and the nuclear envelope. These cell components are responsive to a wide spectrum of physical cues including stiffness, tensile force, hydrostatic pressure and shear stress. Among mechanotransducers, the Transient Receptor Potential (TRP) and the PIEZO family members are mechanosensitive ion channels, coupling force transduction with intracellular cation transport. Their activity contributes to embryo development, tissue remodeling and repair, and cell homeostasis. In particular, vessel development is driven by hemodynamic cues such as flow direction and shear stress. Perturbed mechanotransduction is involved in several pathological vascular phenotypes including hereditary hemorrhagic telangiectasia. This review is conceived to summarize the most recent findings of mechanotransduction in development. We first collected main features of mechanosensitive proteins. However, we focused on the role of mechanical cues during development. Mechanosensitive ion channels and their function in vascular development are also discussed, with a focus on brain vessel morphogenesis. Full article

Background: Cerebral cavernous malformations (CCMs) are vascular lesions linked to mutations in the CCM1, CCM2, and CCM3 genes, resulting in angiogenesis dysregulation. This case study highlights the clinical course of a child with severe CCMs and explores the genetic basis of the condition. Methods: We used comprehensive clinical assessment and magnetic resonance imaging (MRI) to monitor the patient’s neurological status and CCM progression and genetic analysis by whole-exome sequencing to identify mutations in CCM-related genes. Results: The patient presented with developmental delays, multiple CCMs, and recurrent hemorrhagic events, requiring five surgical interventions. Genetic analysis revealed a novel frameshift mutation in the PDCD10 gene. Despite surgical efforts, the patient developed significant disability by age 13. Conclusions: This case illustrates the aggressive clinical course associated with CCMs, particularly in patients with CCM3 mutations. It underscores the importance of genetic screening and monitoring in understanding hereditary CCM progression and guiding treatment strategies. Full article

Background/Objectives: Childhood hemophilia, a hereditary bleeding disorder predominantly affecting males, arises due to gene mutations encoding clotting factors VIII or IX. Intracranial hemorrhage represents a significant and life-threatening complication in pediatric patients with hemophilia. The incidence of intracranial hemorrhage in children with hemophilia, although relatively low, is notably higher compared to the general pediatric population. Methods: In this study, the objective is to examine patients with hemophilia who have experienced intracranial hemorrhage retrospectively. This study is a multicenter, retrospective analysis using data from three tertiary care centers in a provincial city in Turkey. Data were obtained from the participants’ hospital records. The presence of inhibitors against FVIII in the participants and the prophylaxis used against them were included in the analysis. Trauma history was queried, with types of traumas examined, including traffic accidents, falls, and a traumatic vaginal delivery. The duration and causes of complaints among the participants were investigated. The causes of complaints were categorized as fever, hematoma, convulsions, loss of consciousness, and hemiparesis. The participants’ Physical Examination Findings were classified as fever, hematoma, and loss of consciousness. The duration of hospital stays was evaluated. The hemorrhage location was classified into five groups: parenchymal, subdural, scalp, subarachnoid, and multiple hemorrhagic foci. The recurrence of bleeding, the need for transfusion, surgical intervention, and mortality were also examined. Results: A significant difference was identified between the participants’ survival rates and age variables, as well as transfusion in <36 months. A total of 9 participants had spontaneous intracranial bleeding, 2 experienced cranial trauma as a result of traffic accidents, and 25 participants were exposed to head trauma due to falls. Of the remaining individuals, one suffered head trauma from a severe impact, and one had cranial trauma following a traumatic vaginal delivery. Fourteen participants required transfusion, and three underwent surgical intervention. Conclusions: According to the results of the statistical analyses, the variables Factor Level, Physical Examination Findings, Transfusion, Recurrent Bleeding, Inhibitor, and Prophylaxis were found to affect survival significantly. No significant relationship was determined between the other analyzed variables and survival. During our study, five of the participants examined died. Accordingly, the mortality rate identified in our study is 13.1%. Full article

Objective: The aim of this study was to evaluate patients with hereditary hemorrhagic telangiectasia (HHT) for the potential reperfusion of pulmonary arteriovenous malformations (PAVM) treated by catheter embolization using coils or embolization plugs and to analyze causes of possible reperfusion in order to further improve treatment. Methods: This retrospective study analyzed the data of 345 patients who underwent screening for pulmonary arteriovenous malformations in cases of suspected or confirmed HHT (Osler’s disease). Of these, 118 patients with PAVM that underwent catheter embolization and had at least one follow-up study were included in our study and evaluated for potential reperfusion. Screening and follow-up for the detection of PAVM was performed by dynamic and high-resolution contrast-enhanced magnetic resonance angiography (MRA). The average follow-up time was 6.2 years. Results: Reperfusion was detected in 43 of 118 patients at follow-up. Thirty-five of these patients showed a recanalization of the treated vessel and in eleven patients the formation of collateral vessels resupplying the PAVM were identified as the cause of reperfusion. The average time between embolization and detected reperfusion was 5.6 years. The recanalization of both coils and plugs was observed. The recanalization of coils could be attributed in most cases to an insufficient packing density of the implanted coils. In addition, an enlarged diameter of the feeding artery was confirmed as a risk factor for reperfusion. Conclusions: As the reperfusion of embolized pulmonary arteriovenous malformations can occur after a long time interval post-treatment, regular lifelong follow-up studies after embolization are essential to detect reperfusion at an early stage and avoid serious complications like a brain abscess or stroke through prompt re-embolization. After coil embolization, attention should be paid to sufficiently dense packing to achieve adequate and permanent occlusion. Full article

Background/Objectives: Angiogenesis is involved in the pathogenesis of hereditary hemorrhagic telangiectasia (HHT). VEGF, ANG2, TGFβ1, and ENG are the most studied angiogenic factors, but their clinical significance in blood samples is still not completely defined. The genetic study of HHT mutations is the test of choice for diagnosing the disease, but this route is expensive, and the causative mutation is not found in up to 10% of cases. Therefore, the use of angiogenic biomarkers could facilitate a cheaper and easier approach to the diagnosis of HHT. To determine the diagnostic and prognostic value of the VEGFA, TGFβ1, ANG2, and ENG plasmatic concentrations in patients with HHT. Methods: All the participants were clinically evaluated and the concentrations of these angiogenic factors were measured using MILLIPLEX^®MAP immunoassays in plasma samples collected from 44 patients with HHT and 19 controls. To evaluate the diagnostic validity of these parameters, we estimated the maximum Youden index of the ROC curve and evaluated their diagnostic value using multiple logistic regression. Results: Patients with HHT had increased blood levels of TGFβ1 and decreased ENG compared to the control group. We could not identify any angiogenic markers related to the clinical severity or epistaxis. TGFβ1 and ENG exhibited a higher discriminant capacity for HHT, especially patients with HHT1, and it was possible to develop signatures of these factors with diagnostic value. Conclusions: We identified several angiogenic factors that may be important diagnostic biomarkers for HHT and propose that the combination of TGFβ1 and ENG could represent a signature with diagnostic value for this disease. Full article

Background/Objectives: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal blood vessel formation, leading to recurrent epistaxis, cutaneous and mucosal telangiectases, and visceral arteriovenous malformations (AVMs). Hepatic involvement may result in complications such as high-output heart failure, portal hypertension, and biliary ischemia. We report an uncommon case of ischemic cholecystitis in a patient with HHT. Methods: A 57-year-old male with HHT type 1, including gastric telangiectases and hepatic AVMs, presented with anemia, melena, epigastric pain, and a history of recurrent epistaxis. Imaging revealed gastric telangiectases and liver AVMs, consistent with HHT. Following an episode of severe epistaxis and aspiration pneumonia, the patient developed right upper quadrant pain. Results: Abdominal CT and ultrasound identified thickening of the gallbladder wall, segmental enhancement defects, and a perivesicular fluid effusion, suggestive of acalculous cholecystitis. A laparoscopic cholecystectomy was performed, revealing ischemic cholecystitis with necrotic gallbladder walls. Conclusions: This case underscores the potential for ischemic cholecystitis in patients with HHT and liver involvement, particularly under conditions of acute hemodynamic instability. Clinicians should be vigilant in recognizing this rare complication, especially in patients with established HHT and associated hepatic vascular anomalies. Full article

Background/Objectives: To propose criteria for retreating previously embolized PAVMs and determining the effectiveness of the criteria to prevent paradoxical embolization. Methods: A retrospective review of patients with PAVMs treated at a single HHT center of excellence between 1 January 2013, and 10 September 2023, was performed. Patients with PAVM recurrence were either retreated or observed based on the following criteria for PAVM reintervention: 1. Embolic device(s) not creating a sufficiently dense matrix, such that a channel through them may be >/ 2 mm; 2. Accessory feeding artery or pulmonary collateral >/ 2 mm; 3. Hemoptysis in a patient with no other explanation. Results: A total of 438 PAVMs were treated in 151 patients, including 106 patients with definite, 14 possible, and 31 doubtful HHT. Post-embolization PAVM recurrence occurred in 36 patients (36/151, 23.8%), including 15 patients (15/151, 9.9%) with 22 PAVMs (22/438, 5.0%) meeting criteria for reintervention. A total of 21 patients (21/151, 13.9%) with recurrence did not meet reintervention criteria and were therefore observed. Pre-treatment paradoxical embolization occurred in 36 patients (36/151) for a lifetime prevalence rate of 23.7%. Post-treatment paradoxical embolization did not occur in any patients following PAVM embolization (0/151). There was one case of iatrogenic paradoxical embolization in a patient being treated for systemic collateral reperfusion and hemoptysis. However, this was not included given that it was not a spontaneous event. Conclusions: Utilizing modern embolization techniques and devices, the proposed reintervention criteria, and screening intervals, paradoxical embolizations can be effectively prevented in patients with PAVMs. Full article

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder leading to frequent bleeding in several organs. As HHT diagnosis is demanding and depends on clinical criteria, liquid biopsy would be beneficial. Exosomes from biofluids are nano-sized vesicles for intercellular communication. Their cargo and characteristics represent biomarkers for many diseases. Here, exosomes of HHT patients were examined regarding their biosignature. Methods: Exosomes were isolated from the plasma of 20 HHT patients and 17 healthy donors (HDs). The total exosomal protein was quantified, and specific proteins were analyzed using Western blot and antibody arrays. Human umbilical vein endothelial cells (HUVECs) co-incubated with exosomes were functionally examined via immunofluorescence, proliferation, and scratch assay. Results: The levels of the angiogenesis-regulating protein Thrombospondin-1 were significantly higher in HHT compared to HD exosomes. Among HHT, but not HD exosomes, a negative correlation between total exosomal protein and soluble Endoglin (sENG) levels was found. Other exosomal proteins (ALK1, ALK5) and the particle concentration significantly correlated with disease severity parameters (total consultations/interventions, epistaxis severity score) in HHT patients. Functionally, HUVECs were able to internalize both HD and HHT exosomes, inducing a similar change in the F-Actin structure and a reduction in migration and proliferation. Conclusions: This study provided first insights into the protein cargo and function of HHT-derived exosomes. The data indicate changes in sENG secretion via exosomes and reveal exosomal Thrombospondin-1 as a potential biomarker for HHT. Several exosomal characteristics were pointed out as potential liquid biomarkers for disease severity, revealing a possible new way of diagnosis and prognosis of HHT. Full article

Background: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations and telangiectases, in which the endothelium and immune system play a role in the pathophysiology. Therefore, treatments with antiangiogenic properties which are also regarded as immunomodulators were demonstrated to play an important role in treatment. This systematic review aimed to gather the accumulated information of the use of thalidomide and its analogs in the treatment of HHT. Methods: In this systematic review, publications that were published up to March 2024 and met the inclusion criteria were compiled using the keywords ‘thalidomide’, ‘lenalidomide’, ‘pomalidomide’, ‘immunomodulatory drugs’ and ‘HHT’ in Medline and Scholars databases. Results: A total of 53 articles were evaluated and 15 were included in the study. Thalidomide was the predominant used agent and was observed to be used in patients with ages ranging from 37 to 77 years, with doses ranging from 50 to 200 mg daily, and the mean follow-up period was observed to be 6–60 months. Assessments regarding efficacy were based on the epistaxis severity score (ESS), hemoglobin level, and transfusion independence. While thalidomide showed significant efficacy, it also had an adverse event rate of any severity of up to 85% of patients. Use of lenalidomide to control bleeding in HHT was reported in a single case report, while the use of pomalidomide was observed to be investigated in Phase 1 and Phase 2 studies in patients aged 48 to 70 years, with doses ranging from 1 to 5 mg daily for 6–24 months. This treatment was reported to provide significant improvement in hemoglobin levels and ESS. Adverse events of any severity were observed at a frequency of 60–66%. Conclusions: Antiangiogenic agents such as thalidomide, lenalidomide, and pomalidomide may be effective in managing HHT. However, further studies are needed to optimize the timing, dose, and sequence. Full article