Malformations In Hereditary Hemorrhagic Telangiectasia Research Articles

Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Brain Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Review of the Natural History, Clinical Diagnosis, and Treatment Guidelines

Brain Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Review of the Natural History, Clinical Diagnosis, and Treatment Guidelines

Brain Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Review of the Natural History, Clinical Diagnosis, and Treatment Guidelines

Brain Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Review of the Natural History, Clinical Diagnosis, and Treatment Guidelines

Bilateral choroidal vascular malformations in hereditary hemorrhagic telangiectasia.

To describe a case of bilateral choroidal vascular malformations in a patient with hereditary hemorrhagic telangiectasia (HHT). Case report. A 78-year-old man with HHT was incidentally noted to have focal, large deep choroidal vessels on optical coherence tomography with corresponding elevation of the overlying retina. Indocyanine green angiography revealed dilated, intensely fluorescent vessels in arterial phase emptying into massively dilated choroidal veins consistent with choroidal arteriovenous malformation. This case presents multimodal imaging findings of choroidal arteriovenous malformations in HHT. Choroidal vascular malformations may represent an underrecognized clinical feature of this syndrome.

MRI as screening for pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia.

A four-year-old boy was newly diagnosed with Hereditary Haemorrhagic Telangiectasia (HHT) based on cascade genetic testing This article is protected by copyright. All rights reserved.

Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia

BackgroundVascular malformations in hereditary hemorrhagic telangiectasia (HHT) lead to chronic recurrent bleeding, hemorrhage, stroke, heart failure, and liver disease. There is great interest in identifying novel therapies for epistaxis in HHT given its associated morbidity and impact on quality of life. We aimed to measure the effectiveness of oral doxycycline for the treatment of epistaxis and explore mechanisms of action on angiogenic, inflammatory and pathway markers in HHT using a randomized controlled trial.Methods13 HHT patients with epistaxis were recruited from the Toronto HHT Center at St. Michael’s Hospital. Recruitment was stopped early due to COVID-19-related limitations. The study duration was 24 months. Patients were randomly assigned to the treatment-first or placebo-first study arm. We compared the change in weekly epistaxis duration and frequency, biomarkers, blood measurements, and intravenous iron infusion and blood transfusion requirements between treatment and placebo.ResultsThere was no significant difference in the change in weekly epistaxis duration (p = 0.136) or frequency (p = 0.261) between treatment and placebo. There was no significant difference in the levels of MMP-9, VEGF, ANG-2, IL-6 or ENG with treatment. Hemoglobin levels were significantly higher (p = 0.0499) during treatment. Ferritin levels were not significantly different between treatment and placebo. There was no significant difference in RBC transfusions between treatment periods (p = 0.299).ConclusionOverall, our study did not demonstrate effectiveness of doxycycline as a treatment for epistaxis in patients with HHT, though the study was underpowered. Secondary analyses provided new observations which may help guide future trials in HHT.Trial Registration ClinicalTrials.gov, NCT03397004. Registered 11 January 2018 – Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT03397004

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.

Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.

Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia

BackgroundHereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.MethodsWe selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.ResultsThe proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).ConclusionsIn this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.

Comparison of Ferumoxytol-enhanced MR Angiography and CT Angiography for the Detection of Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: Initial Results.

To perform a preliminary comparison of the sensitivity and positive predictive value of ferumoxytol-enhanced MR angiography with those of CT angiography for detection of pulmonary arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Institutional review board approval and informed patient consent were obtained. Ten patients with pulmonary AVMs who had undergone CT of the chest within 12 months underwent MRI of the chest and abdomen with ferumoxytol at 3.0 T at a dose of 4 mg per kilogram of body weight. Consensus review of MR and CT images assessed the presence and characteristics of pulmonary AVMs, image quality, vessel visibility, and artifact grade. Forty-three AVMs were detected, 13 native and 30 recanalized. Twenty-one AVMs had a feeding artery diameter of greater than 2 mm, of which detection occurred in 19 (at MRI and CT), in two (at MRI only), and zero (at CT only). Twenty-two AVMs had a feeding artery diameter of less than or equal to 2 mm, of which detection occurred in 16 (at MRI and CT), six (at CT only), and zero (at MRI only). For the entire cohort, the sensitivity of ferumoxytol-enhanced MRI using CT as the reference standard was 85.4% (35 of 41), and the positive predictive value was 100% (35 of 35). No significant difference was found between CT and MRI in AVM size, feeding artery and draining vein diameter, and artifact score (P >.05 for all). Initial results suggest that ferumoxytol-enhanced MRI is a feasible alternative to CT for detection of pulmonary AVM in HHT, while avoiding repeated exposure to radiation, nephrotoxic contrast material, or gadolinium-based contrast agent.© RSNA, 2020.

Abstract No. 417 Arteriography of pulmonary arteries for pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: national trends, patient characteristics, and outcomes

to examine the national estimates for admission of patients with hereditary hemorrhagic telangiectasia (HHT) who were diagnosed with pulmonary arteriovenous malformations (PAVMs) and received arteriography of pulmonary arteries (PA arteriography) during their inpatient stays. Data from the National Inpatient Sample (NIS) 2012–2015 was used for this study. A survey analysis approach was used to calculate nationally representative estimates of inpatient stays of HHT patients with PAVM diagnosis. Patient and hospital characteristics, as well as short-term outcomes were compared based on PAVM diagnosis and need for PA arteriography. HHT patients were responsible for an estimated 4210 to 4450 number of admissions per year (2012–2015), 4.3% to 7.6% of which were related to a PAVM diagnosis and 1.0% to 2.0% of them required PA arteriography (45-85 per year). HHT patients with PAVM who received PA arteriography were younger (43.1 ± 3.6 vs. 60.0 ± 0.4), were more likely to be female (69% vs. 58%) and had lower frequency of chronic blood loss anemia (6% vs. 14%), congestive heart failure (3% vs. 17%), chronic pulmonary disease (14% vs. 26%) and coagulopathy (3% vs. 8%) when compared to an average pool of HHT admissions. PA arteriography was more frequently performed in large (80.0%), private-owned (85.7%), and urban teaching (91.4%) hospitals. PA arteriography admissions were associated with no significant mortality (frequency <0.1%), an average 7.4 ± 1.5 days of in-hospital stay, 77.1% routine disposition, and total hospital charge of 141,742 ± 27,994 USD. PA arteriography for PAVM in HHT patients is an uncommon procedure (1.0%-2.0% of all admissions of HHT patients), that is more commonly performed in patients with better comorbidity profiles and is associated with limited mortality.Tabled 1National Outcomes for HHT Admission According to PAVM and PA ArteriographHHTHHT + PAVMHHT + PAVM Receiving ArteriographyDied (%)2.0 (0.2)2.0 (1.1)<0.1 (<0.1)Length of Stay (days)4.6 (0.1)5.5 (0.5)7.4 (1.5)*Routine discharge (%)68.0 (0.9)71.4 (3.6)77.1 (0.7)*Total charges (USD)44,190 (1505)55,282 (4654)141,742 (27,994)**P for trend <0.05. Open table in a new tab

Benefits of Treating Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Retrospective Analysis of 14 Patients

BackgroundArteriovenous malformations (AVMs) are a cardinal feature of hereditary hemorrhagic telangiectasia (HHT). However, whether to treat brain AVMs in patients with HHT remains questionable because of the possible risks.MethodsWe performed a retrospective study of patients with HHT who had been treated for brain AVMs at our institution from January 1, 2003, to December 31, 2016. An institutional database was queried for the phrases “hereditary hemorrhagic telangiectasia” and “HHT,” and those patients who had been treated during the study period were identified. Data were extracted regarding presentation, AVM characteristics, treatment modality, and treatment outcomes.ResultsWe identified 14 patients (10 males, 4 females) with HHT who had had AVMs (n = 27) from the institutional database. The mean age of the patients was 43 years (range, 2–64). Of the 27 brain AVMs, 13 were Spetzler-Martin grade I, 12 were grade II, and 2 were grade III; none were grade IV or V. Treatment was by microsurgery only (11 AVMs in 10 patients), embolization followed by microsurgery (2 AVMs in 2 patients), and radiosurgery only (12 AVMs in 2 patients). AVM obliteration was achieved in 100% of the patients. No new fixed neurologic deficits developed after treatment of unruptured HHT AVMs.ConclusionsThe risk of treatment of brain AVMs in patients with HHT is quite low for appropriately selected patients with treatment individualized to radiosurgery, microsurgery, or a combination of embolization and microsurgery.

Pericytes in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by multi-systemic vascular dysplasia affecting 1 in 5000 people worldwide. Individuals with HHT suffer from many complications including nose and gastrointestinal bleeding, anemia, iron deficiency, stroke, abscess, and high-output heart failure. Identification of the causative gene mutations and the generation of animal models have revealed that decreased transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling and increased vascular endothelial growth factor (VEGF) signaling activity in endothelial cells are responsible for the development of the vascular malformations in HHT. Perturbations in these key pathways are thought to lead to endothelial cell activation resulting in mural cell disengagement from the endothelium. This initial instability state causes the blood vessels to response inadequately when they are exposed to angiogenic triggers resulting in excessive blood vessel growth and the formation of vascular abnormalities that are prone to bleeding. Drugs promoting blood vessel stability have been reported as effective in preclinical models and in clinical trials indicating possible interventional targets based on a normalization approach for treating HHT. Here, we will review how disturbed TGF-β and VEGF signaling relates to blood vessel destabilization and HHT development and will discuss therapeutic opportunities based on the concept of vessel normalization to treat HHT.

A theory for polymicrogyria and brain arteriovenous malformations in HHT.

Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.

PULMONARY ARTERIOVENOUS MALFORMATION: A MYRIAD OF PRESENTATIONS

SESSION TITLE: Medical Student/Resident Pulmonary Vascular Disease 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Pulmonary arteriovenous malformations (PAVM) are abnormal direct communications between the pulmonary arteries and veins without interposition of a capillary bed. Heart failure in Hereditary hemorrhagic telangiectasia (HHT) due to hepatic AVM is a known entity. Heart failure due to PAVM is not well elucidated CASE PRESENTATION: A 78-year-old female with known history of HHT presented with orthopnea and pedal edema. Clinical examination was consistent with heart failure with raised jugular venous pressure and crackles on lung bases. She was started on lasix and digoxin. Echocardiogram and coronary angiogram on her initial presentation did not show any wall motion abnormalities or obstructive coronary disease. Over the following 3 years, her clinical course was complicated by gradually worsening cardiac function (table 1), atrial fibrillation, dual chamber pacemaker insertion, recurrent hypoxic episodes requiring supplemental home oxygen and 12 hospitalizations for above mentioned reasons. Bubble study during one of the recent hospitalizations showed appearance of bubbles in the left heart after 7 cardiac cycles suggesting an extra cardiac shunt. A CT angiogram of chest showed a 6.6 cm PAVM shunting blood from left pulmonary artery to left pulmonary vein (image 1 white arrow). Cardiac catheterization showed increased right heart pressures, with a mean pulmonary capillary wedge pressure of 27 mm hg and a step up in oxygen saturation of left pulmonary artery to 81% from 55% in right ventricle confirming shunting. Her PAVM was deemed to be the cause of her recurrent heart failure. Interventional radiology was consulted and pulmonary artery angiogram was performed with embolization of AVM by placing an amplatzer vascular plug (image 2). Post embolization her EF improved to 45%. Thereafter, she didn’t have any more hospitalizations for heart failure and is currently off Lasix. DISCUSSION: Congenital PAVMs are strongly associated with HHT. Up to one third of the patients with HHT can have PAVMs. The main pathophysiologic disturbance is shunting of blood from the pulmonary artery to veins resulting in delivery of desaturated oxygen to heart. Long standing hypoxia can cause pulmonary hypertension and preferential shunting of blood through PAVM, imposing an unusual volume load on the left ventricle which could initially result in high cardiac output. In the long run, this can cause dilated cardiomyopathy causing reduced ejection fraction and recurrent heat failure. Timely closure of symptomatic PAVMs with embolic agents,vascular plugs, coiling, surgical ligation or lobectomy could reduce or prevent the disease progression to recurrent or refractory heart failure, paradoxical embolisms. CONCLUSIONS: PAVM could be considered in the differential diagnosis when treating a patient with recurrent unexplained heart failure and hypoxia Reference #1: Pulmonary arteriovenous malformations presenting as refractory heart failure Reference #2: Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview DISCLOSURES: No relevant relationships by Abdullah Abdullah, source=Web Response No relevant relationships by Manuel Matos, source=Web Response No relevant relationships by Pratyusha Tirumanisetty, source=Web Response

Pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia: Correlations between computed tomography findings and cerebral complications.

Computed tomography (CT) is the modality of choice to characterise pulmonary arteriovenous malformations (PAVMs) in patients with hereditary haemorrhagic telangiectasia (HHT). Our objective was to determine if CT findings were associated with frequency of brain abscess and ischaemic stroke. This retrospective study included patients with HHT-related PAVMs. CT results, i.e. PAVM presentation (unique, multiple, disseminated or diffuse), the number of PAVMs and the largest feeding artery size, were correlated to prevalence of ischaemic stroke and brain abscess. All CTs were reviewed in consensus by two radiologists. Of 170 patients, 73 patients had unique (42.9 %), 49 multiple (28.8 %), 36 disseminated (21.2 %) and 12 diffuse (7.1 %) PAVMs. Fifteen patients presented with brain abscess; 26 patients presented with ischaemic stroke. The number of PAVMs was significantly correlated with brain abscess (11.5 vs. 6.2, respectively; p=0.025). The mean diameter of the largest feeding artery was significantly correlated with ischaemic stroke frequency (4.9 vs. 3.2 mm, respectively; p=0.0098). The number of PAVMs correlated significantly with risk of brain abscess, and a larger feeding artery significantly with more ischaemic strokes. These findings can lead to a better recognition and management of the PAVMs at risk of cerebral complications. • Chest CT helps clinicians to facilitate appropriate PAVM management strategies. • Pulmonary arteriovenous malformation CT findings are correlated with risk of cerebral complications. • Risk of brain abscess is significantly correlated with number of PAVMs. • Risk of ischaemic stroke is significantly correlated with large feeding artery PAVMs. • Prevalence of observed of brain abscess and ischaemic stroke is 26 %.

Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy. This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.

PROFILING AND CHARACTERIZING MICRORNAS IN PATIENTS WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA

Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant, vascular disorder that affects 1 in 5000 to 8000 individuals worldwide. HHT is characterized by vascular abnormalities, such as telangiectasias and arteriovenous malformations (AVMs). Telangiectasias are dilated skin and mucocutaneous blood vessels that are susceptible to spontaneous hemorrhage. AVMs are direct connections between arteries and veins, without intervening capillaries, and can cause significant right to left shunts. HHT arises from heterozygous mutations in at least 3 genes, ENG, ACVRL1, and SMAD4. Haploinsufficiency of their respective protein products perturb TGF signalling, affecting the angiogenic potential of endothelial cells (ECs) and the migratory capacity of monocytes, contributing to vascular malformations in HHT. MicroRNAs (miRs) are small non-coding RNAs that post-transcriptionally target mRNA transcripts. We aimed to profile and characterize miRs in HHT patient derived early endothelial progenitor cells (eEPCs) and peripheral blood mononuclear cells (PBMCs) to explore their potential role in HHT pathogenesis. EEPCs are early outgrowth ECs cultured from the mononuclear cell layer (buffy coat) of peripheral blood. They have been shown to augment angiogenesis in a paracrine manner by secreting various growth factors and are a widely accepted surrogate for studying EC function 28 HHT patients with confirmed mutations, and 25 controls were recruited. 40 ml of peripheral blood was collected for eEPC culture and PBMC isolation. Total RNA was isolated from PBMCs and eEPCs. PBMC and eEPC expression profiling was conducted with a human miR array analysis. Dysregulated miRs identified from the analyses were then validated with RT-qPCR. Significant differences were determined using a two-tailed t-test. Of the 800 miRs screened, 167 and 121 dysregulated miRs were identified in PBMCs and eEPCs, respectively. Selected PBMC miRs (MiRs-28-5p, -30b-5p, -361-3p and -374a-5p) and eEPC miRs (miRs-132-3p, -221-3p and -424-5p) were validated with RT-qPCR. PBMC miR-361-3p (p=0.025) known to target IGF1, and eEPC miR-132-3p (p=0.047) known to target SMAD2, were found to be significantly decreased compared to controls. Subsequently, IGF1 messenger RNA (mRNA) levels were significantly increased (p=0.005) in PBMCs of HHT patients compared to controls. Our results show dysregulation of select miRs in PBMCs and eEPCs from HHT patients. The finding of increased IGF1 mRNA and its possible relation to decreased miR-361-3p levels is both novel and exciting. This may represent a putative pathogenic mechanism involved in HHT, and may provide a unique miR therapeutic target for the treatment of clinical manifestations. National Institutes of Health (NIH)

Antithrombotic Use Predicts Recanalization of Embolized Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Antithrombotic Use Predicts Recanalization of Embolized Pulmonary Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia

Enfermedades vasculares del hígado. Guías Clínicas de la Sociedad Catalana de Digestología y de la Asociación Española para el Estudio del Hígado

Despite their relatively low prevalence, vascular diseases of the liver represent a significant health problem in the field of liver disease. A common characteristic shared by many such diseases is their propensity to cause portal hypertension together with increased morbidity and mortality. These diseases are often diagnosed in young patients and their delayed diagnosis and/or inappropriate treatment can greatly reduce life expectancy.This article reviews the current body of evidence concerning Budd-Chiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension, sinusoidal obstruction syndrome, hepatic vascular malformations in hereditary haemorrhagic telangiectasia, cirrhotic portal vein thrombosis and other rarer vascular diseases including arterioportal fistulas. It also includes a section on the diagnostic imaging of vascular diseases of the liver and their treatment from a haematological standpoint (study of thrombotic diathesis and anticoagulation therapy). All recommendations are based on published studies extracted from PubMed. The quality of evidence and strength of recommendations were rated in accordance with the GRADE system (Grading of Recommendations, Assessment Development and Evaluation). In the absence of sufficient evidence, recommendations were based on the opinion of the committee that produced the guide.