99 results found
Gill SS, Roddie ME, Shovlin CL, et al., 2015, Pulmonary arteriovenous malformations and their mimics., Clin Radiol, Vol: 70, Pages: 96-110
Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between the pulmonary arteries and veins, which result in a right-to-left (R-L) shunt with resultant hypoxemia, the severity of which will depend upon the size and number of lesions. Most PAVMs occur in individuals with hereditary haemorrhagic telangiectasia (HHT) and are a cause of serious morbidity and mortality largely related to cerebrovascular complications secondary to paradoxical embolization. The importance of their recognition and treatment by embolization, even in the absence of symptoms, is well known. Their appearances on chest radiographs are often, but not always, characteristic and the CT appearances are diagnostic; however, there are a number of both vascular and non-vascular diseases that can cause confusion. This review serves to highlight these PAVM "mimics".
Shovlin CL, 2014, Pulmonary arteriovenous malformations., Am J Respir Crit Care Med, Vol: 190, Pages: 1217-1228
Within the past decade, pulmonary arteriovenous malformations (PAVMs) have evolved from rare curiosities to not uncommon clinical states, with the latest estimates suggesting a prevalence of ~1 in 2,600. PAVMs provide anatomic right-to-left shunts, allowing systemic venous blood to bypass gas exchange and pulmonary capillary bed processing. Hypoxemia and enhanced ventilatory demands result, although both are usually asymptomatic. Paradoxical emboli lead to strokes and cerebral abscesses, and these commonly occur in individuals with previously undiagnosed PAVMs. PAVM hemorrhage is rare but is the main cause of maternal death in pregnancy. PAVM occlusion by embolization is the standard of care to reduce these risks. However, recent data demonstrate that currently recommended management protocols can result in levels of radiation exposure that would be classified as harmful. Recent publications also provide a better appreciation of the hematologic and cardiovascular demands required to maintain arterial oxygen content and oxygen consumption in hypoxemic patients, identify patient subgroups at higher risk of complications, and emphasize the proportion of radiologically visible PAVMs too small to treat by embolization. This review, therefore, outlines medical states that exacerbate the consequences of PAVMs. Chief among these is iron deficiency, which is commonly present due to concurrent hereditary hemorrhagic telangiectasia: iron deficiency impairs hypoxemia compensations by restricting erythropoiesis and increases the risk of ischemic strokes. Management of periodontal disease, dental interventions, pulmonary hypertension, and pregnancy also requires specific consideration in the setting of PAVMs. The review concludes by discussing to what extent previously recommended protocols may benefit from modification or revision.
Santhirapala V, Chamali B, McKernan H, et al., 2014, Orthodeoxia and postural orthostatic tachycardia in patients with pulmonary arteriovenous malformations: a prospective 8-year series, THORAX, Vol: 69, Pages: 1046-1047, ISSN: 0040-6376
Howard LSGE, Santhirapala V, Murphy K, et al., 2014, Cardiopulmonary Exercise Testing Demonstrates Maintenance of Exercise Capacity in Patients With Hypoxemia and Pulmonary Arteriovenous Malformations, CHEST, Vol: 146, Pages: 709-718, ISSN: 0012-3692
Elphick A, Shovlin CL, 2014, Relationships Between Epistaxis, Migraines, and Triggers in Hereditary Hemorrhagic Telangiectasia, LARYNGOSCOPE, Vol: 124, Pages: 1521-1528, ISSN: 0023-852X
Shovlin CL, 2014, Curable hypoxia in an octogenarian with an undiagnosed inherited condition: a case commentary, Breathe, Vol: 10, Pages: 153-156
Shovlin CL, 2014, Iron deficiency, ischaemic strokes, and right-to-left shunts: From pulmonary arteriovenous malformations to patent foramen ovale?, Intractable & Rare Diseases Research, Vol: 3, Pages: 60-64
Has the recent identification of iron deficiency as a risk factor for ischaemic stroke in patients with pulmonary arteriovenous malformations (AVMs) unmasked a new paradigm for stroke/ infarct pathogenesis? This commentary reviews evidence that spans associations between iron deficiency and ischaemic strokes, iron deficiency enhancement of platelet aggregation in response to serotonin/5HT, settings in which plasma 5HT is elevated, and clinical trial confirmation that 5HT receptor antagonists prevent ischaemic stroke. The critical leap which directs attention away from atherothrombotic events at the neurovascular wall is that ischaemic strokes due to pulmonary AVMs are attributable to compromised pulmonary capillary bed filtration of venous blood. Right-to-left shunting is continuous through pulmonary AVMs, but also occurs intermittently in approximately 30% of the general population with intracardiac shunts such as patent foramen ovale (PFO). The testable hypothesis presented is that paradoxical embolism of venous platelet-based aggregates may constitute part of the causal chain between iron deficiency and ischaemic stroke, not only in the rare disease state of pulmonary AVMs, but also in major subgroups of the general population.
Santhirapala V, Williams LC, Tighe HC, et al., 2014, Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations., PLOS One, Vol: 9
Devlin HL, Hosman AE, Silva BM, et al., 2014, Evaluation of anticoagulant and antiplatelet use in a haemorrhagic disorder, LANCET, Vol: 383, Pages: 40-40, ISSN: 0140-6736
Shovlin CL, Chamali B, Santhirapala V, et al., 2014, Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets., PLOS One
Background: Pulmonary first pass filtration of particles marginally exceeding ~7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.Methodology: 497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.Principal Findings: Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p =
Shovlin CL, Ganesan V, 2014, Hereditary hemorrhagic telangiectasia, Up to Date in Clinical Medicine, Editors: Ternauer
Hosman AE, Devlin HL, Silva BM, et al., 2013, Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls, ORPHANET JOURNAL OF RARE DISEASES, Vol: 8, ISSN: 1750-1172
Finnamore H, Le Couteur J, Hickson M, et al., 2013, Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency, PLOS ONE, Vol: 8, ISSN: 1932-6203
Shovlin CL, 2013, Hereditary hemorrhagic telangiectasia
Govani FS, Giess A, Mollet IG, et al., 2013, Directional Next-Generation RNA Sequencing and Examination of Premature Termination Codon Mutations in Endoglin/Hereditary Haemorrhagic Telangiectasia, Molecular Syndromology, Vol: 4, Pages: 184-196, ISSN: 1661-8777
Hereditary haemorrhagic telangiectasia (HHT) is a disease characterised by abnormal vascular structures, and most commonly caused by mutations in ENG, ACVRL1 or SMAD4 encoding endothelial cell-expressed proteins involved in TGF- superfamily signalling. The majority of mutations reported on the HHT mutation database are predicted to lead to stop codons, either due to frameshifts or direct nonsense substitutions. The proportion is higher for ENG (67%) and SMAD4 (65%) than for ACVRL1 (42%), p<0.0001). Here, by focussing on ENG, we report why conventional views of these mutations may need to be revised. Of the 111 stop codon-generating ENG mutations, on ExPASy translation, all except one was a premature termination codon, sited at least 50-55bp upstream of the final exon-exon boundary of the main endoglin isoform, L-endoglin. This strongly suggests that the mutated RNA species will undergo nonsense mediated decay. We provide new in vitro expression data to support dominant negative activity of stable truncated endoglin proteins but suggest these will not generate HHT: The single natural stop codon mutation in L-endoglin (sited within 50-55nucleotides of the final exon-exon boundary) is unlikely to generate functional protein since it replaces the entire transmembrane domain, as would eight further natural stop codon mutations, if the minor S-endoglin isoform were implicated in HHT pathogeneses. Finally, next generation RNA sequencing data of seven different RNA libraries from primary human endothelial cells demonstrate that multiple intronic regions of ENG are transcribed. The potential consequences of heterozygous deletions or duplications of such regions are discussed. These data support the haploinsufficiency model for HHT pathogenesis; explain why final exon mutations have not been detected to date in HHT; emphasise the potential need for functional examination of non PTC-generating mutations; and lead to proposals for an alternate stratification system of
Devlin HL, Hosman AE, Shovlin CL, 2013, Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia., New England Journal of Medicine, Vol: 368, Pages: 876-878
Silva BM, Hosman AE, Devlin HL, et al., 2013, Lifestyle and Dietary Influences on Nosebleed Severity in Hereditary Hemorrhagic Telangiectasia, Laryngoscope, Vol: 123, Pages: 1092-1099, ISSN: 0023-852X
BJECTIVES/HYPOTHESIS:To identify factors influencing the severity of epistaxis in hereditary hemorrhagic telangiectasia (HHT).STUDY DESIGN:Participants with and without HHT were recruited from a specialist service and online following advertisement by the HHT Foundation International. Both groups were asked to complete a nonbiased questionnaire.METHODS:The reported effects of specific treatments or lifestyle factors on epistaxis were assigned positive values if beneficial, negative values if detrimental, or zero if "no difference" and were summed to enable statistical analysis.RESULTS:Epistaxis affected 649 of 666 (97%) participants with HHT and was significantly more frequent than in control participants. Specialist invasive treatments were reported as beneficial, laser therapy more frequently than cauterization. Medical treatments commonly used for HHT epistaxis (female hormones, antiestrogens, tranexamic acid, aminocaproic acid, nasal creams, and bevacizumab) also had significantly positive (beneficial) scores. Lifestyle and dietary factors were generally detrimental, but room humidification, nasal lubrication, and saline treatments were all reported as beneficial (95% confidence intervals greater than zero). Multiple food items were volunteered as being detrimental to epistaxis. The most frequently reported items were alcohol (n = 45; 6.8% of participants) and spices (n = 26, 3.9% of participants). Remaining foods reported to exacerbate epistaxis were also found to be high in salicylates (including red wine, spices, chocolate, coffee, and certain fruits), natural antiplatelet activity (garlic, ginger, ginseng, ginkgo biloba, and vitamin E15), or omega-3 acids (oily fish, salmon).CONCLUSIONS:This study supports existing treatments and suggests lifestyle and dietary maneuvers that may also improve nosebleeds in HHT.
Letarte M, Shovlin CL, 2012, Hemostasis and Thrombosis, Hemostasis and Thrombosis, Editors: Marder, Aird, Bennett, Schulman S, White, Publisher: LWW, Pages: 855-864, ISBN: 9781608319060
Hereditary hemorrhagic telangiectasia
Mason CG, Shovlin CL, 2011, Flight-related complications are infrequent in patients with hereditary haemorrhagic telangiectasia/pulmonary arteriovenous malformations, despite low oxygen saturations and anaemia., Thorax
Individuals with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia (HHT) commonly have low oxygen saturations and anaemia, two parameters generally used to indicate medical fitness to fly. Using a retrospective questionnaire-based study, the authors examined in-flight complications and predictors in 145 HHT patients (96 with PAVMs) who reported 3950 flights, totalling 18 943 flight hours. Dyspnoea and thrombotic complications were less common than expected, and could not be predicted from sea level oxygen saturations or haemoglobin concentrations. Nosebleeds that can bar individuals from boarding a flight occurred in 13.6% (11.5% to 15.8%) of long-haul flights. The findings should influence preflight advice.
Ahmedzai S, Balfour-Lynn IM, Bewick T, et al., 2011, Managing passengers with stable respiratory disease planning air travel: British Thoracic Society recommendations, THORAX, Vol: 66, Pages: 1-30, ISSN: 0040-6376
Roked F, Jackson JE, Fuld J, et al., 2011, Pulmonary Thromboemboli Modifying the Natural History of Pulmonary Arteriovenous Malformations, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 183, Pages: 828-829, ISSN: 1073-449X
Shovlin CL, Wilmshurst P, Jackson JE, 2011, Pulmonary arteriovenous malformations and other pulmonary aspects of hereditary haemorrhagic telangiectasia, Eur Respir Mon, Pages: 218-245
Hart JL, Aldin Z, Braude P, et al., 2010, Embolization of pulmonary arteriovenous malformations using the Amplatzer vascular plug: successful treatment of 69 consecutive patients, EUROPEAN RADIOLOGY, Vol: 20, Pages: 2663-2670, ISSN: 0938-7994
Shovlin CL, 2010, Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment., Blood Reviews, Vol: 24, Pages: 203-219, ISSN: 1532-1681
Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings.
Shovlin CL, Oh P, 2010, Hereditary hemorrhagic telangiectasia, Molecular Basis of Lung Disease, Editors: McCormack, Panos, Trapnell, Publisher: Springer Science and Business Media, Pages: 167-183
Govani FS, Shovlin CL, 2010, Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes., J Angiogenes Res, Vol: 2
BACKGROUND: There is significant interest in new loci for the inherited condition hereditary haemorrhagic telangiectasia (HHT) because the known disease genes encode proteins involved in vascular transforming growth factor (TGF)-beta signalling pathways, and the disease phenotype appears to be unmasked or provoked by angiogenesis in man and animal models. In a previous study, we mapped a new locus for HHT (HHT3) to a 5.7 Mb region of chromosome 5. Some of the polymorphic markers used had been uninformative in key recombinant individuals, leaving two potentially excludable regions, one of which contained loci for attractive candidate genes encoding VE Cadherin-2, Sprouty4 and FGF1, proteins involved in angiogenesis. METHODS: Extended analyses in the interval-defining pedigree were performed using informative genomic sequence variants identified during candidate gene sequencing. These variants were amplified by polymerase chain reaction; sequenced on an ABI 3730xl, and analysed using FinchTV V1.4.0 software. RESULTS: Informative genomic sequence variants were used to construct haplotypes permitting more precise citing of recombination breakpoints. These reduced the uninformative centromeric region from 141.2-144 Mb to between 141.9-142.6 Mb, and the uninformative telomeric region from 145.2-146.9 Mb to between 146.1-146.4 Mb. CONCLUSIONS: The HHT3 interval on chromosome 5 was reduced to 4.5 Mb excluding 30% of the coding genes in the original HHT3 interval. Strong candidates VE-cadherin-2 and Sprouty4 cannot be HHT3.
Shovlin CL, Angus G, Manning RA, et al., 2010, Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension., PLoS One, Vol: 5
BACKGROUND: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by RT-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab-reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5' exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms. CONCLUSIONS/SIGNIFICANCE: The pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future re
Shovlin CL, Jackson JE, 2010, Pulmonary arteriovenous malformations and other pulmonary vascular abnormalities., Murray and Nadel’s Textbook of Respiratory Medicine, Editors: Mason, Broaddus, Martin, King, Schraufnagel, Murray, Nadel, Publisher: Saunders Elsevier, Pages: 1261-1282
Shovlin CL, 2009, Ischaemic stroke and thrombolysis- time to consider the HHT question, eBMJ
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.