Imperial College London

Claire L. Shovlin PhD FRCP

Faculty of MedicineNational Heart & Lung Institute

Professor of Practice (Clinical and Molecular Medicine)
 
 
 
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c.shovlin Website

 
 
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534Block L Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

123 results found

Shovlin CL, Buscarini E, SabbĂ  C, Mager HJ, Kjeldsen AD, Pagella F, Sure U, Ugolini S, Toerring PM, Suppressa P, Rennie C, Post MC, Patel MC, Nielsen TH, Manfredi G, Lenato GM, Lefroy D, Kariholu U, Jones B, Fialla AD, Eker OF, Dupuis O, Droege F, Coote N, Boccardi E, Alsafi A, Alicante S, Dupuis-Girod Set al., 2022, The European rare disease network for HHT frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care., European Journal of Medical Genetics, Vol: 65, Pages: 104370-104370, ISSN: 1769-7212

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

Journal article

Joyce KE, Onabanjo E, Brownlow S, Nur F, Olupona K, Fakayode K, Sroya M, Thomas GA, Ferguson T, Redhead J, Millar CM, Cooper N, Layton DM, Boardman-Pretty F, Caulfield MJ, Genomics England Research Consortium GE, Shovlin CLet al., 2022, Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variants, Blood Advances, Vol: 6, Pages: 3956-3969, ISSN: 2473-9529

The abnormal vascular structures of hereditary hemorrhagic telangiectasia (HHT) often cause severe anemia due to recurrent hemorrhage, but HHT-causal genes do not predict the severity of hematological complications. We tested for chance inheritance and clinical associations of rare deleterious variants where loss-of-function causes bleeding or hemolytic disorders in the general population. In double-blinded analyses, all 104 HHT patients from a single reference centre recruited to the 100,000 Genomes Project were categorised on new MALO (more/as-expected/less/opposite) sub-phenotype severity scales, and whole genome sequencing data tested for high impact variants in 75 HHT-independent genes encoding coagulation factors, platelet, hemoglobin, erythrocyte enzyme and erythrocyte membrane constituents. Rare variants (all GnomAD allele frequencies <0.003) were identified in 56 (75%) of these 75 HHT-unrelated genes, and in 38/104 (36.5%) of the HHT patients. Likely deleteriousness assignments by Combined Annotation Dependent Depletion (CADD) scores >15 were supported by gene-level mutation significance cutoff (MSC) scores. CADD>15 variants were found for 1 in 10 patients within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to HHT vessels had more CADD-deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. However, the HHT cohort had 60% fewer deleterious variants in platelet and coagulation genes than expected (Mann Whitney p=0.021). In conclusion, HHT patients commonly have rare variants in genes of relevance to their phenotype, offering new therapeutic targets and opportunities for informed, personalised medicine strategies.

Journal article

Topiwala KK, Patel SD, Saver JL, Streib CD, Shovlin CLet al., 2022, Ischemic Stroke and Pulmonary Arteriovenous Malformations (vol 98, pg 188, 2022), NEUROLOGY, Vol: 98, Pages: 864-864, ISSN: 0028-3878

Journal article

Pirmohammed M, O’Donoghue D, Turner R, Magavern E, Roebuck D, Ross P, Keavney B, Shovlin C, Popoola J, Nasser S, McEntagart M, Sanghvi S, Seller A, Bishop M, Caulfield M, Sharma R, Rafi I, Hayward Jet al., 2022, Personalised Prescribing. Using pharmacogenomics to improve patient outcomes. A report from the Royal College of Physicians and British Pharmacological Society joint working party

A new report from the Royal College of Physicians and British Pharmacological Society joint working party considers the opportunities provided by increasing pharmacogenomic testing.

Report

Balachandar S, Graves TJ, Shimonty A, Kerr K, Kilner J, Xiao S, Slade R, Sroya M, Alikian M, Curetean E, Thomas E, McConnell VPM, McKee S, Boardman-Pretty F, Devereau A, Fowler TA, Caulfield MJ, Alton EW, Ferguson T, Redhead J, McKnight AJ, Thomas GA, Aldred MA, Shovlin CLet al., 2022, Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations, American Journal of Medical Genetics Part A, Vol: 188, Pages: 959-964, ISSN: 0148-7299

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.

Journal article

Anderson E, Sharma L, Alsafi A, Shovlin CLet al., 2022, Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia, THORAX, Vol: 77, Pages: 628-630, ISSN: 0040-6376

Journal article

Anderson E, Sharma L, Alsafi A, Shovlin Cet al., 2022, Genetically confirmed hereditary haemorrhagic telangiectasia commonly displays few manifestations - pulmonary arteriovenous malformations may be the sole clinical diagnostic criterion, Thorax, ISSN: 0040-6376

Pulmonary arteriovenous malformations (PAVMs) result in preventable complications demanding speciality care. Underlying hereditary haemorrhagic telangiectasia (HHT) can be identified by genetictesting, if the diagnosis is considered. Retrospectively reviewing 152 unrelated adults with genetically-confirmed HHT due to ACVRL1, ENG, or SMAD4, only 104/152 (68%) met a clinical diagnosis of HHT with 3 Curaçao criteria. The genetic diagnostic rate was similar for patients with 3 criteria (104/137 [76%]) or 1-2 (48/71 [68%], p=0.25). Of 83 unrelated probands with PAVM(s) and genetically-confirmed HHT, 20/83 [24%] had few if any features of HHT. Enhanced clinical suspicion, and HHT genetic testing, is recommended if one or more PAVMs are present.

Journal article

Topiwala KK, Patel SD, Saver JL, Streib CD, Shovlin CLet al., 2021, Ischemic stroke and pulmonary arteriovenous malformations: a review., Neurology, Vol: 98, Pages: 1-1, ISSN: 0028-3878

The potential of covert pulmonary arteriovenous malformations (PAVMs) to cause early onset, preventable ischemic strokes is not well known to neurologists. This is evident by their lack of mention in serial American Heart Association/ American Stroke Association (AHA/ASA) Guidelines, and the single case-report biased literature of recent years. To inform, we performed PubMed and Cochrane database searches for major studies on ischemic stroke and PAVMs published from January 1, 1974 through April 3, 2021. This identified twenty-four major observational studies, three societal guidelines, one nationwide analysis, three systematic reviews, twenty-one other review/opinion articles, and eighteen recent (2017-2021) case-reports/series that were synthesized. Key points are that patients with PAVMs suffer ischemic stroke a decade earlier than routine stroke, losing nine extra healthy-life-years per patient in the recent US nationwide analysis (2005-2014). Large-scale thoracic CT screens of the general population in Japan estimate PAVM prevalence to be 38/100,000 (95% confidence interval 18-76), with ischemic stroke rates exceeding 10% across PAVM series dating back to the 1950s, with most PAVMs remaining undiagnosed until the time of clinical stroke. Notably, the rate of PAVM diagnoses doubled in US ischemic stroke hospitalizations between 2005-2014. The burden of silent cerebral infarction approximates to twice that of clinical stroke. Over 80% patients have underlying hereditary hemorrhagic telangiectasia (HHT). The predominant stroke mechanism is paradoxical embolization of platelet-rich emboli, with iron-deficiency emerging as a modifiable risk-factor. PAVM related ischemic strokes may be cortical or subcortical, but very rarely cause proximal large vessel occlusions. Single antiplatelet therapy maybe effective for secondary stroke prophylaxis, with dual antiplatelet or anticoagulation therapy requiring nuanced risk-benefit analysis given their risk of aggravating iron

Journal article

Bernabeu-Herrero M, Patel D, Bielowka A, Srikaran S, Guerrero PC, Govani F, Mollet I, Noseda M, Aldred M, Shovlin Cet al., 2021, Heterozygous transcriptional and nonsense decay signatures in blood outgrowth endothelial cells from patients with hereditary haemorrhagic telangiectasia, Publisher: BioRxiv

In order to identify cellular phenotypes resulting from nonsense (gain of stop/premature termination codon) variants, we devised a framework of analytic methods that minimised confounder contributions, and applied to blood outgrowth endothelial cells (BOECs) derived from controls and patients with heterozygous nonsense variants in ACVRL1 , ENG or SMAD4 causing hereditary haemorrhagic telangiectasia (HHT). Following validation of 48 pre-selected genes by single cell qRT-PCR, discovery RNASeq ranked HHT-differential alignments of 16,807 Ensembl transcripts. Consistent gene ontology (GO) processes enriched compared to randomly-selected gene lists included bone morphogenetic protein, transforming growth factor-β and angiogenesis GO processes already implicated in HHT, further validating methodologies. Additional terms/genes including for endoplasmic reticulum stress could be attributed to a generic process of inefficient nonsense mediated decay (NMD). NMD efficiency ranged from 78-92% (mean 87%) in different BOEC cultures, with misprocessed mutant protein production confirmed by pulse chase experiments. Genes in HHT-specific and generic nonsense decay (ND) lists displayed differing expression profiles in normal endothelial cells exposed to an additional stress of exogenous 10μmol/L iron which acutely upregulates multiple mRNAs: Despite differing donors and endothelial cell types, >50% of iron-induced variability could be explained by the magnitude of transcript downregulation in HHT BOECs with less efficient NMD. The Genotype Tissue Expression (GTEx) Project indicated ND list genes were usually most highly expressed in non-endothelial tissues. However, across 5 major tissues, although 18/486 nonsense and frameshift variants in highly expressed genes were captured in GTEx, none were sufficiently prevalent to obtain genome-wide significant p values for expression quantitative trait loci (GnomAD allele frequencies <0.0005). In conclusion, RNASeq analytics of

Working paper

Joyce KE, Onabanjo E, Brownlow S, Nur F, Olupona KO, Fakayode K, Sroya M, Thomas G, Ferguson T, Redhead J, Millar CM, Cooper N, Layton DM, Boardman-Pretty F, Caulfield MJ, Shovlin CLet al., 2021, High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine, Publisher: Cold Spring Harbor Laboratory

Possession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman ρ=0.25, p=0.008) and coagulation (Spearman ρ=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.

Working paper

Davieson CD, Joyce KE, Sharma L, Shovlin CLet al., 2021, DNA variant classification–reconsidering “allele rarity” and “phenotype” criteria in ACMG/AMP guidelines, European Journal of Medical Genetics, Vol: 64, Pages: 1-5, ISSN: 1769-7212

Recent guidance suggested modified DNA variant pathogenicity assignments based on genome-wide allele rarity. Different a priori probabilities of pathogenicity operate where patients already have clinical diagnoses, and are found to have a very rare variant in a gene known to cause their disease, compared to predictive testing of a clinically unaffected individual. We tested new recommendations from the ClinGen Sequence Variant Interpretation Working Group for ClinVar-listed, loss-of-function variants meeting the very strong evidence of pathogenicity criterion [PVS1] in genes for 3 specific diseases where causal gene identification can modify clinical care of an individual- Von Willebrand disease, cystic fibrosis and hereditary haemorrhagic telangiectasia. Across these diseases, current rules leave 20/1278 (1.6%) of loss-of-function variants as variants of uncertain significance (VUS that may not be reported to clinicians), and 207/1278 (17.2%) as likely pathogenic. Applying the new ClinGen rule enabling PM2 and PVS1 to delineate likely pathogenicity still left 8/1278 (0.9%) as VUS (reflecting non-PVS1 calls by the submitters), and the majority of null alleles meeting PVS1 as merely likely pathogenic. We favour an approach whereby, for PVS1 variants in patients who personally meet PP4 in a disease where casual variants are commonly family-specific, the PM2 allele rarity criterion is upgraded to permit a pathogenic call. Of 1278 ClinVar-listed frameshift, nonsense and canonical splice site variants that met PVS1 in the 3 conditions, 16.0% (204/1278) would be newly designated as pathogenic, avoiding misinterpretation outside of clinical genetics communities. We suggest further discussion around variant assessment across different clinical applications, potentially guided by PP4 alerts to distinguish personal versus family phenotypic history.

Journal article

Alsafi A, Shovlin CL, Jackson JE, 2021, Transpleural systemic artery-pulmonary artery communications in the absence of chronic inflammatory lung disease. A case series and review of the literature, Clinical Radiology, Vol: 76, Pages: 711.e9-711.e15, ISSN: 0009-9260

AIM: To describe the causes and computed tomography (CT) and angiographic appearances of transpleural systemic artery-pulmonary artery shunts in patients without chronic inflammatory lung disease and determine their best management. MATERIALS AND METHODS: All patients referred to a tertiary referral unit between January 2013 and January 2020 in whom a diagnosis of a systemic-pulmonary artery communication without underlying chronic inflammatory lung disease was subsequently made have been included in this report. Medical records and imaging findings were reviewed retrospectively. RESULTS: Ten patients (male: female ratio = 7:3; median age 42 years [range 22-70 years]) with systemic artery-pulmonary artery shunts without chronic inflammatory lung disease were identified. Five were misdiagnosed as having a pulmonary arteriovenous malformation and had been referred for embolisation. In six patients, there was either a history of accidental or iatrogenic thoracic trauma or of inflammatory disease involving the pleura, and in two patients, in whom a previous medical history could not be obtained, there were CT features suggesting previous pleural inflammatory disease. Two shunts were thought to be congenital. All individuals were asymptomatic other than one with localised thoracic discomfort that dated from the time of surgery. All patients were managed conservatively and have remained well with a median follow-up of 4.5 years (range 1-11.3 years). CONCLUSIONS: Localised transpleural systemic artery-pulmonary artery shunts in the absence of chronic inflammatory lung disease are usually related to previous thoracic trauma/intervention or abdominal or pulmonary sepsis involving a pleural or diaphragmatic surface. Congenital shunts are rare. The present study and much of the literature supports conservative management.

Journal article

Topiwala KK, Patel SD, Pervez M, Shovlin CL, Alberts MJet al., 2021, Ischemic stroke in patients with pulmonary arteriovenous fistulas, Stroke, Vol: 52, Pages: E311-E315, ISSN: 0039-2499

Background and Purpose:Pulmonary arteriovenous fistulas (PAVFs) are a treatable cause of acute ischemic stroke (AIS), not mentioned in current American Heart/Stroke Association guidelines. PAVFs are recognized as an important complication of hereditary hemorrhagic telangiectasia.Methods:The prevalence of PAVF and hereditary hemorrhagic telangiectasia among patients admitted with AIS in the United States (2005–2014) was retrospectively studied, utilizing the Nationwide Inpatient Sample database. Clinical factors, morbidity, mortality, and management were compared in AIS patients with and without PAVF/hereditary hemorrhagic telangiectasia.Results:Of 4 271 910 patients admitted with AIS, 822 (0.02%) were diagnosed with PAVF. Among them, 106 of 822 (12.9%) were diagnosed with hereditary hemorrhagic telangiectasia. The prevalence of PAVF per million AIS admissions rose from 197 in 2005 to 368 in 2014 (Ptrend, 0.026). Patients with PAVF were younger than AIS patients without PAVF (median age, 57.5 versus 72.5 years), had lower age-adjusted inpatient morbidity (defined as any discharge other than home; 39.6% versus 46.9%), and had lower in-hospital case fatality rates (1.8% versus 5.1%). Multivariate analyses identified the following as independent risk markers (odds ratio [95% CI]) for AIS in patients with PAVF: hypoxemia (8.4 [6.3–11.2]), pulmonary hemorrhage (7.9 [4.1–15.1]), pulmonary hypertension (4.3 [4.1–15.1]), patent foramen ovale (4.2 [3.5–5.1]), epistaxis (3.7 [2.1–6.8]), venous thrombosis (2.6 [1.9–3.6]), and iron deficiency anemia (2 [1.5–2.7]). Patients with and without PAVF received intravenous thrombolytics at a similar rate (5.9% versus 5.8%), but those with PAVF did not receive mechanical thrombectomy (0% versus 0.7%).Conclusions:Pulmonary arteriovenous fistula–related ischemic stroke represents an important younger demographic with a unique set of stroke risk markers, including treatable

Journal article

Clarke J, Alikian M, Xiao S, Kasperaviciute D, Thomas E, Turbin I, Rose G, Olupona K, Cifra E, Curetean E, Ferguson T, Redhead J, Genomics England Research Consortium, Shovlin Cet al., 2020, Low grade mosaicism in hereditary haemorrhagic telangiectasia identified by bidirectional whole genome sequencing reads through the 100,000 Genomes Project clinical diagnostic pipeline, Journal of Medical Genetics, Vol: 57, Pages: 859-862, ISSN: 0022-2593

For rare inherited diseases an important question is what type of clinical diagnostic test to select, for instance Sanger-based single genesequencing; a high read depth gene panel; whole exomesequencingor whole genome sequencing. There is emerging recognitionthat a transmissible parental variant present at less than expected heterozygous frequency (due to mosaicism) may escape detection by certain methods. This risk has been proposed as a factor infavourof higher depth sequencingstrategies. Here we report a case where barely 30-fold depth whole genome sequencing through the 100,000 Genomes Project identified low grade mosaicismthat had been missed by conventional Sanger sequencing.

Journal article

Shovlin C, Simeoni I, Downes K, Frazer Z, Megy K, Bernabeu-Herrero M, Shurr A, Brimley J, Patel D, Kell L, Stephens J, Turbin I, Aldred M, Penkett C, Stirrups K, Ouwehand W, Jovine L, Turro Eet al., 2020, Mutational and phenotypic characterisation of hereditary hemorrhagic telangiectasia, Blood, Vol: 136, Pages: 1907-1918, ISSN: 0006-4971

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

Journal article

Vizcaychipi M, Shovlin C, McCarthy A, Howard A, Brown A, Hayes M, Singh S, Christie L, Sisson A, Davies R, Lockie C, Popescu M, Gupta A, Armstrong J, Said H, Peters T, Keays RT, Consortium CCet al., 2020, Development and implementation of a COVID-19 near real time traffic light system in an acute hospital setting, Emergency Medicine Journal, Vol: 37, Pages: 630-636, ISSN: 1472-0205

Common causes of death in COVID-19 due to SARS-CoV-2 include thromboembolic disease, cytokine storm and adult respiratory distress syndrome (ARDS). Our aim was to develop a system for early detection of disease pattern in the emergency department (ED) that would enhance opportunities for personalised accelerated care to prevent disease progression. A single Trust’s COVID-19 response control command was established, and a reporting team with bioinformaticians was deployed to develop a real-time traffic light system to support clinical and operational teams. An attempt was made to identify predictive elements for thromboembolism, cytokine storm and ARDS based on physiological measurements and blood tests, and to communicate to clinicians managing the patient, initially via single consultants. The input variables were age, sex, and first recorded blood pressure, respiratory rate, temperature, heart rate, indices of oxygenation and C-reactive protein. Early admissions were used to refine the predictors used in the traffic lights. Of 923 consecutive patients who tested COVID-19 positive, 592 (64%) flagged at risk for thromboembolism, 241/923 (26%) for cytokine storm and 361/923 (39%) for ARDS. Thromboembolism and cytokine storm flags were met in the ED for 342 (37.1%) patients. Of the 318 (34.5%) patients receiving thromboembolism flags, 49 (5.3% of all patients) were for suspected thromboembolism, 103 (11.1%) were high-risk and 166 (18.0%) were medium-risk. Of the 89 (9.6%) who received a cytokine storm flag from the ED, 18 (2.0% of all patients) were for suspected cytokine storm, 13 (1.4%) were high-risk and 58 (6.3%) were medium-risk. Males were more likely to receive a specific traffic light flag. In conclusion, ED predictors were used to identify high proportions of COVID-19 admissions at risk of clinical deterioration due to severity of disease, enabling accelerated care targeted to those more likely to benefit. Larger prospective studies are encouraged.

Journal article

Faughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, Deslandres E, Kasthuri RS, Lausman A, Poetker D, Ratjen F, Chesnutt MS, Clancy M, Whitehead KJ, Al-Samkari H, Chakinala M, Conrad M, Cortes D, Crocione C, Darling J, de Gussem E, Derksen C, Dupuis-Girod S, Foy P, Geisthoff U, Gossage JR, Hammill A, Heimdal K, Henderson K, Iyer VN, Kjeldsen AD, Komiyama M, Korenblatt K, McDonald J, McMahon J, McWilliams J, Meek ME, Mei-Zahav M, Olitsky S, Palmer S, Pantalone R, Piccirillo JF, Plahn B, Porteous MEM, Post MC, Radovanovic I, Rochon PJ, Rodriguez-Lopez J, Sabba C, Serra M, Shovlin C, Sprecher D, White AJ, Winship I, Zarrabeitia Ret al., 2020, Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia., Annals of Internal Medicine, Pages: 1-16, ISSN: 0003-4819

DESCRIPTION: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. METHODS: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. RECOMMENDATIONS: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into

Journal article

Vizcaychipi MP, Shovlin CL, McCarthy A, Godfrey A, Patel S, Shah PL, Hayes M, Keays RT, Beveridge Iet al., 2020, Increase in COVID-19 inpatient survival following detection of Thromboembolic and Cytokine storm risk from the point of admission to hospital by a near real time Traffic-light System (TraCe-Tic), The Brazilian Journal of Infectious Diseases, Vol: 24, Pages: 412-421, ISSN: 1413-8670

IntroductionOur goal was to evaluate if traffic-light driven personalized care for COVID-19 was associated with improved survival in acute hospital settings.MethodsDischarge outcomes were evaluated before and after prospective implementation of a real-time dashboard with feedback to ward-based clinicians. Thromboembolic categories were “medium-risk” (D-dimer >1000 ng/mL or CRP >200 mg/L); “high-risk” (D-dimer >3000 ng/mL or CRP >250 mg/L) or “suspected” (D-dimer >5000 ng/mL). Cytokine storm risk was categorized by ferritin.Results939/1039 COVID-19 positive patients (median age 69 years, 563/939 (60%) male) completed hospital encounters to death or discharge by 21st May 2020. Thromboembolic flag criteria were reached by 568/939 (60.4%), including 238/275 (86.6%) of the patients who died, and 330/664 (49.7%) of the patients who survived to discharge, p < 0.0001. Cytokine storm flag criteria were reached by 212 (22.5%) of admissions, including 80/275 (29.0%) of the patients who died, and 132/664 (19.9%) of the patients who survived, p < 0.0001. The maximum thromboembolic flag discriminated completed encounter mortality (no flag: 37/371 [9.97%] died; medium-risk: 68/239 [28.5%]; high-risk: 105/205 [51.2%]; and suspected thromboembolism: 65/124 [52.4%], p < 0.0001). Flag criteria were reached by 535 consecutive COVID-19 positive patients whose hospital encounter completed before traffic-light introduction: 173/535 (32.3% [95% confidence intervals 28.0, 36.0]) died. For the 200 consecutive admissions after implementation of real-time traffic light flags, 46/200 (23.0% [95% confidence intervals 17.1–28.9]) died, p = 0.013. Adjusted for age and sex, the probability of death was 0.33 (95% confidence intervals 0.30–0.37) before traffic light implementation, 0.22 (0.17–0.27) after implementation, p < 0.001. In subgroup analyses, older patients, males, and patients with hypertension (p ≤ 0.01)

Journal article

Shovlin CL, Vizcaychipi MP, 2020, Vascular inflammation and endothelial injury in SARS-CoV-2 infection: the overlooked regulatory cascades implicated by the ACE2 gene cluster, QJM: an international journal of medicine, ISSN: 1460-2393

COVID-19 has presented physicians with an unprecedented number of challenges and mortality. The basic question is why, in contrast to other "respiratory" viruses, SARS-CoV-2 infection can result in such multi-systemic, life-threatening complications and a severe pulmonary vasculopathy. It is widely known that SARS-CoV-2 uses membrane-bound angiotensin-converting enzyme 2 (ACE2) as a receptor, resulting in internalisation of the complex by the host cell. We discuss the evidence that failure to suppress coronaviral replication within 5 days results in sustained downregulation of ACE2 protein expression, and that ACE2 is under negative-feedback regulation. We then expose openly-available experimental repository data that demonstrate the gene for ACE2 lies in a novel cluster of interegulated genes on the X chromosome including PIR encoding pirin (quercetin 2,3-dioxygenase), and VEGFD encoding the predominantly lung-expressed vascular endothelial growth factor D. The five double-elite enhancer/promoters that are known to be operational, and shared read-through lncRNA transcripts, imply that ongoing SARS-CoV-2 infection will reduce host defences to reactive oxygen species, directly generate superoxide O2 - and H2O2 (a "ROS storm"), and impair pulmonary endothelial homeostasis. Published cellular responses to oxidative stress complete the loop to pathophysiology observed in severe COVID-19. Thus for patients who fail to rapidly suppress viral replication, the newly-appreciated ACE2 co-regulated cluster predicts delayed responses that would account for catastrophic deteriorations. We conclude that ACE2 homeostatic drives provide a unified understanding which should help optimise therapeutic approaches during the wait until safe, effective vaccines and antiviral therapies for SARS-CoV-2 are delivered.

Journal article

Eker OF, Boccardi E, Sure U, Patel MC, Alicante S, Alsafi A, Coote N, Droege F, Dupuis O, Fialla AD, Jones B, Kariholu U, Kjeldsen AD, Lefroy D, Lenato GM, Mager HJ, Manfredi G, Nielson TH, Pagella F, Post MC, Rennie C, Sabba C, Suppressa P, Torring PM, Ugolini S, Buscarini E, Dupuis-Girod S, Shovlin CLet al., 2020, European Reference Network for Rare Vascular Diseases (VASCERN) Position Statement on Cerebral Screening in Adults and Children with Hereditary Haemorrhagic Telangiectasia (HHT), Orphanet Journal of Rare Diseases, Vol: 15, ISSN: 1750-1172

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an “AVM” bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any

Journal article

Shovlin C, Vizcaychipi M, 2020, COVID-19 genomic susceptibility: Definition of ACE2 variants relevant to human infection with SARS-CoV-2 in the context of ACMG/AMP Guidance, Publisher: medRxiv

BACKGROUND Mortality remains very high and unpredictable in COVID-19, with intense public protection strategies tailored to preceived risk. Males are at greater risk of severe COVID-19 complications. Genomic studies are in process to identify differences in host susceptibility to SARS-CoV-2 infection. METHODS Genomic structures were examined for the ACE2 gene that encodes angiotensin-converting enzyme 2, the obligate receptor for SARS-CoV-2. Variants in 213,158 exomes/genomes were integrated with ACE2 protein functional domains, and pathogenicity criteria from the American Society of Human Genetics and Genomics/Association for Molecular Pathology. RESULTS 483 variants were identified in the 19 exons of ACE2 on the X chromosome. All variants were rare, including nine loss-of-function (potentially SARS-CoV-2 protective) alleles present only in female heterozygotes. Unopposed variant alleles were more common in males (262/3596 [7.3%] nucleotides) than females (9/3596 [0.25%] nucleotides, p<0.0001). 37 missense variants substituted amino acids in SARS-CoV-2 interacting regions or critical domains for transmembrane ACE2 expression. Four upstream open reading frames with 31 associated variants were identified. Excepting loss-of-function alleles, variants would not meet minimum criteria for classification as Likely Pathogenic/beneficial if differential frequencies emerged in patients with COVID-19. CONCLUSIONS Males are more exposed to consequences from a single variant ACE2 allele. Common risk/beneficial alleles are unlikely in regions subject to evolutionary constraint. ACE2 upstream open reading frames may have implications for aminoglycoside use in SARS-CoV-2-infected patients. For this SARS-CoV-2-interacting protein with pre-identified functional domains, pre-emptive functional and computational studies are encouraged to accelerate interpretations of genomic variation for personalised and public health use.

Working paper

Vizcaychipi M, Shovlin C, Hayes M, Singh S, Christie L, Sisson A, Davies R, Lockie C, Howard A, Brown A, McCarthy A, Popescu M, Gupta A, Armstrong J, Said H, Peters T, Keays R, ChelWest COVID-19 Consortiumet al., 2020, Early detection of severe COVID-19 disease patterns define near real-time personalised care, bioseverity in males, and decelerating mortality rates., Publisher: medRxiv

BACKGROUND: COVID-19 is a global health emergency. Recent data indicate a 50% mortality rate across UK intensive care units. METHODS: A single institution, two-centre retrospective analysis following implementation of a Decision Support tool and real-time data dashboard for early detection of patients requiring personalised enhanced care, focussing particularly on respiratory rate, diastolic blood pressure, oxygenation indices, C-reactive protein, D-dimer and ferritin. Protocols differing from conventional practice included high-dose prophylactic anticoagulation for all COVID-19 positive patients and antioxidant prescription. RESULTS: By 22nd April 2020, 923 patients tested COVID-19 positive. 569 patients (61.7%) were male. The majority presented with advanced disease: interquartile ranges were C-reactive protein 44.9-179mg/L, D-dimer 1070-3802ng/L, and ferritin 261-1208μg/L. Completed case fatality rates were 25.1% [95% CI 20.0, 30.0] in females, 40.5% [95% CI 35.9, 45.0] in males. 139 patients were admitted to intensive care where current death rates are 16.2% [95% CI 3.8, 28.7] in females, 38.2% [95% CI 28.6, 47.8] in males with no trends for differences based on ethnicity. A real-time traffic lights dashboard enabled rapid assessment of patients using critical parameters to accelerate adjustments to management protocols. In total 513 (55.6%) of patients were flagged as high risk for thromboembolic disease, exceeding the numbers flagged for respiratory deteriorations (N=391, 42.4%), or cytokine storm (N=68, 7.4%). There was minimal evidence that age was associated with disease severity, but males had higher levels of all dashboard indices, particularly C-reactive protein and ferritin (p<0.0001) which displayed no relationship with age. CONCLUSIONS: Survival rates are encouraging. Protocols employed (traffic light-driven personalised care, protocolised early therapeutic anticoagulation based on D-dimer >1,000ng/L and/or CRP>200 mg/L, personalised ven

Working paper

Shovlin C, Vizcaychipi M, 2020, Implications for COVID-19 triage from the ICNARC report of 2204 COVID-19 cases managed in UK adult intensive care units, Emergency Medicine Journal, Vol: 37, Pages: 332-333, ISSN: 1472-0205

Journal article

Xiao S, Kai Z, Brown D, Shovlin C, Genomics England Research Consortiumet al., 2020, Harnessing the 100,000 Genomes Project whole genome sequencing data - an unbiased systematic tool to filter by biologically validated regions of functionality, Publisher: MedRxiv

Whole genome sequencing (WGS) is championed by the UK National Health Service (NHS) to identify genetic variants that cause particular diseases. The full potential of WGS has yet to be realised as early data analytic steps prioritise protein-coding genes, and effectively ignore the less well annotated non-coding genome which is rich in transcribed and critical regulatory regions. To address, we developed a filter, which we call GROFFFY, and validated in WGS data from hereditary haemorrhagic telangiectasia patients within the 100,000 Genomes Project. Before filter application, the mean number of DNA variants compared to human reference sequence GRCh38 was 4,867,167 (range 4,786,039-5,070,340), and one-third lay within intergenic areas. GROFFFY removed a mean of 2,812,015 variants per DNA. In combination with allele frequency and other filters, GROFFFY enabled a 99.56% reduction in variant number. The proportion of intergenic variants was maintained, and no pathogenic variants in disease genes were lost. We conclude that the filter applied to NHS diagnostic samples in the 100,000 Genomes pipeline offers an efficient method to prioritise intergenic, intronic and coding gDNA variants. Reducing the overwhelming number of variants while retaining functional genome variation of importance to patients, enhances the near-term value of WGS in clinical diagnostics.

Working paper

Thurairatnam S, Gawecki F, Strangeways T, Perks J, Santhirapala V, Myers J, Tighe H, Howard LSGE, Shovlin Cet al., 2020, Triage assessment of cardiorespiratory risk status based on measurement of the anaerobic threshold, and estimation by activity limitation in patients with pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia, Publisher: medRxiv

BACKGROUND: Rapid triaging, as in the current COVID-19 pandemic, focuses on age and pre-existing medical conditions. In contrast, preoperative assessments use cardiopulmonary exercise testing (CPET) to categorise patients to higher and lower risk independent of diagnostic labels. Since CPET is not feasible in population-based settings, our aims included evaluation of a triage/screening tool for cardiorespiratory risk. METHODS: CPET-derived anaerobic thresholds were evaluated retrospectively in 26 patients with pulmonary arteriovenous malformations (AVMs) who represent a challenging group to risk-categorise. Pulmonary AVM-induced hypoxaemia secondary to intrapulmonary right-to-left shunts, anaemia from underlying hereditary haemorrhagic telangiectasia and metabolic equivalents derived from the 13-point Veterans Specific Activity Questionnaire (VSAQ) were evaluated as part of routine clinical care. Pre-planned analyses evaluated associations and modelling of the anaerobic threshold and patient-specific variables. RESULTS: In the 26 patients (aged 21-77, median 57 years), anaerobic threshold ranged from 7.6-24.5 (median 12.35) ml.min-1kg-1 and placed more than half of the patients (15, 57.7%) in the >11 ml.min-1kg-1 category suggested as lower-risk for intra-abdominal surgeries. Neither age nor baseline SpO2 predicted anaerobic threshold, or lower/higher risk categories, either alone or in multivariate analyses, despite baseline oxygen saturation (SpO2) ranging from 79 to 99 (median 92)%, haemoglobin from 108 to 183 (median 156)g.L-1. However, lower haemoglobin, and particularly, arterial oxygen content and oxygen pulse were associated with increased cardiorespiratory risk: Modelling a haemoglobin increase of 25g.L-1 placed a further 7/26 (26.9%) patients in a lower risk category. For patients completing the VSAQ, derived metabolic equivalents were strongly associated with anaerobic threshold enabling risk evaluations through a simple questionnaire. CONCLUSIONS: Bas

Working paper

Shovlin C, Millar C, Droege F, Kjeldsen A, Manfredi G, Suppressa P, Ugolini S, Coote N, Fialla A, Geisthoff U, Lenato G, Mager HJ, Pagella F, Post M, Sabba C, Sure U, Torring P, Dupuis Girod S, Buscarini E, VASCERN HHTet al., 2019, Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia, Orphanet Journal of Rare Diseases, Vol: 14, ISSN: 1750-1172

Background: Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anaemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolismand/or atrial fibrillation. Over decades,tolerance data has been publishedfor almost 200HHT-affected usersof warfarinand heparins, but there are no publisheddata forthe newer direct oralanticoagulants(DOACs)in HHT. Methods: To provide such data, aretrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Vascular Disorders (VASCERN),in Denmark, France, Germany, Italy, Netherlands and UK. Results: Although HHT Centreshad not specifically recommended the use of DOACs, 32treatment episodes had been initiated by other cliniciansin 28patients reviewed at the centres, at median age 65years(range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes).The 32 treatment episodes used Apixaban (n=15), Rivaroxaban (n=14), and Dabigatran (n=3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15(26.7%) Apixabanepisodes and 7/14 (50%)Rivaroxaban episodes.By a 4 point scale of increasing severity,there was a trend for Rivaroxaban to be associated with a greaterbleeding riskboth including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associationswere maintained after adjustment for genderand treatment indication. Extreme haemorrhagic responses, worse thananything

Journal article

Gawecki F, Strangeways T, Amin A, Perks J, Wolfenden H, Thurainatnam S, Rizvi A, Jackson JE, Santhirapala V, Myers J, Brown J, Howard LSGE, Tighe HC, Shovlin CLet al., 2019, Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations, QJM: An International Journal of Medicine, Vol: 112, Pages: 335-342, ISSN: 1460-2393

Background: Pulmonary arteriovenous malformations (PAVMs) generate a right-to-left shunt. Impaired gas exchange results in hypoxemia and impaired CO2 clearance. Most patients compensate effectively but a proportion are dyspneic, and these are rarely the most hypoxaemic. Aim: To test degrees of concurrent pathology influencing exercise capacity. Design: Replicate, sequential single centre, prospective studies. Methods: Cardiopulmonary exercise tests (CPET) were performed in 26 patients with PAVMs, including individuals with and without known airflow obstruction. To replicate, relationships were tested prospectively in an independent cohort where self-reported exercise capacity evaluated by the Veterans Specific Activity Questionnaire (VSAQ) was used to calculate metabolic equivalents at peak exercise (METS N = 71). Additional measurements included oxygen saturation (SpO2), forced expiratory volume in 1 second (FEV1), vital capacity (VC), exhaled nitric oxide (FeNO), haemoglobin and iron indices. Results: By CPET, the peak work-rate was only minimally associated with low SpO2 or low arterial oxygen content (CaO2=1.34 x SpO2 x haemoglobin), but was reduced in patients with low FEV1 or VC. Supranormal work-rates were seen in patients with severe right-to-left shunting and SpO2 <90%, but only if FEV1 was >80% predicted. VSAQ-calculated METS also demonstrated little relationship with SpO2, and in crude and CaO2-adjusted regression, were lower in patients with lower FEV1 or VC. Bronchodilation increased airflow even where spirometry was in the normal range: exhaled nitric oxide measurements were normal in 80% of cases, and unrelated to any PAVM-specific variable. Conclusions: Exercise capacity is reduced by relatively mild airflow limitation (obstructive or restrictive) in the setting of PAVMs.

Journal article

Alsafi A, Jackson JE, Fatania G, Patel MC, Glover A, Shovlin Cet al., 2019, Patients with in-situ metallic coils and amplatzer vascular plugs used to treat pulmonary arteriovenous malformations since 1984 can safely undergo magnetic resonance imaging, The British Journal of Radiology, Vol: 92, ISSN: 0007-1285

OBJECTIVES:To examine the magnetic resonance imaging (MRI) safety of metallic coils and Amplatzer vascular plugs. Currently, concern regarding MR-safety of devices used to treat pulmonary arteriovenous malformations (PAVMs) causes delays in performing emergency MRI in patients presenting with acute neurological symptoms.METHODS:A retrospective audit was performed on all patients who underwent PAVM embolization at our institution between 1984 – 2017. Outcomes of all MRI studies performed at our institution were recorded. In addition, known outcomes of all known MRI studies performed on patients treated with the earliest steel coils (1984 – 1995) were recorded.RESULTS:At our institution, 20 patients underwent 1.5 T MRI after the insertion of 100 steel coils (15.5 – 28.6, median 22 years later), 140 coils designated MR-conditional (0.42 – 12.7, median 9.3 years later), and 54 MRI-conditional Amplatzer vascular plugs (0.17 – 8.0, median 0.75 years later), many in combination. The majority of scans were for cerebral indications, but other body regions scanned included spinal, thoracic, and pelvic regions. No adverse events were reported. Similarly, there were no adverse events in any MR scan known to have been performed in other institutions in seven further patients treated with the earliest steel coils (1984 – 1995). Again, the majority of scans were for cerebral indications.CONCLUSIONS:The findings demonstrate MR safety at 1.5 T of all PAVM embolization devices inserted in a main UK centre since inception in 1984.ADVANCES IN KNOWLEDGE:Magnetic resonance imaging of patients who have had pulmonary AVMs treated by embolization can be implemented without contacting specialist pulmonary arteriovenous malformation treatment centres for approval.

Journal article

Thielemans L, Layton DM, Shovlin CL, 2019, Low serum haptoglobin and blood films suggest intravascular haemolysis contributes to severe anaemia in hereditary haemorrhagic telangiectasia, Haematologica, Vol: 104, Pages: e127-e130, ISSN: 0390-6078

Journal article

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