Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): Association with venous thromboembolism

Shovlin, Claire L.; Sulaiman, Nada; Govani, Fatima S; Jackson, James E.; Begbie, Megan E.

doi:10.1160/th07-01-0064

Cited by 81 publications

(52 citation statements)

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“…In contrast, complications from thromboembolic complications of HHT show clear age-dependent increases, 17,34 as in the general population. 175,176 6-7% of HHT patients have pathological thromboemboli.…”

Section: 4) Thrombosis and Hhtmentioning

confidence: 85%

“…2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and potential immune dysfunction. 18 Three of the genes mutated in HHT have been identified: endoglin (resulting in HHT1, OMIM #187300) 19 ; ACRVL1/ALK1; (resulting in HHT2, OMIM#600376) 20 , and more rarely, SMAD4 (mutated in HHT in association with juvenile polyposis, JPHT OMIM #175050) 11 .…”

Section: Overview Of Hhtmentioning

confidence: 99%

“…Recognition of this pattern, in contrast to more conventional monogenic diseases 124 , allowed the development of a model (Fig 3) 125 that has permitted identification of non-genetic factors associated with disease manifestations. 17,34 (Livesey et al, manuscript in preparation). Identification of HHT modifier genes is also eagerly awaited .…”

Section: 1d) Familial Patterns Of Diseasementioning

confidence: 99%

“…Recognition that venous thromboses occur in HHT, associated in many cases with coincidental inheritance of prothrombotic genetic variants such as FV Leiden, has raised concern regarding thrombophilic risk with these agents. 17 It was therefore suggested that routine measurement of FVIII, FV Leiden, and other thrombophilic markers in HHT patient assessments may assist individualised risk-benefit considerations before prothrombogenic systemic treatments are given. 3,17…”

Section: Antifibrinolytics and Prothrombotic Agentsmentioning

confidence: 99%

“…175,176 6-7% of HHT patients have pathological thromboemboli. 17,177 It seems likely, therefore, that symptoms from the increasing number of telangiectases with age are partly off-set by age-related increases in prothrombotic states. …”

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confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 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. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

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Section: 4) Thrombosis and Hhtmentioning

confidence: 85%

Section: Overview Of Hhtmentioning

confidence: 99%

Section: 1d) Familial Patterns Of Diseasementioning

confidence: 99%

Section: Antifibrinolytics and Prothrombotic Agentsmentioning

confidence: 99%

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confidence: 99%

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Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

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Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis

et al. 2018

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IMPORTANCE In systemic sclerosis (SSc), to date, no study has precisely described the total number and fine distribution of telangiectases (TAs), their clinical association with the disease, and the biological mechanisms causing their development. OBJECTIVES To describe the whole-body distribution of TAs and assess the association between the whole-body TA number and the characteristics of patients with SSc. DESIGN, SETTING, AND PARTICIPANTS A single-center, cross-sectional study was conducted between July 11, 2016, and March 15, 2017, at the National Referral Centre for Rare Systemic and Autoimmune Diseases in France. A population-based sample of 106 adults who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc were included; 8 patients who had previously received laser treatment for TAs were excluded. MAIN OUTCOMES AND MEASURES The number of TAs on the whole body (total and those >5 mm) and TA distribution in different areas were recorded. The association with clinical and biological data was studied using univariate and multivariate linear regression. RESULTS A total of 106 patients (83 [78.3%] women) were enrolled, including 12 with precapillary pulmonary hypertension (PH). Mean (SD) age was 60.6 (13.5) years. Telangiectasia distribution was 37.2% on the face, 33.2% on the upper limbs, including 26.4% on the hands, 28.1% on the trunk, including 17.1% for the upper part of the trunk, and 1.5% on the lower limbs. In analysis using the multivariate linear regression model, the whole-body TA number was independently associated with male sex (percentage change, 144.4%; 95% CI, 7.5% to 455.9%; P = .03), PH (162.8%; 95% CI, 5.6% to 553.8%; P = .04), history of pulmonary embolism (336.4%; 95% CI, 39.0% to 1270.1%; P = .01), glomerular filtration rate (−1.6%; 95% CI, −3.2% to −0.1% per 1-mL/min/1.73 m 2 increase; P = .04), and soluble endoglin level (28.2%; 95% CI, 1.2% to 62.5% per 1-ng/mL increase; P = .04). Receiver operating characteristic analyses assessing the ability of TAs to identify the presence of PH revealed that the area under the curve was significant for the TA number on the whole body (0.77; 95% CI, 0.57 to 0.88), on the hands and face (0.81; 95% CI, 0.57 to 0.91), and on the hands (95% CI, 0.77; 95% CI, 0.57 to 0.89). CONCLUSIONS AND RELEVANCE In the patients in this study with SSc, TAs were predominantly located on the face, hands, and the upper part of the trunk. Telangiectases appeared to be associated with vasculopathy features of SSc, particularly with PH and soluble endoglin levels.

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

Mukhtar

Shovlin

2023

eJHaem

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

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Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): Association with venous thromboembolism

Cited by 81 publications

References 43 publications

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Whole-Body Distribution and Clinical Association of Telangiectases in Systemic Sclerosis

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

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