abnormalities, with attendant hemorrhage risks per annum. Risks from imaging studies Computed tomography (CT) is not sufficiently sensitive, and CT carries risks of radiation. Magnetic resonance imaging (MRI) is the preferred screening modality, though while this eliminates the risk of radiation for the initial screen, radiation may be used for subsequent evaluations and treatment. Imaging in young children may require sedation or general anesthesia [19]. Outcomes following identification of different types of lesions: Brain AVF These are usually considered for treatment. Brain AVM Symptomatic cerebral AVMs are usually considered for treatment. Asymptomatic AVMs are less likely to be treated according to the results of a consensus from European interventional neuroradiologists and neurosurgeons in three specialist societies spanning the three forms of treatment: the European Association of Neurosurgical Societies (EANS), the European Society of Interventional Therapy (ESMINT), and the European Society for Radiosurgery (EGKS) [19,59]. The expert authors specifically integrated review of the ARUBA trial (A Randomized trial of Unruptured Brain AVM), which found that in unruptured cerebral AVMs, conservative management was less harmful than interventional treatments [60]. There were several concerns with this trial, and participants were mainly adults with non-HHT-related AVMs. (See "Brain arteriovenous malformations", section on 'Unruptured AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 12/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Following expert joint review, neurosurgical, interventional neuroradiological, and radiosurgical teams may elect not to treat a lesion for other reasons [59]. However, those managing HHT families are aware there may be value in knowing of the presence of a cerebral AVM, either for early intervention should it become symptomatic, or for other aspects of health planning. There may also be negative implications from the awareness of a cerebral AVM for which treatment is not recommended. Other lesions Other lesions more commonly seen in HHT patients include capillary malformations/telangiectases (sometimes referred to incorrectly as "micro-AVMs"), cavernous malformations (formerly known as "cavernomas") and developmental venous anomalies (DVA) [19]. (See "Vascular malformations of the central nervous system".) For these, management in HHT patients follows general population guidance; these lesions are usually not treated due to low risks of hemorrhage [19]. Cerebral aneurysm The rate in HHT patients is similar to the general population [19,61] and management follows general population guidance. Across European expert centers, these issues are discussed with all patients as part of formal pretest counseling. Our preferred practice is to enable any HHT patient to have a screening brain MRI scan if that is their wish following pretest counseling [41]. A 2020 Position Statement from the European Reference Network stated that discussions of potential screening are undertaken for asymptomatic patients and noted that MRI scans are performed in only a proportion of patients having the screening discussions [19]. One center's experience stratifying 603 HHT patients with no neurologic symptoms of concern according to whether there was a positive family history of cerebral hemorrhage were reported in 2018 [41]. Screening scan uptake was higher after publication of the ARUBA trial, and patients with a family history of cerebral hemorrhage were 4-fold to 14-fold more likely to have a screening scan than patients with no such family history [41]. In a survey of 28 North American HHT Centers of Excellence, all reported screening adults with HHT for vascular lesions in the brain; 25 of 28 routinely screen children [62]. If screening is performed, brain MRI with contrast is recommended; this may entail general anesthesia in young children. The optimal timing and frequency of MRI is not established, and it is important to recognize that small lesions may be missed without catheter cerebral angiography. Other important considerations related to the incidence of cerebral AVMs include the following: The risk of a new AVM developing after a previous negative scan is unknown. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 13/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Screening scans commonly detect silent cerebral infarction due to pulmonary AVMs (PAVMs) [19]. At our institution, these considerations are openly discussed with the patient [41]. While cerebral AVMs lesions are more common in HHT1 (ENG) and SMAD4 families, they also are present and may hemorrhage in individuals from ACVRL1 families [29,63-68]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Genotype-phenotype correlations and variable penetrance'.) The lifelong risk of hemorrhage is higher for younger patients because of their longer predicted lifespan. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Cerebral vascular abnormalities' and "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.) HEPATIC AVM SCREENING Symptomatic liver lesions should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Hepatic AVMs'.) Screening for liver lesions was recommended in the 2020 International Guideline on HHT [13]. Reasons included the fact that diagnosis of symptomatic hepatic AVMs may be delayed because symptoms are incorrectly attributed to other causes (eg, high output cardiac failure attributed to "heart" disease). Hepatic vascular malformations are most common in individuals with HHT2 due to ACVRL1 variants.(See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) In terms of approaches to hepatic AVM screening, data are not available to guide the choice of imaging modality or the frequency of monitoring; additional study of these questions is needed. The choice of imaging modality may depend on local expertise and should be discussed with the radiology team who will be performing liver imaging. A Practice Guideline from the French Association for the Study of the Liver (AFEF) and European Reference Network (ERN) provides details of the types of lesions that may be found [69]. Management is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Initial management of hepatic AVMs'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 14/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate SPECIAL SCENARIOS Individuals who require anticoagulation (VTE and AF) Appropriate use of anticoagulation VTE prophylaxis Patients with HHT are at increased risk for venous thromboembolism (VTE) [37]. They should have prophylactic anticoagulation at high-risk times as for the general population. AF or VTE treatment Patients may also receive full anticoagulation if needed for conditions such as atrial fibrillation (AF) or VTE, or other indications; HHT is not an absolute contraindication, as discussed in the HHT 2020 Guideline and the 2022 VASCERN Framework manuscript [13,20]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".) Cautions While some caution is required during anticoagulation (particularly because nosebleeds may increase), anticoagulant or antithrombotic therapy should not be withheld purely on a presumption of potential bleeding risk in HHT [13,18,70]. Patients can be alerted that for approximately one-half of individuals, nosebleed severity may increase, but there is no evidence that AVM hemorrhage has been precipitated by therapeutic anticoagulation [18,70]. Securing additional ear, nose, and throat (ENT) treatments may be required [18]. Occasionally patients report that their nosebleeds improve. Choice of anticoagulant Conventional heparin and warfarin have been first-choice anticoagulants in HHT in International and European guidance [13]. However, a 2023 study found rates of dose reduction or discontinuation with warfarin and direct oral anticoagulants (DOACs), and the consensus for anticoagulant choice may shift to include DOACs [71]. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Treatment of bleeding'.) If DOACs are considered, apixaban appears to be associated with less risk of bleeding complications than rivaroxaban. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 15/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate If an HHT patient has excessive nosebleeds with one particular anticoagulant, they may successfully switch to an alternate agent, although it is not possible to predict which agent will best suit any particular individual [18]. Supporting evidence Heparin and warfarin Several studies have reported that heparin and warfarin are generally well-tolerated [18,70,72,73]. DOACs In a detailed audit of the use of anticoagulants across the European Reference Network (ERN), none of the eight VASCERN HHT Reference Centers had recommended DOACs [18,70]. There were 32 reports of the use of a DOAC prescribed to HHT patients by other clinicians, 16 times for VTE and 16 times for AF (apixaban in 15, rivaroxaban in 14, and dabigatran in 3). HHT nosebleeds increased in severity in 24 of 32 treatment episodes (75 percent), leading to treatment discontinuation in 11 (34 percent); 8 (25 percent) patients had extreme hemorrhage with nosebleeds lasting hours and requiring hospital admissions, blood transfusions, and in all cases, anticoagulant discontinuation [18]. Discontinuation rates In a cohort of 119 individuals with HHT, 59 (50 percent) reduced the dose or prematurely discontinued therapy due to worsening bleeding [71]. Multivariable analysis identified prior gastrointestinal bleeding as a risk factor for discontinuation. The choice of anticoagulant (warfarin, heparin, or a DOAC) did not affect dose reduction or anticoagulant discontinuation. Air travel As noted separately, air travel is generally well-tolerated in HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Potential complications of PAVMs'.) Traveling by air raises issues in the general population and these have particular relevance for people with HHT. VTE Individuals with HHT can follow advice for the general population regarding reducing the likelihood of VTE associated with prolonged immobility during air travel. It is important to recognize that HHT nosebleeds (that may prohibit flying) may occur before or during flights whether antiplatelet or anticoagulant agents are prescribed. (See "Prevention of venous thromboembolism in adult travelers".) Epistaxis The risk of nosebleeds during airline travel may be increased due to reduced humidity and air pressure: in a series of 145 individuals with HHT who replied to a questionnaire about airline flight-related complications, significant nosebleeds occurred in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 16/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate approximately 14 percent of long-haul flights [74]. In our institution, we advise patients to use Vaseline or other nasal lubricants and to be prepared with tissues. SCREENING AND GENETIC TESTING OF AT-RISK FAMILY MEMBERS Data from a 2022 study emphasize the paucity of clinical symptoms in many patients with genetically-confirmed HHT [1]. Of 152 unrelated adults with genetically confirmed HHT due to a pathogenic variant in ACVRL1, ENG, or SMAD4, only 104 (68 percent) met a clinical diagnosis of HHT with three Cura ao criteria. Of 83 unrelated probands with one or more PAVMs and genetically-confirmed HHT, 20 (24 percent) had few, if any, features of HHT. Unaffected status should not be assumed based on the absence of nosebleeds or other HHT symptoms. Children Children in HHT families who have symptoms should be investigated, as discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) Determining what should happen to healthy children within HHT families is much more controversial. Genetic testing The 2020 second International Consensus HHT Guideline recommended genetic screening to be offered to all children of a parent with HHT (96 percent agreement) and all who are diagnosed with HHT based on clinical criteria [13]. Where genetic testing is offered, this should always be in the context of counseling and informed decision-making, with discussions of the potential implications for the child. If the familial disease-causing (pathogenic) variant is known and the child tests negative for that variant, parents can be reassured that the child does not have HHT. However, if the familial variant is not known, a negative test cannot exclude the diagnosis of HHT. Those who do not undergo genetic testing should be considered to have possible HHT. (See 'Genetic counseling and testing of family members' below and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.) If formal genetic testing and exclusion of a familial variant has not (or cannot) be done, it is not possible to eliminate the possibility of HHT in a child, since symptoms and vascular lesions may not become apparent until later in life [13]. There are differences in practice for children for whom it is not possible to use formal genetic testing, ranging from screening for all manifestations of HHT to deferring any screening in asymptomatic children until after puberty, unless dictated otherwise by family history [57]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 17/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Clinical evaluation Across practices, for children with HHT, recommendations range from evaluating for all manifestations of HHT to deferring the evaluation in most asymptomatic children until post-puberty, unless dictated otherwise by family history [57]. Similar variation in practices applies to children for whom it is not possible to use formal genetic testing [57]. Pulmonary AVMs For pulmonary arteriovenous malformations (PAVMs), the first International HHT Guideline recommended screening all patients with possible or confirmed HHT for PAVMs and included children in the screening recommendation [3]. The second International Guideline specifically addressed children and recommended pulmonary AVM screening at the time of diagnosis, and in those at risk for HHT based on a parent's diagnosis (94 percent agreement from the clinician and patient expert panel), and a repeat pulmonary AVM screening in children with an initial negative screen, at an interval of every five years (86 percent agreement) [13]. Cerebral AVMs For cerebral AVMs, the first International HHT Guideline recommended screening children with possible or definite HHT for CVMs in the first six months of life or at time of diagnosis (64 percent agreement) [3]. The second International HHT Guideline also recommended screening for brain vascular malformations in asymptomatic children with HHT or at risk for HHT, at the time of presentation or diagnosis (87 percent agreement) [13]. It should be noted that the pulmonary and cerebral screening recommendations contrast with other position statements (eg cerebral AVMs from the European Reference Network for Rare Vascular Diseases [VASCERN] [19]), particularly regarding the indication for repeated screening, imaging, and treatment of asymptomatic pulmonary AVMs. Further data on the outcomes post treatment are expected. Based on the latest evidence, pediatric-specific risks and benefits of screening include the following: Greater burdens and risks Burdens and risks of screening may be greater in children than in adults. Greater risks from exposure to ionizing radiation, including increased risk of cancer [23,75-77] Possible need for general anesthesia to enable imaging Inability to give full informed consent and/or to understand the implications of screening https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 18/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Less evidence for benefit There is less evidence for benefits of screening in children, especially for pulmonary AVMs. Risk of complications from pulmonary AVMs in children is less well-documented than risk of complications in adults. Some of these considerations are discussed in more detail separately. (See "Radiation-related risks of imaging", section on 'Children and adolescents' and "Genetic testing", section on 'Testing children'.) Briefly, as for adult screening, all experts are in agreement that decisions to screen children should be made with shared decision-making to allow all concerns and questions to be addressed and implications of screening decisions understood, including by the child when they are near the age of consent in the particular country (age varies from 16 to 21 years in different countries). The key considerations are: Whether asymptomatic children are at similar or different risks to asymptomatic adults if rationales for screening programs are based on data in adults (for example, pulmonary arteriovenous malformation [PAVM] screens given almost all complications occur in adult life). Whether treatment of asymptomatic children modifies the natural history of the development of their condition in a detrimental manner [51]. Practice variations in the aggressiveness of testing and screening reflect the uncertainty as to whether silent AVMs pose sufficient danger in childhood to balance the risks of childhood radiation exposure from imaging studies. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Onset of disease manifestations' and 'Cerebral AVM screening' above.) Pediatric treatment recommendations (as opposed to screening of asymptomatic children) are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Children'.) Genetic counseling and testing of family members Individuals with HHT should be aware of the autosomal-dominant transmission and the possibility of having an affected child or other affected first-degree relative, which is approximately 50 percent. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) Individuals with HHT should be aware of that data [1] absence or paucity of nosebleeds does not exclude HHT: of 83 unrelated probands genetically screened for HHT due to the presence of PAVM(s), 20 (24 percent) had few, if any, features of HHT. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 19/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Genetic testing of family members is complicated in HHT because there are several potential genes involved, there are no common pathogenic variants, founder members may be mosaic with challenging molecular diagnostics, and the causative pathogenic variant is not identified in all families, highlighting that additional HHT genes or genomic regions are yet to be characterized [3]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics'.) If genetic testing is pursued, an affected individual in the family should be tested first, followed by testing of selected family members for the specific variant that has been identified to be pathogenic or likely pathogenic in that family. If a familial disease-causing variant for HHT has been identified, genetic testing for this variant can reliably identify family members who have and have not inherited the variant. Individuals with the HHT genotype can be evaluated as described above. However, this is only possible if a specific familial gene variant has been tested [3]. Details of this testing are presented separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Genetics' and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Diagnosis'.) Practices vary regarding the age at which to perform genetic testing, reflecting the ethical considerations involved in screening an asymptomatic child who is too young to give consent and will likely not understand the implications of testing. (See 'Children' above and "Genetic testing", section on 'Testing children'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Symptomatic individuals Individuals with hereditary hemorrhagic telangiectasia (HHT) who are symptomatic should be investigated. Clinicians should be aware of typical arteriovenous malformation (AVM) symptoms. Many recommendations are based on expert opinion and observational studies; the uniformity of expert opinion varies depending on the clinical situation and prevailing practices. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions".) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 20/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate Asymptomatic individuals; general principles Education and screening are important. Educational materials and specialized testing and management centers are available from the European Reference Network on Rare Multisystemic Vascular Diseases and country- specific patient groups. (See 'General principles of management' above.) Screening AVM screening in individuals at risk of HHT or asymptomatic individuals with HHT is recommended universally for PAVMs. For other AVMs, screening is more controversial than evaluating symptomatic lesions. It is good practice to counsel patients on risks and benefits prior to screening. Assuming the individual agrees, screening generally consists of an examination, evaluation for anemia and iron deficiency, pulmonary AVM (PAVM) screening, and discussions of screening for AVMs at other sites (hepatic, cerebral). Individuals with SMAD4-related HHT require more extensive surveillance due to the risk of juvenile polyposis and aortopathy. (See 'Overview of screening strategy' above and 'Cerebral AVM screening' above and 'Individuals with SMAD4 HHT' above.) Iron deficiency We obtain regular complete blood counts (CBC) and examine serial trends and red cell indices, particularly for patients who have hypoxemia due to PAVMs, for whom a "normal" hemoglobin may be inappropriately low for the expected degree of polycythemia. We regularly assess iron status regardless of the hemoglobin level, since iron deficiency is likely to progress to anemia if not treated. (See 'Iron status' above.) PAVMs Adults with HHT should be screened for PAVMs. Unsuspected PAVMs are common, and treatment reduces risks of stroke and brain abscess in adults. Females with HHT should undergo screening before becoming pregnant, since PAVMs can bleed in later pregnancy leading to life-threatening hemoptysis or hemothorax. Screening may consist of contrast (bubble) echocardiography in institutions with very strong local expertise, or with chest computed tomography (CT). Negative contrast echocardiography in experienced hands or negative CT can rule out PAVMs; a negative chest radiograph cannot. The timing and repeat screening in individuals with a negative initial screen depends on patient age and other findings. (See 'PAVM screening' above.) Cerebral AVMs Screening for cerebral arteriovenous (AV) shunts can be undertaken, noting the importance of shared decision-making and other considerations discussed above. (See 'Cerebral AVM screening' above.) Children Screening asymptomatic children within HHT families differs between institutions due to variable risk-benefit assessment. Evidence of benefit is generally lacking, and certain risks are recognized (radiation exposure from some imaging https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-routine-care-including-screening-for-asymptomatic-avms/print 21/32 7/5/23, 12:21 PM Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs - UpToDate studies). All specialists agree on the importance of informed consent that weighs risks and benefits for each individual. Other considerations include uncertainty about the risk of complications from silent AVMs in children, concerns about the ethics of screening children, and lack of information about how treatment affects the natural history of disease in children. (See 'Children' above.) VTE risk Individuals with HHT have an increased risk of venous thromboembolism (VTE) and should follow general population guidance for VTE treatment and prophylaxis. (See 'Individuals who require anticoagulation (VTE and AF)' above and 'Air travel' above.) Reproductive counseling and testing Individuals with HHT should be aware of the autosomal dominant transmission and possibility of having an affected child. Genetic testing of family members can be complicated. The possibility of disease can be excluded in relatives only if a familial pathogenic variant has been identified. (See 'Genetic counseling and testing of family members' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Anderson E, Sharma L, Alsafi A, Shovlin CL. Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia. Thorax 2022; 77:628. 2. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. 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