MicroRNA-135b-5p Is a Pathologic Biomarker in the Endothelial Cells of Arteriovenous Malformations.

Arteriovenous malformations (AVMs) are congenital vascular anomalies with a poor prognosis. AVMs are considered intractable diseases, as there is no established approach for early diagnosis and treatment. Therefore, this study aimed to provide new evidence by analyzing microRNAs (miRNAs) associated with AVM. We present fundamental evidence for the early diagnosis and treatment of AVM by analyzing miRNAs in the endothelial cells of AVMs. This study performed sequencing and validation of miRNAs in endothelial cells from normal and AVM tissues. Five upregulated and two downregulated miRNAs were subsequently analyzed under hypoxia and vascular endothelial growth factor (VEGF) treatment by one-way analysis of variance (ANOVA). Under hypoxic conditions, miR-135b-5p was significantly upregulated in the AVM compared to that under normal conditions, corresponding to increased endothelial activity (p-value = 0.0238). VEGF treatment showed no significant increase in miR-135b-5p under normal conditions, however, a surge in AVM was observed. Under both hypoxia and VEGF treatment, comparison indicated a downregulation of miR-135b-5p in AVM. Therefore, miR-135b-5p was assumed to affect the pathophysiological process of AVM and might play a vital role as a potential biomarker of AVMs for application related to diagnosis and treatment.

Arteriovenous malformation with hair collar sign.

We report the case of a newborn who was noted at birth to have an occipital scalp nodule presenting with a hair collar sign (HCS). The nodule had enlarged since birth. An MRI revealed a soft tissue mass on the occipital scalp without deep extension or cranial bone involvement. A biopsy of the nodule led to a diagnosis of arteriovenous malformation (AVM). A vascular malformation with HCS has not been reported before in North America. This case highlights the complexity of diagnosing a lesion with a hair collar sign.

Relative expression of hormone receptors by endothelial and smooth muscle cells in proliferative and non-proliferative areas of congenital arteriovenous malformations.

BACKGROUND: Episodic growth due to microvascular proliferations (MVP) has been reported in congenital arteriovenous malformations (AVM), which are normally quiescent lesions composed of mature malformed vessels. Since AVM also may worsen under conditions of hormonal dysregulation, we hypothesized that hormonal influences may stimulate this process of vasoproliferative growth through potential interactions with hormone receptors (HR). METHODS: 13 Cases of AVM tissue with histologically documented vasoproliferative growth were analyzed quantitatively for the presence and tissue localization of estrogen receptor (ER), progesterone receptor (PGR), growth hormone receptor (GHR) and follicle-stimulating hormone receptor (FSHR) in relation to resident cells of interest (endothelial cells (EC), smooth muscle cells (SMC) and mast cells (MC)) by applying multiplex immunohistochemistry (IHC) staining. Expression patterns in lesions with MVP and mature vessels were quantified and compared. Available fresh frozen tissues of 3 AVM samples were used to confirm the presence of HR using Reverse-Transcriptase quantitative Polymerase Chain Reaction (RT-qPCR). RESULTS: All four HR studied were expressed in all cases within EC and SMC in areas of MVP and mature vessels, but not in normal skin tissue. ER, GHR, and FSHR showed more expression in EC of MVP and in SMC of mature vessels. RT-qPCR confirmed presence of all 4 HR in both areas. CONCLUSION: Expression of ER, PGR, GHR, and FSHR in vasoproliferative areas of congenital AVM could explain onset of sudden symptomatic growth, as has observed in a subpopulation of patients. These findings may have implications for eventual anti-hormonal targeted therapy in the lesions involved.

Executive summary of the 14th HHT international scientific conference.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by small, dilated clustered vessels (telangiectasias) and by larger visceral arteriovenous malformations (AVMs), which directly connect the feeding arteries with the draining veins. These lesions are fragile, prone to rupture, and lead to recurrent epistaxis and/or internal hemorrhage among other complications. Germline heterozygous loss-of-function (LOF) mutations in Bone Morphogenic Protein 9 (BMP9) and BMP10 signaling pathway genes (endoglin-ENG, activin like kinase 1 ACVRL1 aka ALK1, and SMAD4) cause different subtypes of HHT (HHT1, HHT2 and HHT-juvenile polyposis (JP)) and have a worldwide combined incidence of about 1:5000. Expert clinicians and international scientists gathered in Cascais, Portugal from September 29th to October 2nd, 2022 to present the latest scientific research in the HHT field and novel treatment strategies for people living with HHT. During the largest HHT scientific conference yet, participants included 293 in person and 46 virtually. An impressive 209 abstracts were accepted to the meeting and 59 were selected for oral presentations. The remaining 150 abstracts were presented during judged poster sessions. This review article summarizes the basic and clinical abstracts selected as oral presentations with their new observations and discoveries as well as surrounding discussion and debate. Two discussion-based workshops were also held during the conference, each focusing on mechanisms and clinical perspectives in either AVM formation and progression or current and future therapies for HHT. Our hope is that this paper will represent the current progress and the remaining unanswered questions surrounding HHT, in order to serve as an update for those within the field and an invitation to those scientists and clinicians as yet outside of the field of HHT.

Late chronic local inflammation, synaptic alterations, vascular remodeling and arteriovenous malformations in the brains of male rats exposed to repetitive low-level blast overpressures.

In the course of military operations in modern war theaters, blast exposures are associated with the development of a variety of mental health disorders associated with a post-traumatic stress disorder-related features, including anxiety, impulsivity, insomnia, suicidality, depression, and cognitive decline. Several lines of evidence indicate that acute and chronic cerebral vascular alterations are involved in the development of these blast-induced neuropsychiatric changes. In the present study, we investigated late occurring neuropathological events associated with cerebrovascular alterations in a rat model of repetitive low-level blast-exposures (3 × 74.5 kPa). The observed events included hippocampal hypoperfusion associated with late-onset inflammation, vascular extracellular matrix degeneration, synaptic structural changes and neuronal loss. We also demonstrate that arteriovenous malformations in exposed animals are a direct consequence of blast-induced tissue tears. Overall, our results further identify the cerebral vasculature as a main target for blast-induced damage and support the urgent need to develop early therapeutic approaches for the prevention of blast-induced late-onset neurovascular degenerative processes.

Mandibular Arteriovenous Malformation (Vascular Lesion) in a 16-Year-Old Patient.

Intraosseous arteriovenous malformations in jaws are rare congenital vascular abnormalities that the dentist may encounter. A vascular lesion or disease should be suspected when there is unexplained bleeding from the oral cavity. Diagnostic imaging is a valuable tool in diagnosing and localizing vascular lesions. An understanding of some of the salient clinical and radiographic features of arteriovenous malformations in jaws aids the clinician in correctly diagnosing this condition and avoids iatrogenic injuries, such as hasty tooth extraction, which may potentially cause severe bleeding and possibly death. The dentist should acknowledge their expertise/limitation, and know when the need for referral arises.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

Recurrence Rates Following Treatment of Spinal Vascular Malformations: A Systematic Review and Meta-Analysis.

BACKGROUND: Spinal vascular malformations (SVMs), including arteriovenous malformations (AVMs) and arteriovenous fistulas (AVFs), are a varied group of vascular lesions that can be subclassified according to localization, vascular structure, and hemodynamics. Early intervention is necessary to halt progression of disease and minimize irreversible dysfunction. We sought to characterize initial treatment success and recurrence rates following interventional treatment of various types of SVMs. METHODS: A systematic review and meta-analysis were performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. SVMs were categorized into 4 groups: dural AVFs, perimedullary AVFs, intramedullary AVMs, and extradural-intradural AVMs (e.g., epidural, paraspinal). Initial occlusion, recurrence, and complication rates were compared using random-effects analysis. RESULTS: There were 112 manuscripts included, with a total of 5626 patients with SVM. For treatment, 2735 patients underwent endovascular embolization, 2854 underwent surgical resection, and 37 underwent stereotactic radiosurgery. The initial treatment success and overall recurrence rates following surgical resection of all SVMs were 89.5% (95% CI: 80.5%-98.5%) and 2.3% (95% CI: 0.9%-3.7%), respectively. Those rates following endovascular embolization were 55.9% (95% CI: 30.3%-81.5%) and 27.7% (95% CI: 11.2%-44.2%), respectively. Higher rates of initial treatment success and lower rates of recurrence with surgery were observed in all subtypes compared to embolization. Overall complication rates were higher after embolization for each of the SVM categories. CONCLUSIONS: Surgical resection of SVMs provided higher rates of initial complete occlusion and lower rates of recurrence than endovascular techniques. Attaining technical success through obliteration must still be weighed against clinical impact and natural history of the specific vascular malformation.

Resting-state functional alterations in patients with brain arteriovenous malformations involving language areas.

Brain arteriovenous malformations (AVMs) may involve language areas but usually do not lead to aphasia. This study evaluated resting-state functional alterations and investigated the language reorganization mechanism in AVM patients. Thirty-nine patients with AVMs involving language areas and 32 age- and sex-matched healthy controls were prospectively enrolled. The AVM patients were categorized into three subgroups according to lesion location: the frontal (15 patients), temporal (14 patients), and parietal subgroups (10 patients). All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the amplitude of low-frequency fluctuation (ALFF) approach was applied to analyze rs-fMRI data. Language abilities were normal in all participants based on the Western Aphasia Battery. Compared with those of healthy subjects, ALFF values significantly increased (FDR corrected p < .01) in the anterior part of the right putamen in the frontal AVM subgroup, in the posterior part of the right inferior and middle temporal gyrus in the temporal AVM subgroup, and in the inferior lateral part of the left cerebellar hemisphere (lobule VIII) and the right inferior parietal lobule in the parietal AVM subgroup. Functional annotation using Neurosynth indicated that the ALFF t-map was only significantly positively associated with the language-related domain (FDR corrected p < .01). In patients with AVMs involving the language cortex, language network reorganization occurs to maintain normal language abilities. The brain areas recruited into the reorganized language network were located in the right cerebral and left cerebellar hemispheres, both of which are nondominant hemispheres. Differences in lesion location led to distinct reorganization patterns.

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-ß (TGF-ß) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

A clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations.

Vascular anomalies are common orbital lesions, while variations in previous nomenclature might hamper robust characterization of their clinicopathological and genetic features. We reviewed and reclassified 92 orbital vascular lesions by the modified International Society for the Study of Vascular Anomalies (ISSVA) classification with reappraising clinicopathological parameters of 4 main types of vascular malformations, including orbital venous malformation 1 (OVM1, cavernous venous malformation), OVM2 (varix), OVM3 (infiltrating venous malformation), and arteriovenous malformation (AVM). GJA4, BRAF, and KRAS mutations were assessed by Sanger sequencing. There were 90 cases of vascular malformations, consisting of 60 OVM1 (67%), 13 AVM (14%), 8 OVM2 (9%), 8 OVM3 (9%), and 1 lymphatic-venous malformation (1%). The prevailing OVM1, histologically characterized by well-delineated borders and a uniform cavernous growth pattern, predominantly occurred in intraconal space (57%, P = .019) with an older median age (49 years) and female predilection (73%). OVM2, OVM3, and AVM exhibited differences in the distributions of patients' ages and lesion locations. Sizes of lesions were significantly correlated with periorbital and intraconal/extraconal locations (P < .001). OVM1 had the lowest rate of residual and recurrent diseases (3%). GJA4 mutations were identified in 75% (44/59) of OVM1 but not in OVM2/3 and AVM. No BRAF or KRAS mutations were detected. In conclusion, the modified ISSVA scheme enables meaningful classification of orbital vascular malformations by highlighting the molecular correlation between the distinct clinicopathological features and specific GJA4 mutation in OVM1, which implies OVM1 as a unique variant of venous malformation genetically akin to cutaneous and hepatic counterparts.

Extracranial arteriovenous malformations demonstrate dysregulated TGF-ß/BMP signaling and increased circulating TGF-ß1.

Extracranial arteriovenous malformations (AVMs) are characterized by anomalous arterial-to-venous connections, aberrant angiogenesis, local inflammation and hypoxia, and disorganized histological architecture; however, the precise molecular perturbations leading to this phenotype remain elusive. We hypothesized that extracranial AVM tissue would demonstrate deregulation of the TGF-ß/BMP signaling pathway, which may serve as a potential target in the development of molecular-based therapies for AVMs. AVM tissue was harvested during resection from 10 patients with AVMs and compared to control tissue. Blood was collected from 14 AVM patients and 10 patients without AVMs as controls. Expression of TGF-ß/BMP pathway components was analyzed using RT-PCR, western blotting, and immunohistochemistry. Circulating levels of TGF-ß1 were analyzed by ELISA. Paired t tests were utilized to perform statistical analysis. The mRNA levels of TGF-ß1, ALK1, Endoglin (ENG), Smad6, Smad7, and Smad8 were significantly elevated in AVM tissue when compared to controls. Protein levels of TGF-ß1 and Smad3 were elevated in AVM tissue while protein levels of BMP-9, ALK1, Smad1, Smad6, and Smad8 were significantly decreased in AVMs. Immunohistochemistry demonstrated increased TGF-ß1 in the perivascular cells of AVMs compared to normal controls, and circulating levels of TGF-ß1 were significantly higher in AVM patients. Patients with AVMs demonstrate aberrant TGF-ß/BMP expression in AVM tissue and blood compared to controls. Targeting aberrantly expressed components of the TGF-ß/BMP pathway in extracranial AVMs may be a viable approach in the development of novel molecular therapies, and monitoring circulating TGF-ß1 levels may be a useful indicator of treatment success.

A human model of arteriovenous malformation (AVM)-on-a-chip reproduces key disease hallmarks and enables drug testing in perfused human vessel networks.

Brain arteriovenous malformations (AVMs) are a disorder wherein abnormal, enlarged blood vessels connect arteries directly to veins, without an intervening capillary bed. AVMs are one of the leading causes of hemorrhagic stroke in children and young adults. Most human sporadic brain AVMs are associated with genetic activating mutations in the KRAS gene. Our goal was to develop an in vitro model that would allow for simultaneous morphological and functional phenotypic data capture in real time during AVM disease progression. By generating human endothelial cells harboring a clinically relevant mutation found in most human patients (activating mutations within the small GTPase KRAS) and seeding them in a dynamic microfluidic cell culture system that enables vessel formation and perfusion, we demonstrate that vessels formed by KRAS4AG12V mutant endothelial cells (ECs) were significantly wider and more leaky than vascular beds formed by wild-type ECs, recapitulating key structural and functional hallmarks of human AVM pathogenesis. Immunofluorescence staining revealed a breakdown of adherens junctions in mutant KRAS vessels, leading to increased vascular permeability, a hallmark of hemorrhagic stroke. Finally, pharmacological blockade of MEK kinase activity, but not PI3K inhibition, improved endothelial barrier function (decreased permeability) without affecting vessel diameter. Collectively, our studies describe the creation of human KRAS-dependent AVM-like vessels in vitro in a self-assembling microvessel platform that is amenable to phenotypic observation and drug delivery.

Acroangiodermatitis presenting as unilateral hypertrophic verrucous plaques.

Acroangiodermatitis (AAD)[KL1] is a rare vasoproliferative disorder often involving the extremities that has been classified into two variants. Mali-type AAD is more common and associated with chronic venous stasis. Stewart-Bluefarb syndrome[KL2], the other variant, is associated with underlying arteriovenous abnormalities. Mali-type AAD is a relatively benign diagnosis but it may mimic more harmful etiologies such as Kaposi sarcoma both clinically and histologically. A 67-year-old woman with a history of varicose veins, deep vein thrombosis, stroke, and obesity presented to our outpatient clinic with verrucous red-brown papules and plaques on her right lower extremity worsening for three years. Biopsy was consistent with a diagnosis of Mali-type AAD. Providers should be aware of AAD and its variants to accurately differentiate it from more harmful entities.

The Beauty and Complexity of Blood Vessel Patterning.

This review highlights new concepts in vascular patterning in the last 10 years, with emphasis on its beauty and complexity. Endothelial cell signaling pathways that respond to molecular or mechanical signals are described, and examples of vascular patterning that use these pathways in brain, skin, heart, and kidney are highlighted. The pathological consequences of patterning loss are discussed in the context of arteriovenous malformations (AVMs), and prospects for the next 10 years presented.

Capillary Malformation-arteriovenous Malformation Type 2: A Case Report and Review.

Capillary malformation-arteriovenous malformation syndrome is a rare genodermatosis with cutaneous capillary malformations and a risk of associated fast-flow malformations. We describe here a four-generation family with a novel heterozygous pathogenic variant in the EPHB4 gene (NM_004444.5 (EPHB4): c.2224G>C, p.(Ala742Pro)). A review of the literature retrieved 127 patients with capillary malformation-arteriovenous malformation syndrome and confirmed variants in EPHB4. Multiple capillary malformations were present in 114 (89.76%) patients, and 12 (9.44%) patients had a solitary capillary malformation. Arteriovenous malformations/fistulas were present in 23 (18.1%) patients, and were located within the central nervous system in 5 (3.9%) patients. Not all papers included description of epistaxis. Telangiectasias were reported in 28 (22%) patients, and Bier spots were described in 20 (15.7%) patients. The clinical characteristics of capillary malformation-arteriovenous malformation syndrome are diverse and often discrete, which can make it difficult to distinguish capillary malformation-arteriovenous malformation syndrome from hereditary haemorrhagic telangiectasia.

Impairment and Plasticity of Language-Related White Matter in Patients With Brain Arteriovenous Malformations.

BACKGROUND: Language dysfunction is rarely seen in patients with unruptured brain arteriovenous malformation (AVM) albeit the AVM nidus involving language areas, which provides a unique disease model to study language reorganization. The objective of this study was to investigate the impairment and reorganization patterns and characteristics of language-related white matter in AVMs located at different brain areas. METHODS: Thirty-three patients with AVMs involving language areas were prospectively enrolled. Patients were categorized into 3 groups according to the lesion locations: the frontal (14 patients), temporal (15 patients), and parietal groups (4 patients). Thirty age- and sex-matched healthy controls were enrolled as comparison. All participants underwent diffusion tensor imaging scans, and automated fiber quantification method was applied to quantitatively study the difference of segmented language-related white matter connectivity between 3 AVM groups and control group. RESULTS: Language functions were normal in all subjects according to Western Aphasia Battery test. In the frontal group, fractional anisotropy (FA) value decreased in the left arcuate fascicle and increased in left superior longitudinal fasciculus and uncinate fascicle; in the temporal group, FA values decreased in left inferior fronto-occipital fascicle and inferior longitudinal fascicle and increased in right anterior thalamic radiation and uncinate fascicle; in the parietal group, FA values decreased in left arcuate fascicle and inferior longitudinal fascicle and increased in bilateral anterior thalamic radiations and uncinate fascicles and right inferior fronto-occipital fascicle. In fascicles with decreased FA values, the increase of radial diffusivity was common, and fascicles with increased FA values usually presented along with increased axial diffusivity values. CONCLUSIONS: Remodeling of language-related white matter occurs when traditional language areas are involved by AVM nidus, and its reorganization patterns vary with locations of AVM nidus. Fascicle impairment is mainly caused by the myelin deficits, and its plasticity may be dominated by the axon remodeling procedure.

De Novo Germline and Somatic Variants Convergently Promote Endothelial-to-Mesenchymal Transition in Simplex Brain Arteriovenous Malformation.

[Figure: see text].

Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment.

Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

Massive haemorrhagic complications of ruptured pulmonary arteriovenous malformations: outcomes from a 12 years' retrospective study.

BACKGROUND: The life-threatening haemorrhagic complications of pulmonary arteriovenous malformations (PAVMs) are extremely rare, and only described in isolated cases. This study was designed to comprehensively investigate management of ruptured PAVMs. METHODS: We retrospectively assessed clinical and imaging data of ruptured PAVMs to summarize incidence, clinical characteristics, and outcomes following embolisation between January 2008 and January 2021. RESULTS: Eighteen of 406 (4.4%) patients with PAVMs developed haemorrhagic complications. Twelve of 18 patients were clinically diagnosed with hereditary haemorrhagic telangiectasia (HHT). Haemorrhagic complications occurred with no clear trigger in all cases. Eight of 18 patients (44.4%) were initially misdiagnosed or had undergone early ineffective treatment. 28 lesions were detected, with 89.3% of them located in peripheral lung. Computed tomography angiography (CTA) showed indirect signs to indicate ruptured PAVMs in all cases. Lower haemoglobin concentrations were associated with the diameter of afferent arteries in the ruptured lesions. Successful embolotherapy was achieved in all cases. After embolotherapy, arterial oxygen saturation improved and bleeding was controlled (P < 0.05). The mean follow-up time was 3.2 ± 2.5 years (range, 7 months to 10 years). CONCLUSIONS: Life threatening haemorrhagic complications of PAVMs are rare, they usually occur without a trigger and can be easily misdiagnosed. HHT and larger size of afferent arteries are major risk factors of these complications. CTA is a useful tool for diagnosis and therapeutic guidance for ruptured PAVMs. Embolotherapy is an effective therapy for this life-threatening complication.