Intranasal bleomycin versus Avastin® sclerotherapy as an adjunct to laser treatment for epistaxis in hereditary hemorrhagic telangiectasia

Intranasal bleomycin versus Avastin® sclerotherapy as an adjunct to laser treatment for epistaxis in hereditary hemorrhagic telangiectasia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Intranasal bleomycin versus Avastin® sclerotherapy as an adjunct to laser treatment for epistaxis in hereditary hemorrhagic telangiectasia Karin Petra Quirina Oomen, Volkert Boudewijn Wreesmann, Stefan Waner, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7781650/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Hereditary hemorrhagic telangiectasia is a rare disease of vascular development, often accompanied by severe epistaxis. Multimodality treatment may improve epistaxis control, but the optimal combination of modalities has not yet been established. Objective To compare the effects of adding intranasal bleomycin versus Avastin® sclerotherapy to laser treatment for epistaxis in patients with hereditary hemorrhagic telangiectasia. Methods We retrospectively studied the medical records of all hereditary hemorrhagic telangiectasia patients who underwent laser therapy with or without bleomycin or Avastin® sclerotherapy for epistaxis during eight consecutive years. We calculated the mean posttreatment epistaxis severity score changes, proportions of procedures after which a minimal important difference in epistaxis severity score was reached, and intervals between subsequent treatments. Results The mean epistaxis severity score change was significantly higher after laser combined with bleomycin, compared to laser treatment alone. The mean treatment interval after both laser combined with Avastin®, and laser combined with bleomycin, were significantly longer compared to laser treatment alone. Conclusions Adding bleomycin to laser treatment may lead to greater epistaxis severity score improvement compared to laser treatment only or laser combined with Avastin® in patients with hereditary hemorrhagic telangiectasia. Adding bleomycin or Avastin® to laser seems to lengthen treatment intervals compared to laser therapy alone. Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease, characterized by abnormal blood vessel development manifested as mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). The telangiectasias originate mainly from the sinonasal mucosa, and recurrent spontaneous epistaxis is the most common presenting symptom [ 1 ]. More than 98% of adults with HHT will experience recurrent epistaxis at some point in life [ 2 , 3 ]. Epistaxis severity may range from mild to life-threatening, but a common requirement for hospitalization, transfusions and surgical or endovascular procedures is an average hallmark of this disease. Unfortunately, the number of vascular lesions, and resultant severity of epistaxis, increase with age [ 4 ]. This disease progression in part reflects the age-dependent phenotypic penetrance of HHT, but likely also is due to structural blood vessel changes occurring naturally with age, as well as mucosal atrophy causing telangiectasias to become more prominent. Hence HHT often proves progressively detrimental to patients’ general health and quality of life [ 4 – 7 ]. Both its progressive nature and the access issues associated with the complicated anatomic location of the disease are major hurdles to successful treatment of HHT. Traditional HHT treatment includes laser coagulation, intranasal brachytherapy, septodermoplasty, nasal closure via Young’s procedure, and medical/hormonal therapy. Although laser coagulation has the best therapeutic index among these, single modality treatment of HHT-related epistaxis has been rather unsatisfactory [ 8 ]. In the case of laser coagulation, this is partly due to access issues in the sinonasal field. Although multimodality treatment may improve epistaxis control in HHT, the optimal combination of modalities has not been established thus far. Sclerotherapy is a possible adjunct to laser therapy in HHT. It consists of intralesional injection of an agent, which causes localized inflammation, thickening of the vessel wall, obstruction of blood flow, clot formation, and collapse/scarring of the lesion. Sclerotherapy is a widely used treatment modality for vascular lesions of the head and neck [ 9 – 12 ] but its applicability for HHT is under investigation. Recently, a growing number of studies report successful intranasal sclerotherapy in HHT [ 13 – 18 ]. A variety of sclerosants, including Aethoxysklerol® (polydocanol), cyanoacrylate glue, and sodium tetradecyl sulfate, have been described with variable success rates. Newer approaches include intranasal sclerotherapy with Avastin® (bevacizumab), a novel monoclonal antibody with anti-angiogenic properties [ 19 – 21 ]and bleomycin, a classic cytotoxic agent. We previously reported on the safety and efficacy of bleomycin, in the sclerotherapy of vascular malformations of the airway [ 22 ]. In the present study, we retrospectively compared the effects of adding intranasal bleomycin versus Avastin® sclerotherapy to laser treatment for epistaxis in patients with HHT. MATERIALS AND METHODS Study design We retrospectively studied the medical records of all HHT patients who underwent laser therapy with or without bleomycin or Avastin® sclerotherapy for epistaxis at the Vascular Birthmark Institute of New York (VBINY) from January 2011 to February 2023. Routine HHT management All patients received routine HHT care and diagnostic tests in accordance with current practice and guidelines. Intervention Intervention All patients underwent at least one round of one the following treatments: laser only, laser treatment with the addition of bleomycin sclerotherapy, or laser with Avastin® sclerotherapy. Patients underwent general anesthesia with either laryngeal mask ventilation or endotracheal intubation. The patient’s head was placed in the semi-Fowler position. Both nasal cavities were decongested with pledgets soaked in oxymetazoline HCL. Zero- and 30-degree rigid nasal endoscopes were used to evaluate the nasal cavities. Laser treatment Diode, KTP or Nd:YAG laser (wavelength of 532 nm) was delivered through a 550 micron fiber. The distal end of the fiber was passed through a handpiece or a 7Fr Frazier tip suction (Fig. 1 ). The main telangiectasias were identified and treated (Fig. 2 ). These vessels were traced in the non-contact continuous mode. The ideal treatment end point was vasoconstriction of the vessel without damage to the overlying mucosa, although a small area of blanching was often seen (Fig. 3 ). Care was taken to treat one side of the septum per session, thereby decreasing the risk of a septal perforation. The 532 nm Diode, KTP, or Nd: YAG laser was selected based on its well-documented peak absorption for oxyhemoglobin, the target chromophore in telangiectasias for vascular lasers. After absorption of the laser light by oxyhemoglobin, light energy is converted to thermal energy which diffuses within the vessel. Reducing the exposure time to a few microseconds ensures the thermal diffusion to surrounding tissue is kept to a minimum. The end result is thrombosis of the blood vessels with minimal coagulation of the overlying mucosa [ 23 – 25 ]. The laser effectively coagulates vessels larger than 200 microns in diameter and is therefore ideal for telangiectasias. Intralesional sclerotherapy After the main telangiectasias were treated, a sclerosant (bleomycin or Avastin ® ) was injected submucosally using a 1 ml syringe and 25 gauge needle. Bleomycin was used in an undiluted (3mg per 1 ml) concentration, and injected submucosally into the telangiectatic areas. A total of up to 0.9 ml was injected per side. Only one side of the septum was treated per session. Skin precautions were followed in order to decrease hyperpigmentation risk, one of the known side effects of bleomycin. Avastin ® was injected in a similar fashion. 3.75 mg of Avastin® was mixed in 1 ml of injectable saline. The maximum dose used during each treatment was 3.75mg per side [ 26 ]. Baseline assessment and outcome measures Demographic information, past treatments, comorbidities and genetic abnormalities were recorded. The primary outcome measure in this study was the change in Epistaxis Severity Score (ESS) between preoperative and postoperative consultation for treatment session. The ESS is a validated, patient-reported outcome measure concerning the frequency, duration, and intensity of epistaxis, anemia, need for medical attention, and blood transfusions [ 27 ]. The ESS is scored from 0 to 10 on a continuous scale. An ESS improvement of 0.71 or more following treatment is accepted as the minimal important difference (MID) in ESS, defined as the smallest difference in outcome, large enough to have an implication for the patient’s treatment and care [ 28 ]. We modified the ESS for a reference time frame matching the duration of the follow-up intervals of varying duration in this study. Secondary outcome measure was the proportion of procedures per treatment strategy, following which the MID in ESS was reached. Tertiary outcome measure was the interval between subsequent treatments in days, reflecting duration of remission. Analysis We calculated the mean ESS change per treatment session over the entire follow-up period combined, ending at the end of the last recorded follow-up. A positive ESS change reflected a decrease or improvement in ESS after any given follow-up period following the procedure. A negative ESS change reflected an increase or worsening in ESS following any procedure. The mean ESS changes calculated for all treatment sessions were then compared per treatment strategy using single factor (one-way) ANOVA pairwise comparisons. We also calculated the proportion of procedures following which a clinically meaningful difference in ESS of ≥ 0.71 was reached and compared these between the treatment strategies using a chi-square test. Lastly, we calculated and compared the interval between subsequent treatments in days per treatment strategy, using single factor (one way) ANOVA pairwise comparisons. RESULTS Study population Seventeen HHT patients presented with moderate to severe epistaxis between January 2011 to February 2023. We were able to collect sufficient pre- and post-treatment follow-up information for 12 patients. The median (range) age was 49.5 (21–85) years, 5 patients were male, and 7 female (Table 1). All patients underwent multiple sequential treatment sessions due to the recurrent nature of epistaxis in HHT. Altogether, 12 patients underwent 47 treatments which are detailed in Table 2. Table 2 Distribution of procedures; number of treatment sessions per patient, per treatment strategy. Laser + Avastin® sclerotherapy Laser + bleomycin sclerotherapy Laser treatment only Number of treatment sessions per patient Patient 1 2 0 1 3 Patient 2 0 2 1 3 Patient 3 0 1 2 3 Patient 4 0 1 2 3 Patient 5 0 0 2 2 Patient 6 1 3 7 11 Patient 7 0 0 2 2 Patient 8 2 3 6 11 Patient 9 1 0 1 2 Patient 10 0 0 2 2 Patient 11 0 0 2 2 Patient 12 1 0 2 3 Total procedures 7 10 30 47 Five patients underwent 3 separate treatment sessions, five patients underwent 2 treatments, and 2 patients underwent 11 treatments. The type of treatment given was based on patient, physician and disease severity factors. Of note, none of the patients received treatment with sclerotherapy only, this was always combined with laser treatment in the same session. Out of 47 procedures, 38 involved Diode laser, of which 2 procedures involved a combination of Diode and KTP laser. In a few procedures, KTP only (4) or Nd:YAG laser (2) were used, and in a few procedures the type of laser remained unspecified (3). The number of follow-up visits varied per treatment strategy. Sixteen follow up visits were recorded after treatment with laser combined with bleomycin, 10 after treatment with laser combined with Avastin® sclerotherapy, and 52 visits after treatment with laser only. Outcome A statistically significant difference was found between mean ESS improvement after laser combined with bleomycin sclerotherapy, and laser therapy alone (mean ESS improved by 3.160625 versus 0.488077, p = 0.00032). There was no significant difference between the proportion of treatments following which the MID of the ESS was reached for laser plus bleomycin when compared to laser only (9 out of 10 versus 20 out of 30, p = 0.100117). The mean treatment interval in days was significantly longer after laser combined with bleomycin (169.7778 versus 82.23529, p = 0.036903) (Table 3). Table 3 Comparison of laser combined with bleomycin sclerotherapy to laser only for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference. Laser + bleomycin Laser only p Mean ESS change 3.160625 0.488077 0.00032 Number of procedures following which MID reached 9 out of 10 20 out of 30 0.100117 Treatment interval (days) 169.7778 82.23529 0.036903 There was no significant difference between mean ESS improvement after laser combined with Avastin® sclerotherapy when compared to laser therapy alone (1.55 versus 0.488077, p = 0.214604). The proportions of treatments following which the MID of the ESS was reached were similar after laser combined with Avastin® when compared to laser only (4 out of 7 versus 20 out of 30, p = 0.749749). The mean treatment interval in days was significantly longer after laser combined with Avastin® (216.4268 versus 82.23539 days, p = 0.016622) (Table 4). Table 4 Comparison of laser combined with Avastin® sclerotherapy to laser only for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference. Laser + Avastin® Laser treatment only p Mean ESS change 1.55 0.488077 0.214604 Number of procedures following which MID reached 4 out of 7 20 out of 30 0.749749 Treatment interval (days) 216.4286 82.23529 0.016622 We found a slightly higher mean ESS improvement after laser treatment combined with bleomycin sclerotherapy when compared to laser combined with Avastin® (3.160625 versus 1.55, p = 0.09889) The proportion of treatments following which the MID of the ESS was reached was higher after laser combined with bleomycin sclerotherapy than after laser combined with Avastin® sclerotherapy (MID reached after 9 out of 10 procedures versus 4 out of 7, p = 0.073794). The mean treatment intervals were similar for laser combined with bleomycin sclerotherapy and laser combined with Avastin® sclerotherapy (169.778 versus 216.4286 days, p = 0.60675) (Table 5). Table 5 Comparison of laser combined with bleomycin and laser combined with Avastin® sclerotherapy for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference. Laser + bleomycin Laser + Avastin® p Mean ESS change 3.160625 1.55 0.09889 Number of procedures following which MID reached 9 out of 10 4 out of 7 0.073794 Treatment interval (days) 169.7778 216.4286 0.60675 DISCUSSION This retrospective study compares the effects of adding intranasal bleomycin versus Avastin® sclerotherapy to laser treatment only in patients with HHT related epistaxis. We found a significantly higher mean ESS improvement after laser combined with bleomycin sclerotherapy, when compared to laser treatment only. A trend towards a higher mean ESS improvement after laser plus bleomycin was found, when compared to laser plus Avastin®. The proportion of treatments following which the MID of the ESS was reached, was slightly higher for laser combined with bleomycin, when compared to laser combined with Avastin®. When compared to laser only, the mean treatment interval in days was significantly longer, both after laser combined with bleomycin and after laser combined with Avastin®. This study is the first of its kind to assess the effectiveness of intranasal bleomycin sclerotherapy for epistaxis in patients with HHT. One previous case report describes intranasal bleomycin injections for palliation of a single HHT patient [ 29 ]. Bleomycin is an antibiotic with cytotoxic antitumor properties. The side-effect of vascular endothelial destruction was first used therapeutically by Yura et al. [ 30 ] in 8 patients with lymphatic malformation. There are many studies demonstrating that bleomycin causes considerable damage to DNA[ 31 , 32 ]. Bleomycin has been shown to induce this damage through release of bases, single- and double strand DNA breaks, and effects on chromatin. The most clinically significant effect of bleomycin is disruption of the cell cycle during mitosis, preventing of tissue proliferation. This may explain the efficacy of bleomycin in lesions with increased cell turnover. Bleomycin is effective as a sclerosant, with a low tendency for inducing postoperative swelling, as confirmed in recent studies concerning vascular malformations in the head and neck area [ 33 , 34 ]. Because of this low side-effect profile, bleomycin may be particularly useful in children and adults in whom treatment-associated edema may compromise functions such as breathing or vision. Despite these major advantages, some controversies exist regarding the use of bleomycin as a sclerosing agent. Concerns have been raised regarding development of pulmonary fibrosis; a complication seen in oncological patients treated with bleomycin systemically[ 35 ]. To date, however, no cases of pulmonary fibrosis have been reported in association with bleomycin sclerotherapy. This is likely due to the fact that interstitial injection does not result in a substantial amount of systemic absorption. Ionescu et al. [ 36 ] demonstrated no detectable bleomycin in blood samples taken between 10 and 24 hours after sclerotherapy for hemangiomas in children. It is commonly accepted that the risk of bleomycin induced pulmonary fibrosis is dose dependent [ 37 ]. The systemic cumulative dose recognized to be associated with an increased risk of pulmonary fibrosis in the oncological literature is 450 mg over a lifetime [ 38 ]. As patients with HHT often need multiple sclerotherapy procedures, there would be a theoretical risk of a cumulative lifetime dose exceeding this limit. However, previous studies of bleomycin sclerotherapy for venous malformations have demonstrated a per session and cumulative dose of less than 15mg and less than 250 mg, respectively, which is well below the threshold of increased risk [ 39 , 40 ]. The per session sclerotherapy concentration in the present study was 3mg per mL, with a maximum of 0.9 ml injected per nasal cavity. Due to this low dose per session, reaching the maximum cumulative dose in HHT patients would seem to require an unlikely high number of repeat procedures over a lifetime. Despite this, pulmonary clearance was obtained for each patient prior to treatment, and a log was kept of ongoing cumulative bleomycin doses for each patient. Avastin® (bevacizumab) is a humanized monoclonal immunoglobulin G1 antibody which binds to circulating vascular endothelial growth factor A (VEGF-A). Binding of VEGF to its receptors generally results in a strong pro-angiogenic cascade. Previous studies have shown increased plasma concentrations and tissue expression of VEGF and other angiogenetic cytokines in patients with HHT [ 41 , 42 ]. Avastin® has been assumed to inhibit VEGF-mediated angiogenesis in patients with HHT. Previous studies have reported on various modes of administration of bevacizumab for HHT. A phase 2 trial of intravenous bevacizumab for cardiac failure in HHT patients, strikingly showed a reduced duration and number of epistaxis episodes in their study group [ 43 ]. To avoid its systemic adverse effects, direct intranasal treatment with bevacizumab has been suggested as an alternative to intravenous injection [ 19 – 21 ]. Although bevacizumab is considered safe, previous studies have cautioned about development of septal perforations following intranasal topical or sclerotherapy treatment [ 44 ]. In the present study, no adverse effects of Avastin® sclerotherapy were encountered. Since its introduction in 1981, laser photocoagulation has proven successful in mitigating HHT-related epistaxis. Most lasers act specifically on the vascular target and produce photocoagulation of telangiectasia without damage to vessel walls and epithelial coating. These features render laser treatment repeatable, which is often needed due to the recurrent nature of HHT related epistaxis. Nd:YAG laser therapy may yield improved epistaxis outcomes compared to Diode laser in patients with HHT [ 45 ]. Some of our results are in agreement with existing studies. Although many sclerosants have been studied previously, no studies to date address the effectiveness of bleomycin sclerotherapy for treatment of HHT-related epistaxis. However, sclerotherapy in general has been proven effective in improving epistaxis in patients with HHT when added to laser therapy [ 13 – 18 ]. Our results show that adding Avastin® to laser treatment resulted in a significantly longer treatment interval than laser treatment alone. This seems consistent with previous studies on bevacizumab sclerotherapy for HHT related epistaxis when compared to standard treatment [ 19 ]. In order to appreciate the results of this study, some of its limitations need to be discussed. First of all, this study is a retrospective report with a low number of subjects, which renders it difficult to generalize our results. Furthermore, there is no pre-treatment standardization of severity or number of lesions. In the present study, all sclerotherapy treatment sessions were combined with laser therapy. Because of this multimodality approach, it may be challenging to ascribe positive effects on epistaxis to one isolated treatment element only. Similar reports on treatment for HHT-related epistaxis have used ESS change as the main outcome measure. In several studies, the difference was calculated between the median ESS at baseline and at a fixed follow-up time, per treatment group. This approach was not attainable in our study, as patients underwent a varying amount of procedures during varying time periods recorded, with individually varying time intervals between treatment sessions and follow-up visits. The majority of patients (8 out of 12) underwent one or several rounds of at least 2 different treatment modalities sequentially during the study period (Table 2 ). As a result, one patient could be part of several treatment strategy groups at any specific point in time. This precluded setting a fixed follow-up time point to compare ESS changes for each patient. Instead, we calculated the mean ESS change for all treatment sessions per treatment strategy. As a result, the mean ESS change per treatment strategy may have included multiple recordings in the same patient, possibly leading to an under or overestimation of treatment effect. As outlined in our results section, the number of follow-up visits varied per treatment strategy. This may have positively or negatively affected the mean ESS change specifically for the laser treatment only strategy, where the number of visits was highest. Lastly, in our study, duration of mean treatment interval was assumed to assess treatment effect, by reflecting disease remission. However, other factors, such as patient delay may have influenced interval duration as well. Also, the time interval between procedures may have been subjective and could to a certain extent have been driven by either the patient, the doctor, or both. In conclusion, the present study shows a beneficial effect on ESS improvement of adding bleomycin sclerotherapy to laser treatment in patients with HHT. We found a trend towards a higher ESS improvement after adding bleomycin to laser, when compared to laser combined with Avastin®. Both bleomycin and Avastin® sclerotherapy seem to lengthen treatment intervals when added to laser therapy alone. There is a trend towards a higher proportion of the MID of the ESS reached for laser combined with bleomycin when compared to laser combined with Avastin®. Larger studies are needed to assess the efficacy of these sclerosants further. Declarations The Authors declare that there is no financial or non-financial conflict of interest, directly or indirectly related to the work submitted for publication. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Compliance with ethical standards (ethical statement) The protocol was approved by Advara IRB in accordance with the guidelines under 45 CFR 46.104(d)(4)(iii). Consent to participate The need for informed consent was waived by Advara IRB. Consent to publish Not applicable Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Funding Statement This research did not receive funding Clinical trial number: not applicable References Li S, Wang SJ, Zhao YQ. 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J Vasc Surg. 2008;47:1292–9. Spence J, Krings T, ter Brugge KG, et al. Percutaneous sclerotherapy for facial venous malformations: subjective clinical and objective MR imaging follow-up results. Am J Neuroradiol. 2010;31:955–60. Sadick H, Naim R, Sadick M, Hormann K, Riedel F. Plasma level and tissue expression of angiogenic factors in patients with hereditary hemorrhagic telangiectasia. Int J Mol Med. 2005;15:591–6. Sadick H, Riedel F, Naim R, et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta I as well as high ALK1 tissue expression. Haematologica. 2005;90:818–28. Dupuis-Girod S, Ginon I, Saurin JC, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic malformations and high cardiac output. JAMA. 2012;307:948–55. Chen S 4th, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011;121:644–6. Abiri A, Goshtasbi K, Maducdoc M, Sahyouni R, Wang MB, Kuan EC. Laser-Assisted Control of Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Systematic Review. Lasers Surg Med. 2020;52:293–300. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 05 Jan, 2026 Reviews received at journal 03 Jan, 2026 Reviewers agreed at journal 03 Jan, 2026 Reviewers agreed at journal 28 Dec, 2025 Reviews received at journal 28 Dec, 2025 Reviewers agreed at journal 13 Dec, 2025 Reviewers invited by journal 10 Dec, 2025 Editor invited by journal 09 Dec, 2025 Editor assigned by journal 06 Dec, 2025 Submission checks completed at journal 26 Nov, 2025 First submitted to journal 26 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7781650","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":559858975,"identity":"a8c42d9c-e0e3-4cc8-8069-b1f67e5a40d1","order_by":0,"name":"Karin Petra Quirina Oomen","email":"","orcid":"","institution":"Clinica Omega Zeta","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"Petra Quirina","lastName":"Oomen","suffix":""},{"id":559858976,"identity":"cbde8d5b-cc12-4736-a43a-be33eb2545dd","order_by":1,"name":"Volkert Boudewijn Wreesmann","email":"","orcid":"","institution":"Clinica Omega Zeta","correspondingAuthor":false,"prefix":"","firstName":"Volkert","middleName":"Boudewijn","lastName":"Wreesmann","suffix":""},{"id":559858977,"identity":"b26de782-ffce-46cd-b57f-69069ce16794","order_by":2,"name":"Stefan Waner","email":"","orcid":"","institution":"Hofstra University","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"Waner","suffix":""},{"id":559858978,"identity":"087bcc19-5a5a-482c-a8fa-ad385b86dfcf","order_by":3,"name":"Milton Waner","email":"","orcid":"","institution":"Vascular Birthmark Institute of New York","correspondingAuthor":false,"prefix":"","firstName":"Milton","middleName":"","lastName":"Waner","suffix":""},{"id":559858980,"identity":"6b655927-8ece-4758-9f2d-3aa19aa579b7","order_by":4,"name":"Teresa 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01:07:40","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":116755,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/fbe192c1c613125a79f9b50a.html"},{"id":98435464,"identity":"232d5c45-2cd2-4ab4-9624-44067c09fa35","added_by":"auto","created_at":"2025-12-17 16:53:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":191139,"visible":true,"origin":"","legend":"\u003cp\u003eA Diode, KTP or Nd:YAG laser with 532 nm wavelength, coupled with a 550 micron fiber fed through a handpiece or a 7 Fr Frazier tip suction is introduced into the nasal cavity.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/29ef2208daec636250e0d4b2.png"},{"id":98269366,"identity":"648abf02-a41e-48ec-8272-50fb8a69979f","added_by":"auto","created_at":"2025-12-16 01:07:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":144261,"visible":true,"origin":"","legend":"\u003cp\u003eRight nasal cavity with telangiectasias on the septum, lateral wall and middle turbinate, directly prior to laser treatment. The areas of telangiectasias are marked with asterisks.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/99088620c0eaa3e70a51da94.png"},{"id":98269364,"identity":"63e5e60d-d34f-44a3-999c-66abf44a9ba9","added_by":"auto","created_at":"2025-12-16 01:07:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":208772,"visible":true,"origin":"","legend":"\u003cp\u003eRight nasal cavity immediately post-laser treatment. Post treatment, vasoconstriction of the vessel ensued without damage to the overlying mucosa. The arrows point toward the treated areas where a small area of blanching is seen.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/10d1109f3ab67bb2b2735de9.png"},{"id":98445456,"identity":"71170d22-404b-47f6-942f-5e94a952df64","added_by":"auto","created_at":"2025-12-17 17:19:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1261517,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/ddf78342-fa50-4ead-a331-1eed7158b1bd.pdf"},{"id":98269357,"identity":"86e5e43e-50f8-4034-b174-3b7643a2cd18","added_by":"auto","created_at":"2025-12-16 01:07:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19332,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7781650/v1/5b7fca5fedf6dc57d4232d3a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intranasal bleomycin versus Avastin® sclerotherapy as an adjunct to laser treatment for epistaxis in hereditary hemorrhagic telangiectasia","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease, characterized by abnormal blood vessel development manifested as mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). The telangiectasias originate mainly from the sinonasal mucosa, and recurrent spontaneous epistaxis is the most common presenting symptom [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. More than 98% of adults with HHT will experience recurrent epistaxis at some point in life [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Epistaxis severity may range from mild to life-threatening, but a common requirement for hospitalization, transfusions and surgical or endovascular procedures is an average hallmark of this disease. Unfortunately, the number of vascular lesions, and resultant severity of epistaxis, increase with age [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This disease progression in part reflects the age-dependent phenotypic penetrance of HHT, but likely also is due to structural blood vessel changes occurring naturally with age, as well as mucosal atrophy causing telangiectasias to become more prominent. Hence HHT often proves progressively detrimental to patients\u0026rsquo; general health and quality of life [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Both its progressive nature and the access issues associated with the complicated anatomic location of the disease are major hurdles to successful treatment of HHT.\u003c/p\u003e \u003cp\u003eTraditional HHT treatment includes laser coagulation, intranasal brachytherapy, septodermoplasty, nasal closure via Young\u0026rsquo;s procedure, and medical/hormonal therapy. Although laser coagulation has the best therapeutic index among these, single modality treatment of HHT-related epistaxis has been rather unsatisfactory [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In the case of laser coagulation, this is partly due to access issues in the sinonasal field. Although multimodality treatment may improve epistaxis control in HHT, the optimal combination of modalities has not been established thus far.\u003c/p\u003e \u003cp\u003eSclerotherapy is a possible adjunct to laser therapy in HHT. It consists of intralesional injection of an agent, which causes localized inflammation, thickening of the vessel wall, obstruction of blood flow, clot formation, and collapse/scarring of the lesion. Sclerotherapy is a widely used treatment modality for vascular lesions of the head and neck [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] but its applicability for HHT is under investigation. Recently, a growing number of studies report successful intranasal sclerotherapy in HHT [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A variety of sclerosants, including Aethoxysklerol\u0026reg; (polydocanol), cyanoacrylate glue, and sodium tetradecyl sulfate, have been described with variable success rates. Newer approaches include intranasal sclerotherapy with Avastin\u0026reg; (bevacizumab), a novel monoclonal antibody with anti-angiogenic properties [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]and bleomycin, a classic cytotoxic agent. We previously reported on the safety and efficacy of bleomycin, in the sclerotherapy of vascular malformations of the airway [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present study, we retrospectively compared the effects of adding intranasal bleomycin versus Avastin\u0026reg; sclerotherapy to laser treatment for epistaxis in patients with HHT.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe retrospectively studied the medical records of all HHT patients who underwent laser therapy with or without bleomycin or Avastin\u0026reg; sclerotherapy for epistaxis at the Vascular Birthmark Institute of New York (VBINY) from January 2011 to February 2023.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRoutine HHT management\u003c/h3\u003e\n\u003cp\u003e All patients received routine HHT care and diagnostic tests in accordance with current practice and guidelines.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cdiv class=\"Heading\"\u003eIntervention\u003c/div\u003e \u003cp\u003eAll patients underwent at least one round of one the following treatments: laser only, laser treatment with the addition of bleomycin sclerotherapy, or laser with Avastin\u0026reg; sclerotherapy.\u003c/p\u003e \u003cp\u003ePatients underwent general anesthesia with either laryngeal mask ventilation or endotracheal intubation. The patient\u0026rsquo;s head was placed in the semi-Fowler position. Both nasal cavities were decongested with pledgets soaked in oxymetazoline HCL. Zero- and 30-degree rigid nasal endoscopes were used to evaluate the nasal cavities.\u003c/p\u003e\n\u003ch3\u003eLaser treatment\u003c/h3\u003e\n\u003cp\u003eDiode, KTP or Nd:YAG laser (wavelength of 532 nm) was delivered through a 550 micron fiber. The distal end of the fiber was passed through a handpiece or a 7Fr Frazier tip suction (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe main telangiectasias were identified and treated (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThese vessels were traced in the non-contact continuous mode. The ideal treatment end point was vasoconstriction of the vessel without damage to the overlying mucosa, although a small area of blanching was often seen (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCare was taken to treat one side of the septum per session, thereby decreasing the risk of a septal perforation.\u003c/p\u003e \u003cp\u003eThe 532 nm Diode, KTP, or Nd: YAG laser was selected based on its well-documented peak absorption for oxyhemoglobin, the target chromophore in telangiectasias for vascular lasers. After absorption of the laser light by oxyhemoglobin, light energy is converted to thermal energy which diffuses within the vessel. Reducing the exposure time to a few microseconds ensures the thermal diffusion to surrounding tissue is kept to a minimum. The end result is thrombosis of the blood vessels with minimal coagulation of the overlying mucosa [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The laser effectively coagulates vessels larger than 200 microns in diameter and is therefore ideal for telangiectasias.\u003c/p\u003e\n\u003ch3\u003eIntralesional sclerotherapy\u003c/h3\u003e\n\u003cp\u003eAfter the main telangiectasias were treated, a sclerosant (bleomycin or Avastin\u003cb\u003e\u0026reg;\u003c/b\u003e) was injected submucosally using a 1 ml syringe and 25 gauge needle. Bleomycin was used in an undiluted (3mg per 1 ml) concentration, and injected submucosally into the telangiectatic areas. A total of up to 0.9 ml was injected per side. Only one side of the septum was treated per session. Skin precautions were followed in order to decrease hyperpigmentation risk, one of the known side effects of bleomycin. Avastin\u003cb\u003e\u0026reg;\u003c/b\u003e was injected in a similar fashion. 3.75 mg of Avastin\u0026reg; was mixed in 1 ml of injectable saline. The maximum dose used during each treatment was 3.75mg per side [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline assessment and outcome measures\u003c/h2\u003e \u003cp\u003eDemographic information, past treatments, comorbidities and genetic abnormalities were recorded.\u003c/p\u003e \u003cp\u003eThe primary outcome measure in this study was the change in Epistaxis Severity Score (ESS) between preoperative and postoperative consultation for treatment session. The ESS is a validated, patient-reported outcome measure concerning the frequency, duration, and intensity of epistaxis, anemia, need for medical attention, and blood transfusions [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The ESS is scored from 0 to 10 on a continuous scale. An ESS improvement of 0.71 or more following treatment is accepted as the minimal important difference (MID) in ESS, defined as the smallest difference in outcome, large enough to have an implication for the patient\u0026rsquo;s treatment and care [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. We modified the ESS for a reference time frame matching the duration of the follow-up intervals of varying duration in this study.\u003c/p\u003e \u003cp\u003eSecondary outcome measure was the proportion of procedures per treatment strategy, following which the MID in ESS was reached.\u003c/p\u003e \u003cp\u003eTertiary outcome measure was the interval between subsequent treatments in days, reflecting duration of remission.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAnalysis\u003c/h3\u003e\n\u003cp\u003eWe calculated the mean ESS change per treatment session over the entire follow-up period combined, ending at the end of the last recorded follow-up. A positive ESS change reflected a decrease or improvement in ESS after any given follow-up period following the procedure. A negative ESS change reflected an increase or worsening in ESS following any procedure. The mean ESS changes calculated for all treatment sessions were then compared per treatment strategy using single factor (one-way) ANOVA pairwise comparisons.\u003c/p\u003e \u003cp\u003eWe also calculated the proportion of procedures following which a clinically meaningful difference in ESS of \u0026ge;\u0026thinsp;0.71 was reached and compared these between the treatment strategies using a chi-square test.\u003c/p\u003e \u003cp\u003eLastly, we calculated and compared the interval between subsequent treatments in days per treatment strategy, using single factor (one way) ANOVA pairwise comparisons.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eStudy population\u003c/h2\u003e\n \u003cp\u003eSeventeen HHT patients presented with moderate to severe epistaxis between January 2011 to February 2023. We were able to collect sufficient pre- and post-treatment follow-up information for 12 patients. The median (range) age was 49.5 (21–85) years, 5 patients were male, and 7 female (Table 1).\u003c/p\u003e\n \u003cp\u003eAll patients underwent multiple sequential treatment sessions due to the recurrent nature of epistaxis in HHT. Altogether, 12 patients underwent 47 treatments which are detailed in Table 2.\u0026nbsp;\u003c/p\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eDistribution of procedures; number of treatment sessions per patient, per treatment strategy.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + Avastin® sclerotherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + bleomycin sclerotherapy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser treatment only\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of treatment sessions per patient\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatient 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal procedures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eFive patients underwent 3 separate treatment sessions, five patients underwent 2 treatments, and 2 patients underwent 11 treatments. The type of treatment given was based on patient, physician and disease severity factors. Of note, none of the patients received treatment with sclerotherapy only, this was always combined with laser treatment in the same session. Out of 47 procedures, 38 involved Diode laser, of which 2 procedures involved a combination of Diode and KTP laser. In a few procedures, KTP only (4) or Nd:YAG laser (2) were used, and in a few procedures the type of laser remained unspecified (3).\u003c/p\u003e\n \u003cp\u003eThe number of follow-up visits varied per treatment strategy. Sixteen follow up visits were recorded after treatment with laser combined with bleomycin, 10 after treatment with laser combined with Avastin® sclerotherapy, and 52 visits after treatment with laser only.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003eOutcome\u003c/h2\u003e\n \u003cp\u003eA statistically significant difference was found between mean ESS improvement after laser combined with bleomycin sclerotherapy, and laser therapy alone (mean ESS improved by 3.160625 versus 0.488077, p = 0.00032). There was no significant difference between the proportion of treatments following which the MID of the ESS was reached for laser plus bleomycin when compared to laser only (9 out of 10 versus 20 out of 30, p = 0.100117). The mean treatment interval in days was significantly longer after laser combined with bleomycin (169.7778 versus 82.23529, p = 0.036903) (Table\u0026nbsp;3).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of laser combined with bleomycin sclerotherapy to laser only for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + bleomycin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser only\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean ESS change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.160625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.488077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.00032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of procedures following which MID reached\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 out of 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 out of 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.100117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment interval (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e169.7778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.23529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.036903\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eThere was no significant difference between mean ESS improvement after laser combined with Avastin® sclerotherapy when compared to laser therapy alone (1.55 versus 0.488077, p = 0.214604). The proportions of treatments following which the MID of the ESS was reached were similar after laser combined with Avastin® when compared to laser only (4 out of 7 versus 20 out of 30, p = 0.749749). The mean treatment interval in days was significantly longer after laser combined with Avastin® (216.4268 versus 82.23539 days, p = 0.016622) (Table\u0026nbsp;4).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of laser combined with Avastin® sclerotherapy to laser only for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + Avastin®\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser treatment only\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean ESS change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.488077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.214604\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of procedures following which MID reached\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 out of 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 out of 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.749749\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment interval (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e216.4286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82.23529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016622\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eWe found a slightly higher mean ESS improvement after laser treatment combined with bleomycin sclerotherapy when compared to laser combined with Avastin® (3.160625 versus 1.55, p = 0.09889) The proportion of treatments following which the MID of the ESS was reached was higher after laser combined with bleomycin sclerotherapy than after laser combined with Avastin® sclerotherapy (MID reached after 9 out of 10 procedures versus 4 out of 7, p = 0.073794). The mean treatment intervals were similar for laser combined with bleomycin sclerotherapy and laser combined with Avastin® sclerotherapy (169.778 versus 216.4286 days, p = 0.60675) (Table\u0026nbsp;5).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 5\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eComparison of laser combined with bleomycin and laser combined with Avastin® sclerotherapy for all three outcome measures. ESS = epistaxis severity score. MID = minimal important difference.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + bleomycin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLaser + Avastin®\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean ESS change\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.160625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.09889\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of procedures following which MID reached\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 out of 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 out of 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.073794\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment interval (days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e169.7778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e216.4286\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.60675\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis retrospective study compares the effects of adding intranasal bleomycin versus Avastin\u0026reg;\u003c/p\u003e \u003cp\u003esclerotherapy to laser treatment only in patients with HHT related epistaxis.\u003c/p\u003e \u003cp\u003eWe found a significantly higher mean ESS improvement after laser combined with bleomycin sclerotherapy, when compared to laser treatment only. A trend towards a higher mean ESS improvement after laser plus bleomycin was found, when compared to laser plus Avastin\u0026reg;. The proportion of treatments following which the MID of the ESS was reached, was slightly higher for laser combined with bleomycin, when compared to laser combined with Avastin\u0026reg;. When compared to laser only, the mean treatment interval in days was significantly longer, both after laser combined with bleomycin and after laser combined with Avastin\u0026reg;.\u003c/p\u003e \u003cp\u003eThis study is the first of its kind to assess the effectiveness of intranasal bleomycin sclerotherapy for epistaxis in patients with HHT. One previous case report describes intranasal bleomycin injections for palliation of a single HHT patient [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Bleomycin is an antibiotic with cytotoxic antitumor properties. The side-effect of vascular endothelial destruction was first used therapeutically by Yura et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] in 8 patients with lymphatic malformation. There are many studies demonstrating that bleomycin causes considerable damage to DNA[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Bleomycin has been shown to induce this damage through release of bases, single- and double strand DNA breaks, and effects on chromatin. The most clinically significant effect of bleomycin is disruption of the cell cycle during mitosis, preventing of tissue proliferation. This may explain the efficacy of bleomycin in lesions with increased cell turnover.\u003c/p\u003e \u003cp\u003eBleomycin is effective as a sclerosant, with a low tendency for inducing postoperative swelling, as confirmed in recent studies concerning vascular malformations in the head and neck area [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Because of this low side-effect profile, bleomycin may be particularly useful in children and adults in whom treatment-associated edema may compromise functions such as breathing or vision. Despite these major advantages, some controversies exist regarding the use of bleomycin as a sclerosing agent. Concerns have been raised regarding development of pulmonary fibrosis; a complication seen in oncological patients treated with bleomycin systemically[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. To date, however, no cases of pulmonary fibrosis have been reported in association with bleomycin sclerotherapy. This is likely due to the fact that interstitial injection does not result in a substantial amount of systemic absorption. Ionescu et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] demonstrated no detectable bleomycin in blood samples taken between 10 and 24 hours after sclerotherapy for hemangiomas in children.\u003c/p\u003e \u003cp\u003eIt is commonly accepted that the risk of bleomycin induced pulmonary fibrosis is dose dependent [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The systemic cumulative dose recognized to be associated with an increased risk of pulmonary fibrosis in the oncological literature is 450 mg over a lifetime [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. As patients with HHT often need multiple sclerotherapy procedures, there would be a theoretical risk of a cumulative lifetime dose exceeding this limit. However, previous studies of bleomycin sclerotherapy for venous malformations have demonstrated a per session and cumulative dose of less than 15mg and less than 250 mg, respectively, which is well below the threshold of increased risk [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The per session sclerotherapy concentration in the present study was 3mg per mL, with a maximum of 0.9 ml injected per nasal cavity. Due to this low dose per session, reaching the maximum cumulative dose in HHT patients would seem to require an unlikely high number of repeat procedures over a lifetime. Despite this, pulmonary clearance was obtained for each patient prior to treatment, and a log was kept of ongoing cumulative bleomycin doses for each patient.\u003c/p\u003e \u003cp\u003eAvastin\u0026reg; (bevacizumab) is a humanized monoclonal immunoglobulin G1 antibody which binds to circulating vascular endothelial growth factor A (VEGF-A). Binding of VEGF to its receptors generally results in a strong pro-angiogenic cascade. Previous studies have shown increased plasma concentrations and tissue expression of VEGF and other angiogenetic cytokines in patients with HHT [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Avastin\u0026reg; has been assumed to inhibit VEGF-mediated angiogenesis in patients with HHT. Previous studies have reported on various modes of administration of bevacizumab for HHT. A phase 2 trial of intravenous bevacizumab for cardiac failure in HHT patients, strikingly showed a reduced duration and number of epistaxis episodes in their study group [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. To avoid its systemic adverse effects, direct intranasal treatment with bevacizumab has been suggested as an alternative to intravenous injection [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although bevacizumab is considered safe, previous studies have cautioned about development of septal perforations following intranasal topical or sclerotherapy treatment [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In the present study, no adverse effects of Avastin\u0026reg; sclerotherapy were encountered.\u003c/p\u003e \u003cp\u003eSince its introduction in 1981, laser photocoagulation has proven successful in mitigating HHT-related epistaxis. Most lasers act specifically on the vascular target and produce photocoagulation of telangiectasia without damage to vessel walls and epithelial coating. These features render laser treatment repeatable, which is often needed due to the recurrent nature of HHT related epistaxis.\u003c/p\u003e \u003cp\u003eNd:YAG laser therapy may yield improved epistaxis outcomes compared to Diode laser in patients with HHT [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSome of our results are in agreement with existing studies. Although many sclerosants have been studied previously, no studies to date address the effectiveness of bleomycin sclerotherapy for treatment of HHT-related epistaxis. However, sclerotherapy in general has been proven effective in improving epistaxis in patients with HHT when added to laser therapy [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our results show that adding Avastin\u0026reg; to laser treatment resulted in a significantly longer treatment interval than laser treatment alone. This seems consistent with previous studies on bevacizumab sclerotherapy for HHT related epistaxis when compared to standard treatment [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn order to appreciate the results of this study, some of its limitations need to be discussed. First of all, this study is a retrospective report with a low number of subjects, which renders it difficult to generalize our results.\u003c/p\u003e \u003cp\u003eFurthermore, there is no pre-treatment standardization of severity or number of lesions.\u003c/p\u003e \u003cp\u003eIn the present study, all sclerotherapy treatment sessions were combined with laser therapy. Because of this multimodality approach, it may be challenging to ascribe positive effects on epistaxis to one isolated treatment element only.\u003c/p\u003e \u003cp\u003eSimilar reports on treatment for HHT-related epistaxis have used ESS change as the main outcome measure. In several studies, the difference was calculated between the median ESS at baseline and at a fixed follow-up time, per treatment group. This approach was not attainable in our study, as patients underwent a varying amount of procedures during varying time periods recorded, with individually varying time intervals between treatment sessions and follow-up visits. The majority of patients (8 out of 12) underwent one or several rounds of at least 2 different treatment modalities sequentially during the study period (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As a result, one patient could be part of several treatment strategy groups at any specific point in time. This precluded setting a fixed follow-up time point to compare ESS changes for each patient. Instead, we calculated the mean ESS change for all treatment sessions per treatment strategy. As a result, the mean ESS change per treatment strategy may have included multiple recordings in the same patient, possibly leading to an under or overestimation of treatment effect.\u003c/p\u003e \u003cp\u003eAs outlined in our results section, the number of follow-up visits varied per treatment strategy. This may have positively or negatively affected the mean ESS change specifically for the laser treatment only strategy, where the number of visits was highest.\u003c/p\u003e \u003cp\u003eLastly, in our study, duration of mean treatment interval was assumed to assess treatment effect, by reflecting disease remission. However, other factors, such as patient delay may have influenced interval duration as well. Also, the time interval between procedures may have been subjective and could to a certain extent have been driven by either the patient, the doctor, or both.\u003c/p\u003e \u003cp\u003eIn conclusion, the present study shows a beneficial effect on ESS improvement of adding bleomycin sclerotherapy to laser treatment in patients with HHT. We found a trend towards a higher ESS improvement after adding bleomycin to laser, when compared to laser combined with Avastin\u0026reg;. Both bleomycin and Avastin\u0026reg; sclerotherapy seem to lengthen treatment intervals when added to laser therapy alone. There is a trend towards a higher proportion of the MID of the ESS reached for laser combined with bleomycin when compared to laser combined with Avastin\u0026reg;. Larger studies are needed to assess the efficacy of these sclerosants further.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe Authors declare that there is no financial or non-financial conflict of interest, directly or indirectly related to the work submitted for publication.\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards (ethical statement)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol was approved by Advara IRB in accordance with the guidelines under 45 CFR 46.104(d)(4)(iii).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe need for informed consent was waived by Advara IRB.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eFunding Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive funding\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Clinical trial number: not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi S, Wang SJ, Zhao YQ. Clinical features and treatment of hereditary hemorrhagic telangiectasia. Med (Baltim). 2018;97:11687.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChin CJ, Rotenberg BW, Witterick IJ. Epistaxis in hereditary hemorrhagic telangiectasia: an evidence based review of surgical management. J Otolaryngol Head Neck Surg. 2016;45:3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBegbie ME, Wallace GMF, Shovlin CL. Hereditary Haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J. 2003;79:18\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlauchu H, de Chadarebvian JP, Bideau A, et al. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Genet. 1989;32:291\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuan EC, Peng KA, Thompson CF, Suh JD, Wang MB. 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Laryngoscope. 2019;129:2216\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimonds J, Miller F, Mandel J, et al. The effect of bevacizumab (avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2009;119:988\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarnezis TT, Davidson TM. Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy. Laryngoscope. 2012;122:495\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDupuis-Girod S, Ambrun A, Decullier E, et al. Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangiectasia: a randomized clinical trial. JAMA. 2016;316:934\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOomen KP, Paramasivam S, Waner M, Niimi Y, Fifi JT, Berenstein A, O TM. Endoscopic transmucosal direct puncture sclerotherapy for management of airway vascular malformations. Laryngoscope. 2016;126:205\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnderson RR, Parrish J. Microvasculature can be selectively damaged using dye lasers: a basic theory and experimental evidence in human skin. Lasers Surg Med. 1981;1:263\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220:524\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCerrati EW, Chung OTM, Waner H M. Diode laser for the treatment of telangiectasias following hemangioma involution. Otolaryngol Head Neck Surg. 2015;152:239\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRohrmeier C, Sachs HG, Kuehnel TS. 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Bleomycin treatment for cystic hygroma in children. Arch Jap Chir. 1977;46:607\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLopez-Larraza D. The kinetics of DNA damage by bleomycin in mammalian cells. Mutat Res. 1990;232:57\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTwentyman PR. Bleomycin-mode of action with particular reference to the cell cycle. Pharmac Ther. 1984;23:417\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBai Y, Jia J, Huang XX, Alsharif MJ, Zhao JH, Zhao YF. Sclerotherapy of microcystic lymphatic malformations in oral and facial regions. J Oral Maxillofac Surg. 2009;67:251\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathur NN, Rana I, Bothra R, Dhawan R, Kathuria G, Pradhan T. Bleomycin sclerotherapy in congenital lymphatic and vascular malformations of head and neck. Int J Pediatr Otorhinolaryngol. 2005;69:75\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med. 1990;11:1\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIonescu G, Mabeta P, Dippenaar N, Muir T, Fourie P, Shelver G. Bleomycin plasma spill-over levels in pediatric patients undergoing intralesional injection for the treatment of hemangiomas. S Afr Med J. 2008;98:539\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJames MP, Collier PM, Aherne W, Hardcastle A, Lovegrove S. Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts. J Am Acad Dermatol. 1993;28:933\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlum R. A clinical review of bleomycin: a new antineoplastic agent. Cancer. 1973;31:903\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJin Y, Lin X, Li W, Hu X, Ma G, Wang W. Sclerotherapy after embolization of draining vein: a safe treatment for venous malformations. J Vasc Surg. 2008;47:1292\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpence J, Krings T, ter Brugge KG, et al. Percutaneous sclerotherapy for facial venous malformations: subjective clinical and objective MR imaging follow-up results. Am J Neuroradiol. 2010;31:955\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadick H, Naim R, Sadick M, Hormann K, Riedel F. Plasma level and tissue expression of angiogenic factors in patients with hereditary hemorrhagic telangiectasia. Int J Mol Med. 2005;15:591\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSadick H, Riedel F, Naim R, et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta I as well as high ALK1 tissue expression. Haematologica. 2005;90:818\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDupuis-Girod S, Ginon I, Saurin JC, et al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic malformations and high cardiac output. JAMA. 2012;307:948\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen S 4th, Karnezis T, Davidson TM. Safety of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope. 2011;121:644\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbiri A, Goshtasbi K, Maducdoc M, Sahyouni R, Wang MB, Kuan EC. Laser-Assisted Control of Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Systematic Review. Lasers Surg Med. 2020;52:293\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7781650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7781650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHereditary hemorrhagic telangiectasia is a rare disease of vascular development, often accompanied by severe epistaxis. Multimodality treatment may improve epistaxis control, but the optimal combination of modalities has not yet been established.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo compare the effects of adding intranasal bleomycin versus Avastin\u0026reg; sclerotherapy to laser treatment for epistaxis in patients with hereditary hemorrhagic telangiectasia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively studied the medical records of all hereditary hemorrhagic telangiectasia patients who underwent laser therapy with or without bleomycin or Avastin\u0026reg; sclerotherapy for epistaxis during eight consecutive years. We calculated the mean posttreatment epistaxis severity score changes, proportions of procedures after which a minimal important difference in epistaxis severity score was reached, and intervals between subsequent treatments.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe mean epistaxis severity score change was significantly higher after laser combined with bleomycin, compared to laser treatment alone. The mean treatment interval after both laser combined with Avastin\u0026reg;, and laser combined with bleomycin, were significantly longer compared to laser treatment alone.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAdding bleomycin to laser treatment may lead to greater epistaxis severity score improvement compared to laser treatment only or laser combined with Avastin\u0026reg; in patients with hereditary hemorrhagic telangiectasia. Adding bleomycin or Avastin\u0026reg; to laser seems to lengthen treatment intervals compared to laser therapy alone.\u003c/p\u003e","manuscriptTitle":"Intranasal bleomycin versus Avastin® sclerotherapy as an adjunct to laser treatment for epistaxis in hereditary hemorrhagic telangiectasia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 01:07:35","doi":"10.21203/rs.3.rs-7781650/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-05T11:20:57+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-03T19:47:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304874128280108770842184093491981528605","date":"2026-01-03T19:22:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"210323675478350126813794419092384460659","date":"2025-12-28T22:15:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-28T08:12:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"48042713667808412072391515439559814998","date":"2025-12-13T16:10:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-10T13:57:55+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-09T12:40:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-06T05:56:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-26T20:39:29+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Medicine","date":"2025-11-26T20:35:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Discover Medicine](https://link.springer.com/journal/44337)","snPcode":"44337","submissionUrl":"https://submission.springernature.com/new-submission/44337/3","title":"Discover Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4d5ae496-028a-40a9-93e5-b20d7d0d77d9","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T10:53:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 01:07:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7781650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7781650","identity":"rs-7781650","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}