**1. Introduction**

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant disease characterized by recurrent spontaneous epistaxis, visceral arteriovenous malformations (AVMs), and mucocutaneous telangiectases [1–3]. Five genetic types of HHT are recognized, with three being linked to particular genes. More than 80% of all cases of HHT are due to mutations in either *ENG* or *ACVRL1*, which cause HHT1 and HHT2, respectively [1–3]. About 2% of HHT are instead due to *SMAD4* mutations, which cause colonic polyposis in addition to HHT [1–3].

Although the hallmark of HHT is an overwhelming bleeding propensity, it is well known that patients with this disease are not devoid of medical conditions that require antithrombotic therapy (AT). For instance, they may have coronary artery disease (CAD), venous thromboembolism (VTE), or atrial fibrillation (AF) [4–8]. Additionally, they may require thromboprophylactic anticoagulation when they are hospitalized for an acute medical illness or when they undergo surgical procedures [9,10]. However, precise information on the indications, dosage, duration, and e ffectiveness of AT in HHT patients is lacking. Additionally, it is not clear whether subjects with HHT are able to tolerate AT, neither is it known if bleedings associated with AT are more common in some HHT phenotypes than other. Finally, no studies have been carried out to evaluate whether there are di fferences in AT tolerability between subjects with HHT1 or HHT2. The consequence is that clinicians are often afraid to prescribe AT to HHT patients, especially if they are not familiar with the disease. It may also happen that patients are reluctant to take these drugs, since they have been advised to avoid the use of medications that may worsen their risk of bleeding.

One of the most recent studies that evaluated the safety of AT in subjects with HHT was carried out by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), which retrospectively analyzed 28 HHT subjects treated with direct oral anticoagulants (DOACs) for either AF or VTE [11]. The result was that epistaxis worsened in 24 cases and in 11 cases patients had to discontinue treatment. Another recent study analyzed the RIETE Registry—which specifically consists of subjects a ffected by VTE—and found 23 patients with HHT (in a time frame of approximately 10 years), who presented 2 major bleedings and 6 non major bleedings during anticoagulant treatment [12]. More recently, we published the interim results of a prospective study conducted on 12 HHT subjects treated with either antiplatelet or anticoagulant therapy for various clinical indications for a mean period of approximately 6 months, who did not present any bleeding di fferent from epistaxis while on treatment [13]. In addition, there was not epistaxis worsening and there were not significant changes in hemoglobin levels after initiation of AT [13].

Here, we carried out a retrospective analysis of the "Gemelli Hospital HHT Registry", which contains demographic and clinical information of more than 200 subjects managed at the HHT Center of our University Hospital, with the goal to provide real-world data on indications, dosage, duration, e ffectiveness, and safety of AT in subjects with HHT.

#### **2. Materials and Methods**

We searched the Gemelli Hospital HHT Registry, which contains all the demographic and clinical information of the patients followed at the HHT Center of the 'Fondazione Policlinico Universitario A. Gemelli IRCCS', Rome, Italy. The creation of the Registry was approved by the Ethics Committee of the above-mentioned hospital (protocol number 2999). The time frame of the search was from 1 June 2016 (opening day of the HHT Center) to 31 December 2018.

First, we looked for subjects with a 'definite' diagnosis of HHT, i.e., those with genetic confirmation of the disease and/or those displaying at least 3 of the following 4 Curaçao criteria, as established in the literature [14]: (1) recurrent and spontaneous nosebleeds (epistaxis); (2) multiple telangiectases on the skin of the hands, lips, or face, or inside of the nose or mouth; (3) AVMs or telangiectases in one or more internal organs, including the lungs, brain, liver, intestine, stomach, and spinal cord; (4) a family history of HHT (i.e., first-degree relative, such as brother, sister, parent, or child, who meet these same criteria for definite HHT or has been genetically diagnosed).

Next, we identified subjects who were treated, or had been treated in the past, with AT. We registered the indications to prescription and the type and dosage of the prescribed drug. Duration of treatment and patient compliance to treatment were also registered. Since there were cases of patients that were treated with AT more than once and/or with di fferent drugs for di fferent indications, each course of AT was separately analyzed. We also assessed AT e ffectiveness and safety, evaluating whether thrombotic/ischemic events or hemorrhagic events occurred while patients were taking AT. To identify all the events, in addition to searching the Registry, we also asked patients to come to our HHT Center to undergo a detailed medical interview and fill out a questionnaire, upon signature of an informed consent. Hemorrhagic events were classified according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH) [15,16]: major bleedings were defined as fatal bleedings, or symptomatic bleedings in critical areas or organs (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome), or bleedings causing a fall in hemoglobin level of 2 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells; clinically relevant non-major (CRNM) bleedings were defined as acute or subacute clinically overt bleedings that did not satisfy the criteria for major bleedings but led to hospital admission for bleeding, or physician-guided medical or surgical treatment for bleeding, or a change in AT due to bleeding; minor bleedings, with the exception of epistaxis, were defined as acute clinically overt bleedings that did not meet the criteria for either major or CRNM bleedings. We also assessed possible changes in hemoglobin levels after initiation of AT (determined by comparing hemoglobin levels measured within the three months that preceded the initiation of AT with the hemoglobin levels measured after at least 1 month of AT).

The study was approved by the Ethics Committee of the 'Fondazione Policlinico Universitario A. Gemelli IRCSS' (Rome, Italy) (protocol number 49901/18, ID 2329, approval date 20 December 2018).
