Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 https://doi.org/10.1186/s13023-019-1172-8 RESEARCH Open Access Natural history of patients with venous thromboembolism and hereditary hemorrhagic telangiectasia. Findings from the RIETE registry Antoni Riera-Mestre1,2* , José María Mora-Luján1, Javier Trujillo-Santos3, Jorge Del Toro4, José Antonio Nieto5, José María Pedrajas6, Raquel López-Reyes7, Silvia Soler8, Aitor Ballaz9, Pau Cerdà1, Manel Monreal10 and the RIETE Investigators Abstract Background: Limited data exist about the clinical presentation, ideal therapy and outcomes of patients with hereditary hemorrhagic telangiectasia (HHT) who develop venous thromboembolism (VTE). Methods: We used the data in the RIETE Registry to assess the clinical characteristics, therapeutic approaches and clinical outcomes during the course of anticoagulant therapy in patients with HHT according to initial presentation as pulmonary embolism (PE) or deep venous thrombosis (DVT). Results: Of 51,375 patients with acute VTE enrolled in RIETE from February 2009 to January 2019, 23 (0.04%) had HHT: 14 (61%) initially presented with PE and 9 (39%) with DVT alone. Almost half (47.8%) of the patients with VTE had a risk factor for VTE. Most PE and DVT patients received low-molecular-weight heparin for initial (71 and 100%, respectively) and long-term therapy (54 and 67%, respectively). During anticoagulation for VTE, the rate of bleeding events (major 2, non-major 6) far outweighed the rate of VTE recurrences (recurrent DVT 1): 50.1 bleeds per 100 patient-years (95%CI: 21.6-98.7) vs. 6.26 recurrences (95%CI: 0.31–30.9; p = 0.020). One major and three non-major bleeding were epistaxis. No patient died of bleeding. One patient died shortly after being diagnosed with acute PE. Conclusions: During anticoagulation for VTE in HHT patients, there were more bleeding events than VTE recurrences. Most bleeding episodes were non-major epistaxis. Keywords: Deep venous thrombosis, Hemorrhagic hereditary telangiectasia, Pulmonary embolism, Rare diseases, Venous thromboembolism Introduction arteriovenous malformations (AVMs), mostly in the Hereditary hemorrhagic telangiectasia (HHT) or Rendu- lungs or liver [3, 4]. These patients may suffer from Osler-Weber disease is a rare vascular genetic disorder many complications including bleeding, anemia, iron de- with an estimated prevalence of one in 6000 individuals ficiency, stroke and high-output heart failure [4–6]. [1, 2]. Patients with HHT have cutaneous telangiectasia, The diagnosis of HHT is established on clinical cri- mostly in the fleshy part of the hands, or in the oral, teria, according to the Curaçao criteria: recurrent epi- nasal or gastrointestinal (GI) mucosa, and large staxis, cutaneous/mucosal telangiectasia, visceral involvement, and a first line family member with HHT * Correspondence: ariera@bellvitgehospital.cat [7]. The diagnosis may be further confirmed by the iden- 1 HHT Unit and VTE Unit, Internal Medicine Department, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), C/ Feixa Llarga tification of causative mutations mostly in either the s/n. L’Hospitalet de Llobregat, 08907 Barcelona, Spain ENG (endoglin) or the ACVRL1 (activin A receptor type 2 Faculty of Medicine and Health Sciences, Universitat de Barcelona, II-like 1) genes coding for endoglin and activin receptor- Barcelona, Spain Full list of author information is available at the end of the article like kinase-1, respectively [2]. These proteins are © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 2 of 8 involved in the vascular signaling pathway of the trans- intracranial. All clinically evident bleeding not consid- forming growth factor (TGF)-beta family [2, 8]. Recur- ered major, were classified as ‘non-major’. Fatal PE, in rent epistaxis is the most common symptom, appearing the absence of autopsy, was defined as any death appear- in around 95% of HHT patients by 50 years of age [3, 4, ing < 10 days after PE diagnosis, in the absence of any al- 9]. Although recurrent bleeding events are the hallmark, ternative cause of death. Fatal bleeding was defined as some patients with HHT may also develop venous any death occurring < 10 days after a major bleeding epi- thromboembolism (VTE) [9–11]. HHT patients with sode, in the absence of any alternative cause of death. acute venous thromboembolism (VTE) are perceived to For preparation of this manuscript, we followed the be at high risk for major bleeding if anticoagulant ther- Strengthening the Reporting of Observational Studies in apy is prescribed, but the evidence on this issue is scarce Epidemiology (STROBE) statement guidelines for obser- and based on online interviews [12, 13]. vational cohort studies [18]. The RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry is an ongoing, multicenter, Study variables observational registry of consecutive patients with ob- The following parameters were recorded in RIETE: pa- jectively confirmed acute VTE (ClinicalTrials.gov identi- tient’s baseline characteristics; clinical status including fier: NCT02832245). Data from this registry have been any coexisting or underlying conditions, recent major used to evaluate outcomes after acute VTE, such as the bleeding, anemia or renal insufficiency; risk factors for frequency of recurrent VTE, major bleeding or mortal- VTE; the treatment received upon VTE diagnosis; con- ity, and risk factors for these outcomes [14–16]. The ra- comitant drugs and the outcomes during the course of tionale and methodology of RIETE have been published therapy. For normotensive patients with PE, stratifica- elsewhere [17]. In the current study, we aimed to assess tion using the simplified version of the Pulmonary Em- the clinical characteristics, therapeutic approaches and bolism Severity Index (sPESI) was assessed [15]. clinical outcomes of patients with HHT and VTE, ac- Immobilized patients were defined as non-surgical pa- cording to initial presentation as pulmonary embolism tients who had been immobilized (i.e., total bed rest with (PE) or deep venous thrombosis (DVT). or without bathroom privileges) for ≥4 days in the 2- month period prior to VTE diagnosis. Surgical patients Methods were defined as those who had undergone an operation Inclusion criteria in the 2 months prior to VTE. Active cancer was defined Consecutive patients with acute, symptomatic DVT or as newly diagnosed cancer (< 3 months before) or when PE confirmed by objective tests (compression ultrason- receiving anti-neoplastic treatment of any type (i.e., sur- ography or contrast venography for DVT; helical CT- gery, chemotherapy, radiotherapy or hormonal therap- scan of the chest, ventilation-perfusion lung scintigraphy ies). Recent bleeding was considered in those patients or angiography for PE) were enrolled in RIETE. Patients suffering major bleeding < 30 days prior to VTE. Anemia were excluded if they were currently participating in a was defined as hemoglobin levels < 13 g/dL for men blind therapeutic clinical trial. All patients (or their rela- and < 12 g/dL for women. tives) provided written or oral consent for participation in the registry, in accordance with local ethics commit- HHT additional information tee requirements. When preparing this study, we attempted to gather as much specific information on HHT as possible, through Study design personal communication with the attending doctors. For this study, only patients with HHT were considered. The study coordinating center contacted with the inves- This information was added to the RIETE data abstrac- tigators and tried to retrospectively calculate the Epi- tion forms in February 2009. Therefore, only patients re- staxis Severity Score (ESS) at the index VTE event. ESS cruited after this date were eligible for the current study. is an on-line tool that estimates the severity of epistaxis Collected data were appropriately made anonymous and according to clinical data occurring during last 3 each patient was identified by a unique alphanumeric months. Epistaxis is considered moderate or severe if identification code. HHT patients were divided accord- ESS results > 4 or > 7 points, respectively [19]. We also ing to VTE index event as PE or DVT. Primary outcome attempted to assess the genetic study for HHT, specific- was the risk for VTE recurrences and major or non- ally for mutations in ENG or ACVRL1 genes, and infor- major bleeding occurring during the course of anticoa- mation about the Curaçao criteria [2, 7, 8]. gulation. Secondary outcomes were fatal PE and fatal bleeding. Bleeding events were classified as ‘major’ if Treatment and follow-up they were overt and required transfusion of two or more Patients were managed according to the clinical practice red blood cell units, or were retroperitoneal, spinal or of each participating hospital (i.e., there was no Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 3 of 8 standardization of treatment). The type, dose and dur- (4.5%) patient had a GI ulcer. All patients had normal ation of anticoagulant therapy were recorded. After VTE prothrombin test and activated partial thromboplastin diagnosis, all patients were followed-up in the outpatient time. There were no significant differences in the clinical clinic for at least 3 months. During each visit, any signs characteristics between patients who initially presented or symptoms suggesting VTE recurrences or bleeding with PE or DVT. All 14 patients initially presenting with complications were noted. Each episode of clinically sus- PE were admitted in hospital and 7 (50%) were consid- pected recurrent VTE was investigated by using diagnos- ered to be at high risk according to sPESI score tic tests as appropriate. Most outcomes were classified (Table 1). as reported by the clinical centers. However, if staff at Median duration of anticoagulant therapy was 203 the coordinating center were uncertain how to classify a days in patients with PE and 164 days in those with reported outcome, that event was reviewed by a central DVT. Most (71%) PE and all (100%) DVT patients were adjudicating committee (less than 10% of events). initially treated with low-molecular-weight heparin (LMWH), but four (29%) and two (22%) patients re- Statistical analysis spectively received less than 100 IU/kg/day. Among the Categorical variables were compared between PE and remaining patients with PE, two (14%) were prescribed DVT patients with HHT using the chi-square test (two- unfractionated heparin, one (7%) rivaroxaban and one sided) and Fisher’s Exact Test (two-sided). Odds ratio (7%) patient received an inferior vena cava filter without (and its 95% confidence interval) was calculated for cat- anticoagulant therapy. For long-term therapy, 7 (54%) egorical variables. Continuous variables were compared PE patients and 6 (67%) DVT patients continued on using Student t test. The incidence rate of adverse events long-term LMWH therapy, but one (8%) and two (22%) was calculated as events per 100 patient-years of treat- of these patients received less than 100 IU/kg/day, re- ment and compared, according to the initial presentation spectively. Among the remaining patients, five (38%) and of the VTE episode (PE vs. DVT), as rate ratios, both three (33%) switched to vitamin K antagonists (VKAs), with a 95% confidence interval. A P-value of < 0.05 was respectively, and one (8%) PE patient continued on rivar- chosen as the cut off for statistical significance. Statis- oxaban (Table 2). tical analyses were conducted using SPSS for Windows During the course of anticoagulation, (mean, 260 ± Release (version 20, SPSS Inc. Chicago, Illinois). 254 days for PE and 243 ± 195 days for DVT), the rate of bleeding events (major bleeding 2 episodes, non-major Results 6) far outweighed the rate of VTE recurrences (recurrent Of 51,375 patients enrolled in RIETE from February DVT one episode): 50.1 bleeds per 100 patient-years 2009 to January 2019, 23 (0.04%) had HHT. Of these, 13 (95%CI: 21.6-98.7) vs. 6.26 recurrences (95%CI: 0.31– (56.5%) were male, mean age was 61 ± 17 years, 14 (61%) 30.9; p = 0.020). One patient had a major bleeding in the presented initially with PE and 9 (39%) presented with GI tract 534 days after PE diagnosis while receiving DVT alone. Eighteen patients (78%) had a history of re- VKAs, and one patient had a major epistaxis 32 days current epistaxis, and three (13%) had suffered a major after the diagnosis of DVT while receiving LMWH at < bleeding (all epistaxis) in the last 30 days before the 100 IU/kg/day. Three non-major bleeds were epistaxis. index VTE event. There was available information to cal- All four patients with epistaxis had an ESS > 4. No pa- culate the ESS in 16 (69%) patients, and mean ESS was tient died of bleeding. Among DVT patients, one patient 4.4 ± 2.4 (0. 9-8.4) points. Genetic study was positive for presented a DVT recurrence 227 days after the diagno- ENG in 5 (22%) patients, for ACVRL1 in 2 (9%) and one sis, while receiving vitamin K antagonists. One patient (4.5%) patient had negative results (but had 3 of 4 Cura- died of respiratory insufficiency due to hospital-acquired çao criteria). pneumonia 4 days after being diagnosed with acute PE, Six patients (26%) developed the VTE after being while receiving unfractionated heparin. She did not immobilized for ≥4 days (because of decompensated undergo repeat tests to exclude recurrent PE, so we can- chronic lung disease 2, trauma 2, ischemic stroke 1, not rule out the diagnosis of fatal PE (Table 3). pneumonia 1), two (9%) after undergoing surgery (hernia disc repair 1, hip fracture 1), one patient (4.5%) had can- Discussion cer and two (9%) had a history of prior VTE. Only three Since HHT is a rare disorder, the natural history of VTE patients had received prophylaxis before the index VTE: in these patients, and the optimal therapy are not well two patients admitted in the hospital because of decom- known. The only two studies that analyze the effect of pensated chronic lung disease and one patient with hip anticoagulation in HHT patients were not based on ob- fracture. Twelve (52%) patients had anemia at baseline, jectively confirmed diagnosis and outcomes of VTE but six (26%) had creatinine clearance levels < 60 mL/min, on on-line surveys [12, 13]. The first one was an on-line three (13%) had angiodysplasia in the GI tract and one questionnaire about the use of antiplatelet or Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 4 of 8 Table 1 Clinical characteristics of 23 patients with HHT and acute VTE Pulmonary embolism Deep vein thrombosis Odds ratio (95% CI) / P value Patients, N 14 9 Clinical characteristics, Male gender 6 (43%) 7 (78%) 0.21 (0.03–1.43) Mean age (years±SD) 60 ± 16 62 ± 19 P = 0.708 Mean body weight (kg ± SD) 87 ± 28 72 ± 9.7 P = 0.145 a Data on HHT, Spontaneous, recurrent epistaxis (n = 18) 12 (86%) 6 (67%) Epistaxis severity score (n = 9 and 7) 3.5 (0. 9-8.4; ±2.1) 5.4 (2. 7-8.1;±2.3) P = 0.097 ESS > 4 3 (21%) 4 (44%) P = 0.615 ESS > 7 1 (7%) 3 (33%) P = 0.262 Genetic study (n = 11) ENG mutations 2 (14%) 3 (33%) ACVRL1 mutations 1 (7%) 1 (11%) Negative 1 (7%) 0 Family history (n = 16) 10 (71%) 6 (67%) Risk factors for VTE, Recent surgery 1 (7%) 1 (11%) 0.62 (0.03–11.28) Recent immobilization ≥4 days 4 (29%) 2 (22%) 1.40 (0. 20-9.87) Cancer 1 (7%) 0 – Prior VTE 1 (7%) 1 (11%) 0.62 (0.03–11.28) None of the above 6 (43%) 6 (67%) 0.38 (0.07–2. 15) Underlying conditions, Prior ischemic stroke 3 (21%) 0 – Atrial fibrillation 3 (21%) 0 – Gastroduodenal ulcer 1 (7%) 0 – Angiodisplasia in the GI tract 3 (21%) 0 – Recent (< 30 days) major bleeding 0 3 (33%) – Laboratory data, Anemia 6 (43%) 5 (56%) 0.60 (0. 11-3.25) CrCl levels < 30 mL/min 0 0 – CrCl levels 30–60 mL/min 2 (14%) 3 (33%) 0.33 (0.04–2.56) sPESI, ≥ 1 points 7 (50%) – – Abbreviations: SD standard deviation, HHT hemorrhagic hereditary telangiectasia, ENG endoglin gene, ACVRL1 activin A receptor type II-like 1 gene, VTE venous thromboembolism, GI gastrointestinal, sPESI simplified version of the Pulmonary Embolism Severity Index, CrCl creatinine clearance levels; 95%CI, 95% confidence intervals a Retrospective information added, not included in the RIETE Registry anticoagulant agents in HHT patients [12]. A worsening came from nasal or GI tract telangiectasia and not of their usual epistaxis was referred in 86 (57.3%) of 150 from large vascular malformations (i.e. in the liver, patients with HHT who received anticoagulant therapy lung or brain), that are common in HHT patients. for different reasons [12]. In the second study, 20% of 20 The ESS seems to detect those patients at an in- patients with self-reported diagnosis of VTE who re- creased risk to develop epistaxis, as all four patients ceived anticoagulant therapy had to withdraw anticoagu- with epistaxis during anticoagulation had a ESS > 4. lation because of bleeding [13]. ENT management to optimize measures to reduce Our findings, obtained from the largest series of epistaxis could allow to better tolerate anticoagulation HHT patients with objectively confirmed VTE, reveal [3, 20]. Other options, such as tranexamic acid, top- that one in every 3 (35%) patients bled during the ical or systemic estrogens, thalidomide or bevacizu- course of anticoagulant therapy, though no bleed was mab, should be weighted against the risk of VTE for fatal. This may be due to the fact that most bleeds these drugs [3, 21–24]. Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 5 of 8 Table 2 Treatment strategies Pulmonary Deep vein Odds ratio embolism thrombosis (95% CI) / P value Patients, N 14 9 Duration of therapy, Mean days (SD) 260 ± 254 243 ± 195 P = 0.867 Median days (IQR) 171 (111–335) 177 (86–475) P = 0.999 Initial therapy, Unfractionated heparin 2 (14%) 0 – Low-molecular-weight heparin 10 (71%) 9 (100%) – Mean LMWH dose (IU/kg/day) 132 ± 50 151 ± 59 P = 0.474 LMWH doses < 100 IU/kg/day 4 (29%) 2 (22%) 2.33 (0.31–17.55) Rivaroxaban 1 (7%) 0 – Inferior vena cava filter (without anticoagulant therapy) 1 (7%) 0 – Long-term therapy, 13 9 Low-molecular-weight heparin 7 (54%) 6 (67%) 0.58 (0. 10-3.40) Mean LMWH dose (IU/kg/day) 135 ± 35 119 ± 43 P = 0.491 LMWH < 100 IU/kg/day 1 (8%) 2 (22%) 0.27 (0.02–3.52) Vitamin K antagonists 5 (38%) 3 (33%) 1.25 (0. 21-7.41) Rivaroxaban 1 (8%) 0 – No anticoagulant drugs 0 0 – Abbreviations: SD standard deviation, IQR interquartile range, LMWH low-molecular-weight heparin, IU international units, 95%CI, 95% confidence intervals Table 3 Clinical outcomes during the course of anticoagulant therapy Pulmonary embolism Deep vein thrombosis Rate ratio (95%CI) N Events per 100 N Events per 100 patient-years patient-years Patients, N 14 9 Recurrent PE 0 – 0 – – Recurrent DVT 0 – 1 16.67 (0. 22-92.72) – Major bleeding 1 10.02 (0. 13-55.75) 1 16.67 (0. 22-92.72) 0.60 (0.04–9.61) Site of major bleeding (days)a, Epistaxis (32b) 0 – 1 16.67 (0. 22-92.72) – GI (534) 1 10.02 (0. 13-55.75) 0 – – Non-major bleeding 3 30.06 (6.04–87.83) 3 50 (10.05–146.1) 0.60 (0. 12-2.98) Site of minor bleeding (days)a, Epistaxis (9,31,179) 3 30.06 (6.04–87.83) 0 – – Others (0b,5,50) 0 – 3 50 (10.05–146.1) – Death 1 10.02 (0. 13-55.75) 0 – – Causes of death, Respiratory insufficiency 1 10.02 (0. 13-55.75) 0 – – Abbreviations: PE pulmonary embolism, DVT deep vein thrombosis; 95%CI, 95% confidence intervals, GI gastrointestinal a Days from index VTE diagnosis to bleeding event b Receiving LMWH < 100 IU/kg/day Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 6 of 8 Eighteen patients in our cohort (78%) had prior epi- several of the data elements were based on post-hoc staxis, five had renal insufficiency, three had docu- plans and analyses. However, to our knowledge, these mented angiodisplasia in the GI tract and one patient data represent the largest series of patients with HHT had a gastroduodenal ulcer. To what extent the use of and objectively confirmed VTE. Moreover, the main anticoagulant therapy could have influenced on the risk strengths of our study are the strict and objectively diag- for bleeding is unknown. Two of the three patients with nostic criteria for VTE, the long-term follow-up period major epistaxis in the 30 days before the index VTE re- and the objectively established outcomes reported peated epistaxis during the course of anticoagulation: (bleeding, recurrent symptomatic VTE and mortality). one of these had a major re-bleeding. Then, we cannot assume that repeated epistaxis that happened during the Conclusions course of anticoagulant therapy were exclusively related In conclusion, the use of anticoagulant therapy for VTE to anticoagulation, as epistaxis is an inherent feature of in patients with HHT may certainly increase the risk for HHT [3, 4, 9]. However, anticoagulation can increase the bleeding, but it barely influences on mortality. Most duration and severity of epistaxis [12]. Unfortunately, we bleeds come from nasal or digestive telangiectasia and have no monitoring ESS during anticoagulant treatment not from large HHT-related vascular malformations. So, to analyze this association. although bleeding events are more frequent than VTE In spite of the bleeding risk, some HHT patients also recurrences, the use of anticoagulation was not associ- suffer from thrombotic complications [10, 25–27]. Six ated with fatal bleeding. PE is the most common presen- patients in our cohort developed the index VTE after be- tation of VTE in patients with HHT. Almost half of our ing immobilized for an acute medical illness and two HHT patients had a risk factor for VTE. Patients with had recent surgery, but only three of them did receive HHT should be carefully evaluated for nosebleeds when VTE prophylaxis. We hypothesize that the attending needing anticoagulant treatment. The optimal type, dose doctors might have been concerned about the risk for and duration of anticoagulant therapy for VTE in pa- bleeding. In the on-line survey of HHT patients with tients with HHT needs further investigation. self-reported VTE, 76% of them had a risk factor for Abbreviations VTE [13]. There is consistent evidence on the reduction 95%CI: 95% confidence interval; ACVRL1: Activin A receptor type II-like 1 of VTE using prophylaxis in at-risk patients, with very gene; CrCl: Creatinine clearance; DVT: Deep venous thrombosis; low increase in the risk for bleeding [28], but we do not ENG: Endoglin gene; ESS: Epistaxis Severity Score; GI: Gastrointestinal; HHT: Hereditary hemorrhagic telangiectasia; IQR: Interquartile range; know the potential benefit of VTE prophylaxis in at-risk IU: international units; LMWH: Low-molecular-weight heparin; OR: Odds ratio; patients with HHT. Further research is necessary to de- PE: Pulmonary embolism; RIETE: Registro Informatizado Enfermedad fine prophylactic strategies in this frequently hospitalized TromboEmbólica; SD: Standard deviation; sPESI: simplified Pulmonary Embolism Severity Index; TGF: Transforming growth factor; VKAs: Vitamin K HHT population. For these provoked VTE events, anti- antagonists; VTE: Venous thromboembolism coagulant therapy for only 3 months is recommended [29]. Acknowledgements We thank the RIETE Registry Coordinating Center, S&H Medical Science Our study has a number of limitations. First, the pro- Service, for their quality control data, logistic and administrative support and portion of patients with HHT in our cohort was most Prof. Salvador Ortiz, Universidad Autónoma Madrid and Silvia Galindo, both likely conservative because some cases might have been Statistical Advisors in S&H Medical Science Service for the statistical analysis of the data presented in this paper. missed. Second, we were not able to retrospectively col- Coordinator of the RIETE Registry: Manuel Monreal. lect genetic study and reassess Curaçao criteria in all pa- RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner tients [7, 8]. Nonetheless, the high percentage of and Dominique Farge-Bancel. RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), recurrent epistaxis and first degree relatives with HHT Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran in our patients, support the HHT diagnosis. Third, our (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri study was not designed for assessment of comparative Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), Hanh My Bui (Vietnam). effectiveness of management strategies in patients with RIETE Registry Coordinating Center: S & H Medical Science Service. HHT. Since all patients with HHT in our cohort re- Members of the RIETE Group: ceived anticoagulant therapy, we are unable to compare SPAIN: Adarraga MD, Agud M, Aibar MA, Alcalde-Manero M, Alfonso J, Amado C, Arcelus JI, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón- the potential advantages of the different therapeutic ap- Andrés B, Blanco-Molina A, Camon AM, Cañas I, Castro J, Cerdà P, de Miguel proaches. However, our study provides important in- J, del Toro J, Demelo P, Díaz-Pedroche C, Díaz-Peromingo JA, Domínguez IM, sights into the outcomes of HTT patients with VTE. Escribano JC, Falgá C, Fernández-Capitán C, Fernández-Criado MC, Fidalgo MA, Flores K, Font C, Font L, Furest I, García MA, García-Bragado F, García- Fourth, the ESS has been retrospectively calculated after Raso A, Gavín-Blanco O, Gavín-Sebastián O, Gil-Díaz A, Godoy-Díaz D, Gómez some time, being a likely cause of ascertainment bias. Fi- V, Gómez-Cuervo C, González-Martínez J, Grau E, Guirado L, Gutiérrez J, Her- nally, although many of the studies from the RIETE nández-Blasco LM, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou I, Lalueza A, Lecumberri R, Lima J, Llamas P, Lobo JL, López-Jiménez L, López- registry were designed with broad or detailed a priori Meseguer M, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, plans, HHT is a rare disease and the decisions to explore Lorente MA, Loring M, Lumbierres M, Madridano O, Maestre A, Marchena PJ, Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 7 of 8 Martín-Martos F, Martínez-Baquerizo C, Martínez-García MA, Mellado M, Received: 23 May 2019 Accepted: 30 July 2019 Moisés J, Monreal M, Morales MV, Muñoz-Blanco A, Nieto JA, Núñez MJ, Oli- vares MC, Olivera PE, Ortega C, Osorio J, Otalora S, Otero R, Panadero-Macia M, Parra V, Pedrajas JM, Pellejero G, Pérez-Ductor C, Pérez-Rus G, Peris ML, Pesantez D, Porras JA, Riera-Mestre A, Rivas A, Rodríguez-Cobo A, Rodríguez- References Matute C, Rosa V, Rubio CM, Ruiz-Artacho P, Ruiz-Sada P, Sahuquillo JC, Sala- 1. Shovlin CL, Buscarini E, Kjeldsen AD, Mager HJ, Sabba C, Droege F, et al. Sainz MC, Salgueiro G, Sampériz A, Sánchez-Martínez R, Sánchez-Muñoz-Tor- European reference network for rare vascular diseases (VASCERN) outcome rero JF, Seguí E, Soler S, Suárez S, Suriñach JM, Tolosa C, Torres MI, Trujillo- measures for hereditary Haemorrhagic telangiectasia. Orphanet J Rare Dis. 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Follow-up of pulmonary right-to-left shunt in hereditary haemorrhagic Authors’ contributions telangiectasia. Eur Respir J. 2016;47:1750–7. ARM and MM conceived and designed the study. ARM, JMML, JTS, JDT, JAN, 7. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, JMP, RLR, SS, AB, PC, MM and the RIETE Investigators, acquired clinical data. Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic ARM and JTS, performed statistical analysis. ARM, JMML, JTS, PC and MM, telangiectasia (Rendu-Osler-weber syndrome). Am J Med Genet. 2000;91:66. interpreted results and drafted the manuscript. All authors performed critical 8. Alsina-Sanchís E, García-Ibáñez Y, Figueiredo AM, Riera-Domingo C, Figueras revisions, and read and approved the final version of the manuscript. ARM, A, Matias-Guiu X, et al. ALK1 loss results in vascular hyperplasia in mice and JMML, JTS and MM, had full access to all data in the study, and take humans through PI3K activation. Arterioscler Thromb Vasc Biol. 2018;38: responsibility for the integrity of the data and the accuracy of data analysis. 1216–29. 9. Riera-Mestre A, Mora Luján JM, Sanchez Martínez R, Torralba Cabeza MA. Patier de la Peña JL, Juyol Rodrigo MC, et al, on behalf of the researchers of Funding the RiHHTa registry. Computerized registry of patients with hemorrhagic Sanofi support this Registry with an unrestricted educational grant. hereditary telangiectasia (RiHHTa registry) in Spain: objectives, methods, and preliminary results. Rev Clin Esp. 2018;218:468–76. Availability of data and materials 10. Shovlin CL, Sulaiman NL, Govani FS, Jackson JE, Begbie ME. Elevated factor The datasets used and/or analysed during the current study are available VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous from the corresponding author on reasonable request. thromboembolism. Thromb Haemost. 2007;98:1031–9. 11. Livesey JA, Manning RA, Meek JH, Jackson JE, Kulinskaya E, Laffan MA, et al. Low serum iron levels are associated with elevated plasma levels of Ethics approval and consent to participate coagulation factor VIII and pulmonary emboli/deep venous thromboses in This study was approved by the local Ethical Committees of the concerned replicate cohorts of patients with hereditary haemorrhagic telangiectasia. hospitals and was conducted in accordance with the principles of the Thorax. 2012;67:328–33. Helsinki Declaration. All patients (or their relatives) provided written or oral 12. Devlin HL, Hosman AE, Shovlin CL. Antiplatelet and anticoagulant agents in consent for participation in the registry, according to local Ethical hereditary hemorrhagic telangiectasia. N Engl J Med. 2013;368:876–8. Committees requirements. 13. Chaturvedi S, Kohli R, Schaefer N, Clancy M, Kasthuri RS. Characteristics and outcomes of venous thromboembolism in patients with hereditary Consent for publication hemorrhagic telangiectasia. Thromb Res. 2018;169:41–3. This manuscript does not contain any individual person’s data in any form. 14. Nieto JA, Camara T, Gonzalez-Higueras E, Ruiz-Gimenez N, Guijarro R, Each patient was identified by a unique alphanumeric identification code Marchena PJ, et al. Clinical outcome of patients with major bleeding after and all data were made anonymous and analysed as aggregates. venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 2008;100:789–96. 15. Jiménez D, Aujesky D, Moores L, Gómez V, Lobo JL, Uresandi F, et al. Competing interests Simplification of the pulmonary embolism severity index for The authors declare that they have no competing interests. prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170:1383–9. Author details 16. Riera-Mestre A, Jiménez D, Muriel A, Lobo JL, Moores L, Yusen RD, et al; 1 HHT Unit and VTE Unit, Internal Medicine Department, Hospital Universitari RIETE investigators. Thrombolytic therapy and outcome of patients with an de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), C/ Feixa Llarga acute symptomatic pulmonary embolism. J Thromb Haemost. 2012;10:751– s/n. L’Hospitalet de Llobregat, 08907 Barcelona, Spain. 2Faculty of Medicine 9. and Health Sciences, Universitat de Barcelona, Barcelona, Spain. 3Department 17. Bikdeli B, Sharif-Kashani B, Bikdeli B, Valle R, Falga C, Riera-Mestre A, et al. of Internal Medicine, Hospital General Universitario Santa Lucía, Cartagena, RIETE investigators. Impact of Thrombus sidedness on presentation and Universidad Católica de Murcia, Murcia, Spain. 4Department of Internal outcomes of patients with proximal lower extremity deep vein thrombosis. Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Semin Thromb Hemost. 2018;44:341–7. 5 Department of Internal Medicine, Hospital General Virgen De La Luz, 18. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke Cuenca, Spain. 6Department of Internal Medicine, Hospital Clínico San Carlos, JP;STROBE initiative. Strengthening the reporting of observational studies in Madrid, Spain. 7Department of Pneumonology, Hospital Universitari i epidemiology (STROBE) statement: guidelines for reporting observational Politècnic La Fe, Valencia, Spain. 8Department of Internal Medicine, Fundació studies. BMJ. 2007;335:806–8. Hospital d’Olot i Comarcal de la Garrotxa, Gerona, Spain. 9Department of 19. Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for Pneumonology, Hospital De Galdakao, Galdakao, Vizcaya, Spain. hereditary hemorrhagia telangiectasia. Laryngoscope. 2010;120:838–43. 10 Department of Internal Medicine, Hospital Germans Trias i Pujol Badalona, 20. Morais D, Millás T, Zarrabeitia R, Botella LM, Almaraz A. Local sclerotherapy Barcelona, Universidad Autónoma de Barcelona, Barcelona, Spain. with polydocanol (Aethoxysklerol®) for the treatment of epistaxis in Rendu- Riera-Mestre et al. Orphanet Journal of Rare Diseases (2019) 14:196 Page 8 of 8 Osler-weber or hereditary hemorrhagic telangiectasia (HHT): 15 years of experience. Rhinology. 2012;50:80–6. 21. Gaillard S, Dupuis-Girod S, Boutitie F, Rivière S, Morinière S, Hatron PY, et al. ATERO study group. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014;12:1494–502. 22. Yaniv E, Preis M, Shevro J, Nageris B, Hadar T. Anti-estrogen therapy for hereditary hemorrhagic telangiectasia – a long-term clinical trial. Rhinology. 2011;49:214–6. 23. Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single- Centre, phase 2 study. Lancet Haematol. 2015;2:e465–73. 24. Buscarini E, Botella LM, Geisthoff U, Kjeldsen AD, Mager HJ, Pagella F, et al. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019;14(1):28. 25. Dittus C, Streiff M, Ansell J. Bleeding and clotting in hereditary hemorrhagic telangiectasia. World J Clin Cases. 2015;3:330–7. 26. Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol. 2012;157:653–63. 27. Shovlin CL, Chamali B, Santhirapala V, Livesey JA, Angus G, Manning R, et al. Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. PLoS One. 2014;9:e88812. 28. Alikhan R, Bedenis R, Cohen AT. Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev. 2014;5:CD003747. 29. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.