Effect of Genotype and Antifibrinolytic Therapy on the Severity of Epistaxis in Hereditary Hemorrhagic Telangiectasia

Background: Hereditary Hemorrhagic Telangiectasia (HHT, or Osler Weber Rendu syndrome) is an inherited multiorgan disorder characterized by the development of abnormal blood vessels, resulting in the formation of telangiectasias on mucocutaneous surfaces (skin, lips, nasal and buccal mucosa, gastrointestinal mucosa) and arteriovenous malformations (AVMs) in certain visceral organs (brain, lungs, spinal cord and liver). Over 90% of affected individuals develop epistaxis, often leading to complications, such as iron-deficiency anemia and the need for oral and parenteral iron supplementation, blood transfusions, and associated decrease in quality of life. The management of epistaxis in HHT has consisted predominantly of invasive approaches like cautery, laser photocoagulation, and septodermopasty. Antifibrinolytic agents [aminocaproic acid and tranexamic acid] are frequently used in the management of patients with inherited and acquired mucocutaneous bleeding disorders; however data on the use of antifibrinolytics for the treatment of epistaxis in HHT have been limited to case reports. We hypothesize that antifibrinolytic therapy is effective for the treatment of moderate to severe HHT-related epistaxis.

Methods: The medical records of patients with HHT evaluated at University of North Carolina from 2009 to October 31, 2013 were retrospectively reviewed. Patients with epistaxis requiring pharmacologic therapy in whom the epistaxis severity score (ESS) was available were included. The ESS is a clinical scoring system that utilizes six factors associated with self-reported epistaxis severity (frequency, duration, intensity, need for medical attention, anemia, and need for transfusion) to generate a clinical score. The response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. Demographic data and HHT mutation status were also noted and the impact of genotype on the severity of epistaxis was analyzed. All statistical analyses were performed with SigmaStat 2.0 for Windows (SYSTAT Inc, Chicago, IL) using analysis of variance. Values are reported as +/- standard error of means. The study was approved by the Institutional Review Board.

Results: Two hundred and twenty two patient records were reviewed. Of these, 126 were adults with epistaxis and were eligible for study evaluation. Seventy-one of these patients underwent genetic testing and 34 (47.9%) had an ACVRL1 (ALK-1 mutation while 22 (30.99%) had an ENG mutation. Five patients (7%) had a variant of uncertain significance (VUS), while no mutation was identified in 10 patients (14%) with a clinical diagnosis of HHT as per Curacao criteria. There was a correlation between the ESS and HHT genotype. Patients with an ACVRL1 (ALK-1) mutation (n=34) had significantly higher ESS (4.32 ± 0.455, p<0.05) compared to patients without mutations (2.08 ± 0.672). There was no significant difference in ESS between patients with an ENG mutation (n=22, ESS= 3.379 ± 0.455) or with a VUS (n=5, ESS= 5.5 ± 1.049) compared to those with negative genetic testing. Forty-nine HHT patients with moderate to severe ESS were started on an oral antifibrinolytic agent (aminocaproic acid 6 grams per day or tranexamic acid 3.9 grams per day). Patients were allowed to titrate the dose of medication down based on response. Follow-up over an average of 15 months (range 3-39 months) was available on 16 of the 49 patients. Of the 16 patients with follow up data, the average pre-treatment ESS score was 5.7 ± 0.466 and decreased to 4.8 ± 0.321 with antifibrinolytic therapy (p<0.05). All the 16 patients tolerated antifibrinolytic therapy well and without significant adverse effects.

Conclusion: This study demonstrates for the first time that the severity of epistaxis in patients with HHT correlates with the HHT genotype. Epistaxis is more severe in patients with ACVRL1 (ALK-1) mutations. We also show that antifibrinolytic therapy is effective in improving the severity of epistaxis in individuals with HHT and that their chronic use is well tolerated in this population. We are currently in the process of expanding assessments of our study cohort. Larger, multicenter, randomized control trials are needed to study durability of treatment response and safety of these agents with long-term, continuous use.