PB1254 - Functional Alterations Involved In Increased Bleeding In Hereditary Hemorrhagic Telangiectasia Mouse Models

Tuesday, July 12, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Co-Author(s)

CE

Cristina Egido-Turrion

Investigadora
Universidad de Salamanca. Institute for Biomedical Research of Salamanca (IBSAL)
Salamanca, Castilla y Leon, Spain
Elisa Rossi, PhD

Associate Professor
Université Paris Cité, INSERM U1140, Innovative Therapies in Haemostasis, France
Paris, Ile-de-France, France
CO

Claudia Ollauri-Ibáñez

Postdoctoral Researcher
Universidad de Salamanca. Institute for Biomedical Research of Salamanca (IBSAL)
Salamanca, Castilla y Leon, Spain
MP

María L Pérez-García

MD
Department of Internal Medicine, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), Spain
Salamanca, Castilla y Leon, Spain
MS

María A. Sevilla

Professor
Universidad de Salamanca. Institute for Biomedical Research of Salamanca (IBSAL)
Salamanca, Castilla y Leon, Spain

Presenting Author(s)

Jose Mª Bastida, PhD, MD

Hematology Department
Complejo Asistencial Universitario de Salamanca-IBSAL-USAL (Salamanca)
Salamanca, Castilla y Leon, Spain

Co-Author(s)

JG

Jose Ramon Gonzalez Porras

Hematologo
Hospital Clínico Universitario Salamanca
salamanca, Castilla y Leon, Spain
AR

Alicia Rodríguez-Barbero

Professor
Universidad de Salamanca. Institute for Biomedical Research of Salamanca (IBSAL)
Salamanca, Castilla y Leon, Spain
CB

Carmelo Bernabeu

Research Scientist
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC)
Madrid, Madrid, Spain
JL

José M Lopez-Novoa

Full professor
Universidad de Salamanca. Institute for Biomedical Research of Salamanca (IBSAL)
Salamanca, Castilla y Leon, Spain
MP

Miguel Pericacho

Profesor Contratado Doctor
Universidad de Salamanca. Instituto de Investigaciones Biomédicas de Salamanca (IBSAL)
SALAMANCA - 37007, Castilla y Leon, Spain

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal-dominant genetic disorder involving defects in two predominant genes known as endoglin (ENG; HHT-1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT-2). It is characterized by mucocutaneous telangiectases that, due to their fragility, frequently break causing recurrent epistaxis and gastrointestinal bleeding. Because of the severity of hemorrhages, the study of the hemostasis involved in these vascular ruptures is critical to find therapies for this disease.

Aims: The aim of this study is to analyze the different processes involved in hemostasis in the most common genetic models of HHT, namely Eng+/- for HHT-1 and Alk1+/- for HHT-2

Methods: The analysis of the general process of hemostasis was performed by studying the bleeding time of the tail. Platelet activation and aggregation analyses were performed for the study of primary hemostasis, together with in vitro or in vivo platelet-endothelium interaction studies. Fibrinolysis was studied by studying serum levels of fibrinogen, tPA, PAI-1, and D-dimer.

Results: In Eng+/- mice, the results of in vivo and in vitro assays suggest deficient platelet-endothelium interactions that impair a robust and stable thrombus formation. Consequently, the thrombus could be torn off and dragged by the mechanical force exerted by the bloodstream, leading to the reappearance of hemorrhages (Figure 1A). In Alk1+/- mice, overactivation of the fibrinolysis system was observed (Figure 1B)

Conclusion(s): These results support the idea that endoglin and Alk1 haploinsufficiency leads to a common phenotype of impaired hemostasis, but through different mechanisms. This contribution opens new therapeutic approaches to HHT patients’ epistaxis.