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Functional Alterations Involved in Increased Bleeding in Hereditary Hemorrhagic Telangiectasia Mouse Models
Cristina Egido-Turrión1,2, Elisa Rossi3, Claudia Ollauri-Ibáñez1,2
1Department of Physiology and Pharmacology, Universidad de Salamanca, Salamanca, Spain.
Frontiers in Medicine
|June 6, 2022
Summary
Hereditary Hemorrhagic Telangiectasia (HHT) impairs hemostasis through distinct mechanisms in mouse models. Endoglin defects hinder platelet-endothelium interactions, while Alk1 defects overactivate fibrinolysis, impacting bleeding in HHT patients.
Area of Science:
- Vascular Biology
- Genetics
- Hemostasis
Background:
- Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder affecting blood vessel formation.
- HHT involves mutations in endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1/ALK1) genes.
- Characterized by fragile telangiectases causing recurrent bleeding, HHT necessitates understanding hemostasis for effective therapies.
Purpose of the Study:
- To investigate the hemostatic mechanisms in HHT mouse models (Eng+/- and Alk1+/-).
- To elucidate how endoglin and Alk1 haploinsufficiency contribute to bleeding in HHT.
- To identify potential therapeutic targets for epistaxis in HHT patients.
Main Methods:
- Utilized Eng+/- and Alk1+/- mouse models lacking spontaneous bleeding phenotypes.
- Conducted in vivo and in vitro assays to assess hemostatic function.
- Analyzed platelet-endothelium interactions and fibrinolysis system activity.
Main Results:
- Eng+/- mice exhibited deficient platelet-endothelium interactions, impairing stable thrombus formation.
- Alk1+/- mice displayed overactivation of the fibrinolysis system.
- HHT patients with high Epistaxis Severity Score (ESS) showed no prolonged clotting times or factor alterations.
Conclusions:
- Endoglin and Alk1 haploinsufficiency impair hemostasis via distinct pathways.
- Deficient platelet-endothelium interactions in Eng+/- mice contribute to bleeding.
- Fibrinolysis overactivation in Alk1+/- mice also leads to impaired hemostasis.
- Findings suggest novel therapeutic strategies for HHT-related epistaxis.
