Sex differences and risk factors for bleeding in Alagille syndrome

Simona Hankeová; Noémi Van Hul; Jakub Laznovsky; Elisabeth Verboven; Katrin Mangold; Naomi Hensens; Csaba Ádori; Elvira Verhoef; Tomáš Zikmund; Feven Dawit; Michaela Kavková; Jakub Šalplachta; Marika Sjöqvist; Bengt R. Johansson; Mohamed G. Hassan; Linda Fredriksson; Karsten Baumgärtel; Vı́tězslav Bryja; Urban Lendahl; Andrew H. Jheon; Florian Alten; Kristina Teär Fahnehjelm; Björn Fischler; Jozef Kaiser; Emma Rachel Andersson

doi:10.15252/emmm.202215809

Developmental BiologyEMBO Molecular MedicineNov 8, 2022

Peer-reviewed journal article

Sex differences and risk factors for bleeding in Alagille syndrome

Simona Hankeová iD, Noémi Van Hul iD, Jakub Laznovsky iD, Elisabeth Verboven iD, Katrin Mangold iD, Naomi Hensens iD, Csaba Ádori iD, Elvira Verhoef iD, Tomáš Zikmund iD, Feven Dawit, Michaela Kavková iD, Jakub Šalplachta iD, Marika Sjöqvist iD, Bengt R. Johansson iD, Mohamed G. Hassan iD, Linda Fredriksson iD, Karsten Baumgärtel, Vı́tězslav Bryja iD, Urban Lendahl iD, Andrew H. Jheon iD, Florian Alten iD, Kristina Teär Fahnehjelm iD, Björn Fischler iD, Jozef Kaiser iD, Emma Rachel Andersson iD

Abstract

Spontaneous lethal bleeds are major cause of death in the pediatric liver disease Alagille syndrome (ALGS), yet risk factors and screening methods have not been established. We performed a systematic review and identified significantly more female than male patients with idiopathic intracranial hemorrhage (10:1). We investigated bleeding and vasculature in patients and a mouse model for ALGS (Jag1Ndr/Ndr mice) and asked whether phenotypes identified in mice could be detected in patients non-invasively. Jag1Ndr/Ndr mice bled spontaneously, exhibiting a thin skull and vascular defects including artery-vein crossings, tortuous vessels, capillary breakdown and CADASIL-like sparse vascular smooth muscle cell coverage which was aggravated by hypertension. Retinographs from patients confirmed tortuous blood vessels and artery-vein crossings in ALGS. In conclusion, Jag1Ndr/Ndr mice could be used to develop interventions for vascular defects in ALGS, and retinography could provide a non-invasive method for vascular analysis in these pediatric patients.

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