Bleeding in patients and mice with Alagille syndrome: sex differences and risk factors

Alagille syndrome (ALGS) is generally thought of as a pediatric cholestatic liver disease, but spontaneous bleeds are a major cause of death. Here, we investigated bleeding 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 spontaneously bled, exhibiting a thin skull and vascular defects. Vascular abnormalities included artery-vein crossings, tortuous vessels, and capillary breakdown. Furthermore, Jag1Ndr/Ndr arteries had sparse vascular smooth muscle cell coverage, which was further aggravated by hypertension. Retinographs from patients with ALGS, biliary atresia, or CADASIL confirmed tortuous blood vessels and artery-vein crossings in ALGS. We also identified sex-specific differences: fewer major vessels in female Jag1Ndr/Ndr mice, and four-fold more female than male patients with intracranial hemorrhage. In conclusion, dysfunctional Jag1 disrupted vascular growth and homeostasis, with sex-specific differences. The mouse model for Alagille syndrome demonstrated multiple bleeding risk factors and vascular defects that can be identified in patients non-invasively.