Sex differences and risk factors for bleeding in Alagille syndrome.

Spontaneous bleeds are a leading cause of death in the pediatric JAG1‐related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non‐invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex‐specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non‐invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS. Synopsis: Spontaneous bleeds are a significant cause of death in the rare genetic disease Alagille syndrome, but little is known about the risk factors contributing to the bleeding events, or about vascular development and maintenance in the course of the disease. Alagille syndrome is modeled by Jag1Ndr/Ndr mice, including high mortality and sporadic bleeding.More female than male patients with Alagille syndrome are reported with intracranial bleeds, and certain vascular phenotypes are more severe in female Jag1Ndr/Ndr mice.Bleeding risk in Jag1Ndr/Ndr mice may be further modified by thin skull bones, fragile vascular smooth muscle cells, premature vascular aging, and increased venous tortuosity.Developmental and homeostatic vascular defects were detected in both endothelial cells and vascular smooth muscle cells in Jag1Ndr/Ndr mice.The vascular defects observed in Jag1Ndr/Ndr mice could be visualized, quantified, and validated in retinographs from patients, suggesting a non‐invasive method to assess vascular health. [ABSTRACT FROM AUTHOR]