Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

Max Braune; Moritz Metelmann; Jonathan de Fallois; Christian Pfrepper; Alonso Barrantes-Freer; Grit Gesine Ruth Hiller; Susette Unger; Evelyn Seelow; Jan Halbritter; Johann Otto Pelz

doi:10.1186/s42466-024-00327-2

Imbalance of the von Willebrand Factor - ADAMTS-13 axis in patients with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S)

Neurol Res Pract. 2024 Jun 20;6(1):32. doi: 10.1186/s42466-024-00327-2.

Authors

Affiliations

¹ Paul-Flechsig-Institute for Neuropathology, University Hospital Leipzig, Leipzig, Germany.
² Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany.
³ Division of Nephrology, University Hospital Leipzig, Leipzig, Germany.
⁴ Division of Haemostaseology, Medical Department I, University Hospital Leipzig, Leipzig, Germany.
⁵ Institute for Pathology, University Hospital Leipzig, Leipzig, Germany.
⁶ Division of Rheumatology, Hospital St. Georg, Leipzig, Germany.
⁷ Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁸ Division of Nephrology, University Hospital Leipzig, Leipzig, Germany. Jan.Halbritter@charite.de.
⁹ Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany. Jan.Halbritter@charite.de.
¹⁰ Department of Neurology, University Hospital Leipzig, Liebigstraße 20, Leipzig, 04103, Germany. Johann.Pelz@medizin.uni-leipzig.de.

^# Contributed equally.

Abstract

Background: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an ultra-rare, autosomal-dominant small vessel disease caused by loss-of-function variants in the gene TREX1. Recently, elevated serum levels of von Willebrand Factor Antigen (vWF-Ag) pointed to an underlying endotheliopathy, and microvascular ischemia was suggested to contribute to the neurodegeneration in RVCL-S. Aim of this study was to further elucidate the endotheliopathy in RVCL-S.

Methods: vWF-Ag and ADAMTS-13 activity were repeatedly measured in two patients with genetically confirmed RVCL-S. Renal biopsy of both RVCL-S patients and autoptic brain, renal, hepatic, and pulmonary specimen of one patient with RVCL-S were examined immunohistochemically in comparison to matched controls. In addition, cerebral methylome analysis was performed in the autoptic brain specimen calculating differentially methylated positions compared to controls.

Results: While vWF-Ag and activity was strongly elevated, ADAMTS-13 activity was low in RVCL-S and further decreased over the course of the disease. Autoptic brain specimen showed signs of thromboinflammation in cerebral small vessels, and vWF-Ag staining was strongly positive in cerebral and renal small vessels in RVCL-S, while only a light to moderate vWF-Ag staining was found in controls. Cerebral methylome analysis yielded 115 differentially methylated CpGs (p < 0.05) in the deceased RVCL-S patient compared to the eight controls without brain pathology. One of the hypomethylated genes coded for ADAMTS-13 (p = 0.00056).

Conclusions: These findings point to an imbalance of the vWF - ADAMTS-13 axis in patients with RVCL-S, that may finally lead to an accumulation of vWF-Ag in renal and cerebral small vessels. Elevated vWF-Ag levels may serve as an early serum marker reflecting disease activity. If confirmed, therapeutic approaches might aim at an inhibition of vWF-Ag or increase of ADAMTS-13 activity in the future.

Keywords: ADAMTS-13; RVCL-S; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; TREX1; von Willebrand Factor.

Grants and funding

HA 6908/4-1/DFG