The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity
Laura L. Swystun, … , Paula D. James, David Lillicrap
Laura L. Swystun, … , Paula D. James, David Lillicrap
Published August 20, 2018
Citation Information: J Clin Invest. 2018;128(9):4057-4073. https://doi.org/10.1172/JCI96400.
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Research Article Genetics Hematology

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Abstract

Quantitative abnormalities of the von Willebrand factor–factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2–expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2–deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.

Authors

Laura L. Swystun, Jesse D. Lai, Colleen Notley, Ilinca Georgescu, A. Simonne Paine, Jeff Mewburn, Kate Nesbitt, Kai Schledzewski, Cyrill Géraud, Julia Kzhyshkowska, Sergij Goerdt, Wilma Hopman, Robert R. Montgomery, Paula D. James, David Lillicrap

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Figure 5

Stabilin-2 deficiency increases the half-life of human VWF-FVIII.

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Stabilin-2 deficiency increases the half-life of human VWF-FVIII. (A) Pl...
(A) Plasma levels of VWF:Ag were measured in age-matched normal C57BL/6 mice compared with stabilin-2–deficient (STAB2-KO) C57BL/6 mice (n = 26–38 animals per condition by t test). (B and C) Influence of stabilin-2 deficiency on the half-life of infused human rVWF (n = 12 animals per condition) (B) and human pdVWF (FVIII-bound 1:1) (n = 16 animals per condition) (C). (D) The combined influence of macrophage depletion using clodronate liposomes and stabilin-2 deficiency was assessed using human pdVWF (FVIII-free) (n = 8 animals per condition). (E) The combined influence of cyclophosphamide-induced LSEC cytotoxicity and stabilin-2 deficiency was assessed using human pdVWF (FVIII-free) (n = 8–16 animals per condition). (F) The influence of stabilin-2 deficiency on the half-life of infused human pdFVIII (+VWF) (n = 16 animals per condition) was measured in VWF-KO compared with VWF/STAB2 DKO mice. See statistical summary of half-life studies in Table 1.