Background: Coagulation factor VIII (FVIII) is a heavily glycosylated heterodimeric plasma protein that consists of a heavy (domains A1-A2-B) and light chain (domains A3-C1-C2). It has been well established that the clearance of FVIII from the circulation involves mechanisms that are sensitive to the low-density lipoprotein receptor (LDLR) family antagonist receptor-associated protein (RAP), including LDLR-related protein. Because FVIII clearance in the presence of a bolus injection of RAP still occurs fairly efficient, also RAP-independent mechanisms are likely to be involved. Objectives: In the present study, we investigated the interaction of FVIII with the endocytic lectin asialoglycoprotein receptor (ASGPR) and the physiological relevance thereof. Methods and results: Surface plasmon resonance studies demonstrated that FVIII dose-dependently bound to ASGPR with high affinity (Kd ≈ 2 nM). FVIII subunits were different in that only the heavy chain displayed high-affinity binding to ASGPR. Studies employing a FVIII variant that lacks the B domain revealed that FVIII-ASGPR complex assembly is driven by structure elements within the B domain of the heavy chain. The FVIII heavy chain-ASGPR interaction required calcium ions and was inhibited by soluble D-galactose. Furthermore, deglycosylation of the FVIII heavy chain by endoglycosidase F completely abrogated the interaction with ASGPR. In clearance experiments in mice, the FVIII mean residence time was prolonged by the ASGPR-antagonist asialo-orosomucoid (ASOR). Conclusions: We conclude that asparagine-linked oligosaccharide structures of the FVIII B domain recognize the carbohydrate recognition domains of ASGPR and that an ASOR-sensitive mechanism, most likely ASGPR, contributes to the catabolism of coagulation FVIII in vivo.

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doi.org/10.1111/j.1538-7836.2005.01389.x, hdl.handle.net/1765/70815
Journal of Thrombosis and Haemostasis
Department of Hematology

Bovenschen, N., Rijken, D., Havekes, L., van Vlijmen, B., & Mertens, K. (2005). The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor. Journal of Thrombosis and Haemostasis, 3(6), 1257–1265. doi:10.1111/j.1538-7836.2005.01389.x