Type 2B von Willebrand disease (VWD2B) is due to a gain-of-function variant of von Willebrand factor (VWF) characterized by an enhanced interaction with the platelet glycoprotein (Gp)Ib-α [1]. This condition may result in the sequestration of VWF onto the platelet surface, responsible for variable thrombocytopenia [2]. The first report of an increased proteolysis of VWD2B was by Zimmerman et al. [3], who showed the increased intensity of the inner bands of VWF triplet structure in VWD2B patients' plasma. More recently, Nishio et al. [4] demonstrated that the interaction of the GpIb-α with the VWF A1 domain increased the susceptibility of the adjacent A2 domain to ADAMTS-13, justifying the increased proteolysis in VWD2B. However, only recently De Cristofaro et al. [5] described a specific binding of chloride ions (Cl−) to the VWF A1 domain that reduced the susceptibility of the adjacent A2 domain to ADAMTS-13 activity. Furthermore, the VWD2B variant p.R1306W was found to have a reduced affinity for Cl− and an increased susceptibility to ADAMTS-13 proteolysis [6]. In this study, we extended our investigation to another four VWD2B variants, confirming that all reported mutations reduced their binding to Cl−, and increased their susceptibility to ADAMTS-13 cleavage, although to different degrees. In addition, using the VWF:RCo/Ag ratios, that in VWD2B patients are indicative of the partial loss of high molecular weight multimers (HMWM), we tried to correlate the increased susceptibility to ADAMTS-13 cleavage of these five VWD2B variants with the multimeric pattern in the plasma of patients who carry the corresponding mutations [7].

Baronciani, L., Peyvandi, F., Punzo, M., Lancellotti, S., Canciani, M. T., Federici, A. B., De Cristofaro, R., Relevance of chloride binding to von Willebrand factor in type 2B von Willebrand disease patients, <<JOURNAL OF THROMBOSIS AND HAEMOSTASIS>>, 2010; 2010 (2): 416-418 [http://hdl.handle.net/10807/32832]

Relevance of chloride binding to von Willebrand factor in type 2B von Willebrand disease patients

Lancellotti, Stefano;De Cristofaro, Raimondo
2010

Abstract

Type 2B von Willebrand disease (VWD2B) is due to a gain-of-function variant of von Willebrand factor (VWF) characterized by an enhanced interaction with the platelet glycoprotein (Gp)Ib-α [1]. This condition may result in the sequestration of VWF onto the platelet surface, responsible for variable thrombocytopenia [2]. The first report of an increased proteolysis of VWD2B was by Zimmerman et al. [3], who showed the increased intensity of the inner bands of VWF triplet structure in VWD2B patients' plasma. More recently, Nishio et al. [4] demonstrated that the interaction of the GpIb-α with the VWF A1 domain increased the susceptibility of the adjacent A2 domain to ADAMTS-13, justifying the increased proteolysis in VWD2B. However, only recently De Cristofaro et al. [5] described a specific binding of chloride ions (Cl−) to the VWF A1 domain that reduced the susceptibility of the adjacent A2 domain to ADAMTS-13 activity. Furthermore, the VWD2B variant p.R1306W was found to have a reduced affinity for Cl− and an increased susceptibility to ADAMTS-13 proteolysis [6]. In this study, we extended our investigation to another four VWD2B variants, confirming that all reported mutations reduced their binding to Cl−, and increased their susceptibility to ADAMTS-13 cleavage, although to different degrees. In addition, using the VWF:RCo/Ag ratios, that in VWD2B patients are indicative of the partial loss of high molecular weight multimers (HMWM), we tried to correlate the increased susceptibility to ADAMTS-13 cleavage of these five VWD2B variants with the multimeric pattern in the plasma of patients who carry the corresponding mutations [7].
Inglese
Baronciani, L., Peyvandi, F., Punzo, M., Lancellotti, S., Canciani, M. T., Federici, A. B., De Cristofaro, R., Relevance of chloride binding to von Willebrand factor in type 2B von Willebrand disease patients, <<JOURNAL OF THROMBOSIS AND HAEMOSTASIS>>, 2010; 2010 (2): 416-418 [http://hdl.handle.net/10807/32832]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/32832
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