Anti-vWf antibodies induce GPIbα and FcγRII mediated platelet aggregation only at low shear forces

被引：5

作者：

Hoylaerts M.F. ^{[1
]}

Viaene A. ^{[2
]}

Thys C. ^{[1
]}

Deckmyn H. ^{[2
]}

Vermylen J. ^{[1
]}

机构：

[1] Center for Molecular and Vascular Biology, University of Leuven, KU Leuven

[2] Laboratory for Thrombosis Research, Interdisciplinary Research Center, KU Leuven Campus, Kortrijk

来源：

Journal of Thrombosis and Thrombolysis | 2001年 / 12卷 / 3期

关键词：

GPIb; Phage display; Platelet aggregation; Synergism; Von Willebrand factor;

D O I：

10.1023/A:1015279109247

中图分类号：

学科分类号：

摘要：

Background/methods: Anti-von Willebrand factor (vWf) antibody mediated platelet activation was studied using 2 monoclonal anti-vWf antibodies promoting the binding of vWf to GPIbα: 1C1E7 (IgG2a) reacting with the vWf N-terminus and 75H4B12 (IgM), characterized in this paper and studied in association with 1C1E7. Results: 75H4B12 binds to an N-terminal epitope in vWf, different from that reacting with 1C1E7. When combined, 1C1E7 and 75H4B12 promoted vWf binding to isolated GPIb under static conditions, even in the absence of ristocetin or botrocetin, and induced platelet aggregation synergistically in the presence of zero to subthreshold ristocetin concentrations. Specific inhibitors of GPIbα-vWf interactions prevented vWf binding to GPIbα in ELISA and during platelet aggregation. In addition, the 1C1E7 dependent platelet aggregation involved Fc receptor mediated platelet activation, a phenomenon even more pronounced when 1C1E7 and 75H4B12 were combined. A 75H4B12 binding phage expressing a peptide homologous with vWf sequence 88-95 neutralized the antibody induced platelet activation. However, at arterial shear rates, both 1C1E7 and 75H4B12 potently prolonged cartridge closure times in the PFA-100, compatible with inhibition of platelets by vWf, unfolded by the combined action of shear stress and antibodies. Conclusions: We conclude that antibodies directed against different epitopes in the N-terminus of vWf modify the folded vWf structure synergistically and enhance A1 domain mediated vWf binding to platelet GPIb at low shear forces. In addition, once platelet-bound, IgG antibodies potently activate platelets via the FcγII receptor. Thus, such antibodies may promote immune mediated thrombosis at low shear rates, typical of the venous circulation. In contrast, at arterial shear rates, anti-vWf antibodies may rather compromise platelet function following enhanced binding of the unfolded vWf multimers to platelets, shielding platelets from interacting with subendothelial and soluble ligands.

引用

页码：249 / 262

页数：13

共 46 条

[21]

Siedlecki C.A., Lestini B.J., Kottke-Marchant K.K., Eppell S.J., Wilson D.L., Marchant R.E., Shear-dependent changes in the three-dimensional structure of human von Willebrand factor, Blood, 88, pp. 2939-2950, (1996)

[22]

Howard M.A., Perkin J., Salem H.H., Firkin B.G., The agglutination of human platelets by botrocetin: Evidence that botrocetin and ristocetin act at different sites on the factor VIII molecule and platelet membrane, Br J Haematol, 57, pp. 25-35, (1984)

[23]

De Luca M., Facey D.A., Favaloro E.J., Hertzberg M.S., Whisstock J.C., McNally T., Andrews R.K., Berndt M.C., Structure and function of the von Willebrand factor A1 domain: Analysis with monoclonal antibodies reveals distinct binding sites involved in recognition of the platelet membrane glycoprotein Ib-IX-V complex and ristocetin-dependent activation, Blood, 95, pp. 164-172, (2000)

[24]

Christophe O., Rouault C., Obert B., Pietu G., Meyer D., Girma J.P., A monoclonal antibody (B724) to von Willebrand factor recognizing an epitope within the A1 disulphide loop (Cys509-Cys695) discriminates between type 2A and type 2B von Willebrand disease, Br J Haematol, 90, pp. 195-203, (1995)

[25]

Depraetere H., Ajzenberg N., Girma J.P., Lacombe C., Meyer D., Deckmyn H., Baruch D., Platelet aggregation induced by a monoclonal antibody to the A1 domain of von Willebrand factor, Blood, 91, pp. 3792-3799, (1998)

[26]

Tornai I., Arnout J., Deckmyn H., Peerlinck K., Vermylen J., A monoclonal antibody recognizes a von Willebrand factor domain within the amino-terminal portion of the subunit that modulates the function of the glycoprotein Ib- and IIb/IIIa-binding domains, J Clin Invest, 91, pp. 273-282, (1993)

[27]

Tomiyama Y., Kunichi T.J., Zipf T.F., Ford S.B., Aster R.H., Response of human platelets to activating monoclonal antibodies: Importance of Fc gamma II (CD32) phenotype and level of expression, Blood, 80, pp. 2261-2268, (1992)

[28]

Miller J.L., Hustad K.O., Kupinski J.M., Lyle V.A., Kunicki T.J., Increased platelet sensitivity to ristocetin is predicted by the binding characteristics of a GPIb/IX determinant, Br J Haematol, 74, pp. 313-319, (1990)

[29]

Ruggeri Z.M., Zimmerman T.S., Russell S., Bader R., De Marco L., Von Willebrand factor binding to platelet glycoprotein Ib complex, Methods Enzymol, 215, pp. 263-275, (1992)

[30]

Gralnick H.R., Williams S., McKeown L., Kramer W., Krutzch H., Gorecki M., Pinet A., Garfinkel L.I., A monomeric von Willebrand factor fragment, Leu-504-Ser-728, inhibits von Willebrand factor interaction with glycoprotein Ib-IX, Proc Natl Acad Sci USA, 89, pp. 7880-7884, (1992)

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