Fc-receptor Dependent Platelet Aggregation Induced by Monoclonal Antibodies against Platelet Glycoprotein Ib or von Willebrand Factor

Summary

In this paper we describe two pathways leading to platelet activation by crosslinking glycoprotein (GP) Ib to the platelet Fc-receptor (FcγRII). First the monoclonal antibody (MoAb) 9C8, raised against human platelet GPIbα, dose-dependently induced platelet aggregation of citrate-anticoagulated platelet-rich plasma, an effect that can be inhibited by several activation inhibitors. The FcγRII-inhibitory MoAb IV.3 was able to prevent the aggregatory effects of MoAb 9C8, indicating that crosslinking of the antigen GPIbαto the FcγII-receptor is necessary for the activating effect. Secondly we observed a synergistic activating effect of two anti-von Willebrand factor (vWF) MoAbs 1C1E7 and B724, both known to enhance vWF binding to GPIbαin the presence of shear or ristocetin. When these antibodies are added together to PRP, platelet aggregation is induced without further need for an additional modulator. This effect can be blocked by either MoAb IV.3 or an inhibitory anti-GPIbαMoAb, indicating that again the platelet activation results from signaling through FcγRII crosslinked to vWF bound to GPIbα. In addition, both the anti-GPIbαMoAb 9C8, or the two anti-vWF MoAbs 1C1E7 and B724 induce genuine platelet activation, as evidenced by the secretion of ATP and protein tyrosine phosphorylation. These findings with both anti-GPIbαand anti-vWF MoAbs add further proof to recent reports demonstrating an interaction between the platelet receptors GPIbαand FcγRII, suggesting a role for the FcγII-receptor in GPIb-related signaling.

Keywords

Monoclonal antibody - von Willebrand factor - glycoprotein Ib - FcγII-receptor - platelet activation

• References

• 1 Horsewood P, Smith JW, Kelton JG. Monoclonal antibodies against platelet glycoproteins. Transfus Med Rev 1993; 7: 156-72.
• 2 Deckmyn H, Vanhoorelbeke K, Peerlinck K. Inhibitory and activating human antiplatelet antibodies. Baillieres Clin Haematol 1998; 11: 343-59.
• 3 Deckmyn H, De Reys S. Functional effects of human antiplatelet antibodies. Semin Thromb Hemost 1995; 21: 46-59.
• 4 Hoylaerts MF, Thys C, Arnout J, Vermylen J. Recurrent arterial thrombosis linked to autoimmune antibodies enhancing von Willebrand factor binding to platelets and inducing Fc gamma RII receptor-mediated platelet activation. Blood 1998; 91: 2810-7.
• 5 Horsewood P, Hayward CP, Warkentin TE, Kelton JG. Investigation of the mechanisms of monoclonal antibody-induced platelet activation. Blood 1991; 78: 1019-26.
• 6 Rubinstein E, Boucheix C, Worthington RE, Carroll RC. Anti-platelet antibody interactions with Fc gamma receptor. Semin Thromb Hemost 1995; 21: 10-22.
• 7 De Reys S, Hoylaerts MF, De Ley M, Vermylen J, Deckmyn H. Fc-independent cross-linking of a novel platelet membrane protein by a monoclonal antibody causes platelet activation. Blood 1994; 84: 547-55.
• 8 Santoso S, Zimmermann U, Neppert J, Mueller-Eckhardt C. Receptor patching and capping of platelet membranes induced by monoclonal antibodies. Blood 1986; 67: 343-9.
• 9 Yanabu M, Ozaki Y, Nomura S, Miyake T, Miyazaki Y, Kagawa H, Yamanaka Y, Asazuma N, Satoh K, Kume S. et al. Tyrosine phosphorylation and p72syk activation by an anti-glycoprotein Ib monoclonal antibody. Blood 1997; 89: 1590-8.
• 10 Deckmyn H, Vanhoorelbeke K, Cauwenberghs N. A platelet-activating antiglycoprotein Ib monoclonal antibody. Blood 1997; 90: 3807-8.
• 11 Ruggeri ZM. Mechanisms initiating platelet thrombus formation. Thromb Haemost 1997; 78: 611-6.
• 12 Asazuma N, Ozaki Y, Satoh K, Yatomi Y, Handa M, Fujimura Y, Miura S, Kume S. Glycoprotein Ib-von Willebrand factor interactions activate tyrosine kinases in human platelets. Blood 1997; 90: 4789-98.
• 13 Razdan K, Hellums JD, Kroll MH. Shear-stress-induced von Willebrand factor binding to platelets causes the activation of tyrosine kinase(s). Biochem J 1994; 302: 681-6.
• 14 Kroll MH, Harris TS, Moake JL, Handin RI, Schafer AI. von Willebrand factor binding to platelet GPIb initiates signals for platelet activation. J Clin Invest 1991; 88: 1568-73.
• 15 Ikeda Y, Handa M, Kamata T, Kawano K, Kawai Y, Watanabe K, Kawakami K, Sakai K, Fukuyama M, Itagaki I. Transmembrane calcium influx associated with von Willebrand factor binding to GPIb in the initiation of shear-induced platelet aggregation. Thromb Haemost 1993; 3: 496-502.
• 16 Ozaki Y, Satoh K, Yatomi Y, Miura S, Fujimura Y, Kume S. Protein tyro-sine phosphorylation in human platelets induced by interaction between glycoprotein Ib and von Willebrand factor. Biochim Biophys Acta 1995; 1243: 482-8.
• 17 Jackson SP, Schoenwaelder SM, Yuan Y, Rabinowitz I, Salem HH, Mitchell CA. Adhesion receptor activation of phosphatidylinositol β3-kinase. von Willebrand factor stimulates the cytoskeletal association and activation of phosphatidylinositol β3-kinase and pp60c-src in human platelets. J Biol Chem 1994; 269: 27093-9.
• 18 Andrews RK, Fox JE. Interaction of purified actin-binding protein with the platelet membrane glycoprotein Ib-IX complex. J Biol Chem 1991; 266: 7144-7.
• 19 Du X, Harris SJ, Tetaz TJ, Ginsberg MH, Berndt MC. Association of a phospholipase A2 (14-3-3 zeta protein) with the platelet glycoprotein Ib-IX complex. J Biol Chem 1994; 269: 18287-90.
• 20 Falati S, Edmead CE, Poole AW. Glycoprotein Ib-V-IX, a receptor for von Willebrand factor, couples physically and functionally to the Fc receptor gamma-chain, Fyn, and Lyn to activate human platelets. Blood 1999; 94: 1648-56.
• 21 Calverley DC, Kavanagh TJ, Roth GJ. Human signaling protein 14-3-3zeta interacts with platelet glycoprotein Ib subunits Ibalpha and Ibbeta. Blood 1998; 91: 1295-303.
• 22 Gu M, Englund GD, Berndt MC, Du X. Analysis of the roles of 14-3-3 in the platelet glycoprotein Ib-IX-mediated platelet activation of integrin alpha(IIb)beta(3) using a reconstituted mammalian expression model. J Cell Biol 1999; 147: 1085-96.
• 23 Gibbins JM, Okuma M, Farndale R, Barnes M, Watson SP. Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor γ-chain. FEBS Lett 1997; 413: 255-258.
• 24 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 glyco-protein IB- and IIB/IIIA-binding domains. J Clin Invest 1993; 91: 273-82.
• 25 Vanhoorelbeke K, Cauwenberghs N, Vauterin S, Schlammadinger A, Mazurier C, Deckmyn H. A new and reproducible vWF:RiCoF assay. Thromb Haemost 2000; 83: 107-113.
• 26 Christophe O, Rouault C, Obert B, Pietu G, Meyer D, Girma JP. 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 1995; 90: 195-203.
• 27 Depraetere H, Ajzenberg N, Girma JP, Lacombe C, Meyer D, Deckmyn H, Baruch D. Platelet aggregation induced by a monoclonal antibody to the A1 domain of von Willebrand factor. Blood 1998; 91: 3792-9.
• 28 Wicki AN, Clemetson KJ. The glycoprotein Ib complex of human blood platelets. Eur J Biochem 1987; 163: 43-50.
• 29 Cauwenberghs N, Ajzenberg N, Vauterin S, Hoylaerts MF, Declerck PJ, Baruch D, Deckmyn H. Characterization of murine anti-GPIb monoclonal antibodies that differentiate between shear-induced and risto/botrocetin-induced GPIb-vWF interaction. Haemostasis 2000; 30: 139-48.
• 30 Coller BS, Peerschke EI, Scudder LE, Sullivan CA. Studies with a murine monoclonal antibody that abolishes ristocetin-induced binding of von Willebrand factor to platelets: additional evidence in support of GPIb as a platelet receptor for von Willebrand factor. Blood 1983; 61: 99-110.
• 31 Meyer S, Kresbach G, Haring P, Schumpp Vonach B, Clemetson KJ, Had-vary P, Steiner B. Expression and characterization of functionally active fragments of the platelet glycoprotein (GP) Ib-IX complex in mammalian cells. Incorporation of GP Ib alpha into the cell surface membrane. J Biol Chem 1993; 268: 20555-62.
• 32 Cauwenberghs N, Meiring M, Vauterin S, van Wyk V, Lamprecht S, Roodt JP, Novak L, Harsfalvi J, Deckmyn H, Kotzé HF. Antithrombotic effect of platelet glycoprotein Ib blocking monoclonal antibody Fab fragments in non-human primates. Arterioscl Thromb Vasc Biol 2000; 20: 1347-53.
• 33 Deckmyn H, Stanssens P, Hoet B, Declerck PJ, Lauwereys M, Gansemans Y, Tornai I, Vermylen J. An echistatin-like Arg-Gly-Asp (RGD)-containing sequence in the heavy chain CDR3 of a murine monoclonal antibody that inhibits human platelet glycoprotein IIb/IIIa function. Br J Haematol 1994; 87: 562-71.
• 34 De Reys S, Blom C, Lepoudre B, Declerck PJ, De Ley M, Vermylen J, Deckmyn H. Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent. Blood 1993; 81: 1792-800.
• 35 Sullam PM, Hyun WC, Szollosi J, Dong Jf, Foss WM, Lopez JA. Physical proximity and functional interplay of the glycoprotein Ib-IX-V complex and the Fc receptor FcgammaRIIA on the platelet plasma membrane. J Biol Chem 1998; 273: 5331-6.
• 36 Sun B, Kambayashi J. Interaction between GPIbalpha and FcgammaIIA receptor in human platelets. Biochem Biophys Res Comm 1999; 266: 24-7.
• 37 Saci A, Pain A, Rendu F, Bachelot-Loza C. Fc receptor-mediated platelet activation is dependent on phosphatidylinositol β3-kinase activation and involves p120cbl. J Biol Chem 1999; 274: 1898-904.