Pathogenic Effects of Anti-Glycoprotein Ib Antibodies on Megakaryocytes and Platelets

Gulie Alimardani; Josette Guichard; Serge Fichelson; Elisabeth M. Cramer

doi:10.1055/s-0037-1613352

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2002; 88(06): 1039-1046
DOI: 10.1055/s-0037-1613352

Involvement of Thrombin Receptors in the Subject-dependent Variability in Ca2+ Signal Generation

Schattauer GmbH

Pathogenic Effects of Anti-Glycoprotein Ib Antibodies on Megakaryocytes and Platelets

Gulie Alimardani

¹Département d’hématologie, INSERM U.567, Institut Cochin, Paris

²Laboratoire d’hématologie, CHU Amiens, Amiens

,

Josette Guichard

¹Département d’hématologie, INSERM U.567, Institut Cochin, Paris

,

Serge Fichelson

¹Département d’hématologie, INSERM U.567, Institut Cochin, Paris

,

Elisabeth M. Cramer

¹Département d’hématologie, INSERM U.567, Institut Cochin, Paris

³Service d’hématologie et d’immunologie, Hôpital Ambroise Paré (AP-HP) and Faculté Paris-Ile de France-Ouest

› Author Affiliations

Abstract

Summary

Antibodies directed against the glycoprotein (GP) Ib have been identified as the potential cause of various platelet disorders: Immune thrombocytopenic purpura (ITP) may be caused by such autoantibodies; Anti-thrombotic drugs targeting GPIb also induce thrombocytopenia. In order to elucidate the potential mechanism(s) of the anti-GPIb effects, we have examined by electron microscopy (EM) the effect of several antibodies directed against GPIb and GPIIb-IIIa on human culture megakaryocytes (MK). Virtually all antibodies to GPIb enhanced the interaction of newly formed platelets with MK when compared to other antibodies. These effects were retrieved when antibodies were tested on platelets. We conclude that antibodies to GPIb can potentially inhibit platelet release by MK, and can also induce homotypic platelet adhesion. These results may have implications in the pathophysiology of thrombocytopenia and platelet recovery in ITP, and shed light on the pathological effect of anti-GPIb antibodies used as antithrombotic drugs.

Keywords

Megakaryocytes - platelets - GPIb

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References

References
1 Andrews RK, Lopez JA, Berndt MC. Molecular mechanisms of platelet adhesion and activation. Int J Biochem Cell Biol 1997; 29: 91-105.
2 Lopez JA. The platelet glycoprotein Ib-IX complex. Blood Coagul Fibrinolysis 1994; 05: 97-119.
3 Lopez JA, Dong JF. Structure and function of the glycoprotein Ib-IX-V complex. Curr Opin Hematol 1997; 04: 323-9.
4 Debili N, Kieffer N, Nakazawa M, Guichard J, Titeux M, Cramer E, Breton-Gorius J, Vainchenker W. Expression of platelet glycoprotein Ib by cultured human megakaryocytes: ultrastructural localization and biosynthesis. Blood 1990; 76: 368-76.
5 Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
6 Cauwenberghs N, Meiring M, Vauterin S, van Wyk V, Lamprecht S, Roodt JP, Novak L, Harsfalvi J, Deckmyn H, Kotze HF. Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. Arterioscler Thromb Vasc Biol 2000; 20: 1347-53.
7 Cadroy Y, Hanson SR, Kelly AB, Marzec UM, Evatt BL, Kunicki TJ, Montgomery RR, Harker LA. Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates. Blood 1994; 83: 3218-24.
8 Kiefel V, Santoso S, Kaufmann E, Mueller-Eckhardt C. Autoantibodies against platelet glycoprotein Ib/IX: a frequent finding in autoimmune thrombocytopenic purpura. Br J Haematol 1991; 79: 256-62.
9 McMillan R, Tani P, Millard F, Berchtold P, Renshaw L, Woods Jr VL. Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP. Blood 1987; 70: 1040-5.
10 Szatkowski NS, Kunicki TJ, Aster RH. Identification of glycoprotein Ib as a target for autoantibody in idiopathic (autoimmune) thrombocytopenic purpura. Blood 1986; 67: 310-5.
11 Woods Jr. VL, Kurata Y, Montgomery RR, Tani P, Mason D, Oh EH, McMillan R. Autoantibodies against platelet glycoprotein Ib in patients with chronic immune thrombocytopenic purpura. Blood 1984; 64: 156-60.
12 McMillan R. The pathogenesis of chronic immune (idiopathic) thrombocytopenic purpura. Semin Hematol 2000; 37: 5-9.
13 Berchtold P, Wenger M. Autoantibodies against platelet glycoproteins in autoimmune thrombocytopenic purpura: their clinical significance and response to treatment. Blood 1993; 81: 1246-50.
14 Suvajdzic N, Rolovic Z, Elezovic I, Colovic M. Megakaryocytopoiesis in refractory chronic immune thrombocytopenia. Hematol Cell Ther 1999; 41: 163-8.
15 Wang ZY, Shen ZX. Megakaryocytes and platelets in immune thrombocytopenic purpura. Baillieres Clin Haematol 1997; 10: 89-107.
16 He R, Reid DM, Jones CE, Shulman NR. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 1994; 83: 1024-32.
17 Beardsley DS, Ertem M. Platelet autoantibodies in immune thrombocytopenic purpura. Transfus Sci 1998; 19: 237-44.
18 Berchtold P, Muller D, Beardsley D, Fujisawa K, Kaplan C, Kekomaki R, Lipp E, Morell-Kopp MC, Kiefel V, McMillan R, von dem Borne AE, Imbach P. International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies. Br J Haematol 1997; 96: 477-83.
19 Chong BH, Keng TB. Advances in the diagnosis of idiopathic thrombocytopenic purpura. Semin Hematol 2000; 37: 249-60.
20 Warner MN, Moore JC, Warkentin TE, Santos AV, Kelton JG. A prospective study of protein-specific assays used to investigate idiopathic thrombocytopenic purpura. Br J Haematol 1999; 104: 442-7.
21 Hou M, Stockelberg D, Kutti J, Wadenvik H. Antibodies against platelet GPIb/IX, GPIIb/IIIa, and other platelet antigens in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 1995; 55: 307-14.
22 Nomura S, Yanabu M, Soga T, Kido H, Fukuroi T, Yamaguchi K, Nagata H, Kokawa T, Yasunaga K. Analysis of idiopathic thrombocytopenic purpura patients with antiglycoprotein IIb/IIIa or Ib autoantibodies. Acta Haematol 1991; 86: 25-30.
23 McMillan R. Autoantibodies and autoantigens in chronic immune thrombocytopenic purpura. Semin Hematol 2000; 37: 239-48.
24 Mehta YS, Pathare AV, Badakere SS, Ghosh K, Mohanty D. Influence of auto-antibody specificities on the clinical course in patients with chronic and acute ITP. Platelets 2000; 11: 94-8.
25 Hagberg IA, Lyberg T. Blood platelet activation evaluated by flow cytometry: optimised methods for clinical studies. Platelets 2000; 11: 137-50.
26 Cramer EM, Caen JP, Drouet L, Breton-Gorius J. Absence of tubular structures and immunolabeling for von Willebrand factor in the platelet alpha-granules from porcine von Willebrand disease. Blood 1986; 68: 774-8.
27 Cramer EM, Meyer D, le Menn R, Breton-Gorius J. Eccentric localization of von Willebrand factor in an internal structure of platelet alpha-granule resembling that of Weibel-Palade bodies. Blood 1985; 66: 710-3.
28 Cramer EM, Norol F, Guichard J, Breton-Gorius J, Vainchenker W, Masse JM, Debili N. Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 1997; 89: 2336-46.
29 Vitrat N, Cohen-Solal K, Norol F, Guichard J, Cramer E, Vainchenker W, Wendling F, Debili N. Compared effects of Mpl ligand and other cytokines on human MK differentiation. Stem Cells 1998; 02: 37-51.
30 Takahashi R, Sekine N, Nakatake T. Influence of monoclonal antiplatelet glycoprotein antibodies on in vitro human megakaryocyte colony formation and proplatelet formation. Blood 1999; 93: 1951-8.
31 Berndt MC, Du XP, Booth WJ. Ristocetin-dependent reconstitution of binding of von Willebrand factor to purified human platelet membrane glycoprotein Ib-IX complex. Biochemistry 1988; 27: 633-40.
32 Williamson D, Giuliano S, Jackson SP. Platelet adhesion receptors: novel targets for anti-thrombotic therapy. Aust N Z J Med 1999; 29: 452-61.
33 Schafer AI. Antiplatelet therapy. Am J Med 1996; 101: 199-209.
34 Coller BS, Anderson K, Weisman HF. New antiplatelet agents: platelet GPIIb/IIIa antagonists. Thromb Haemost 1995; 74: 302-8.
35 Neumann FJ, Kastrati A, Schmitt C, Blasini R, Hadamitzky M, Mehilli J, Gawaz M, Schleef M, Seyfarth M, Dirschinger J, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll Cardiol 2000; 35: 915-21.
36 Hayes R, Chesebro JH, Fuster V, Dangas G, Fallon JT, Sharma SK, Coller BS, Badimon L, Marmur JD, Badimon JJ. Antithrombotic effects of abciximab. Am J Cardiol 2000; 85: 1167-72.
37 Chang MC, Lin HK, Peng HC, Huang TF. Antithrombotic effect of crotalin, a platelet membrane glycoprotein Ib antagonist from venom of Crotalus atrox. Blood 1998; 91: 1582-9.
38 Yeh CH, Chang MC, Peng HC, Huang TF. Pharmacological characterization and antithrombotic effect of agkistin, a platelet glycoprotein Ib antagonist. Br J Pharmacol 2001; 132: 843-50.