The Effect of Monoclonal Anti-human-platelet Antibodies on Platelet Kinetics in a Baboon Model: IgG Subclass Dependency

Lindi-Marie Coetzee; Henry Pieters; Veronica van Wyk; Susan Cooper; Jan Roodt; Stefan De Reys; Philip N. Badenhorst

doi:10.1055/s-0037-1613771

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 83(01): 148-156
DOI: 10.1055/s-0037-1613771

Commentary

Schattauer GmbH

The Effect of Monoclonal Anti-human-platelet Antibodies on Platelet Kinetics in a Baboon Model: IgG Subclass Dependency

Lindi-Marie Coetzee

¹From the Department of Haematology and Cell Biology, Catholic University, Leuven, Belgium

,

Henry Pieters

¹From the Department of Haematology and Cell Biology, Catholic University, Leuven, Belgium

,

Veronica van Wyk

¹From the Department of Haematology and Cell Biology, Catholic University, Leuven, Belgium

,

Susan Cooper

²Department of Anatomical Pathology of the University of the Orange Free State, Bloemfontein, South Africa, Catholic University, Leuven, Belgium

,

Jan Roodt

¹From the Department of Haematology and Cell Biology, Catholic University, Leuven, Belgium

,

Stefan De Reys

³Laboratory for Thrombosis Research, Campus Kortrijk, Catholic University, Leuven, Belgium

,

Philip N. Badenhorst

¹From the Department of Haematology and Cell Biology, Catholic University, Leuven, Belgium

› Author Affiliations

Abstract

Summary

We assessed the in vivo effect of six intact anti-human antiplatelet antibodies of two major IgG subclasses on platelet kinetics in baboons. Five of the six antibodies tested caused thrombocytopenia of varying degree when injected at a precalculated threshold value. An agglutinating IgG₁ antibody (MA-8L4A12) caused a long-lasting, mild thrombocytopenia with a predominant uptake of radiolabelled platelets in the spleen, while the four IgG₂ antibodies tested (MA-13G8E1, MA-2M5A6, MA-21K2E8 and MA-22M10) caused a severe, transient thrombocytopenia with uptake of platelets in the liver. Two of the IgG2 antibodies (MA-13G8E1 and MA-2M5A6) caused platelet activation and aggregation in vitro, whilst the other two did not elicit a platelet aggregation response. The platelet survival time was shortened with all five of the thrombocytopenia-inducing antibodies, while only one antibody (MA-2M5A6) had a significant effect on the bleeding time. This study indicates that the IgG subclasss may be a determining factor in the outcome of platelet sequestration in immune-induced thrombocytopenia.

Keywords

Platelet kinetics - thrombocytopenia - antibodies

Full Text

References

References
1 George JN, El-Harake MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994; 33: 1207-11.
2 McMillan R, Imbach PA. Immune thrombocytopenic purpura. In: Thrombosis and hemorrhage. Loscalzo J, Schafer AI. Boston: Blackwell Scientific Publications; 1994: 575-95.
3 Newland AC. Idiopathic thrombocytopenic purpura and IgG: A review. J Infect 1987; 15: 41-9.
4 Court WS, Bozeman JM, Soong S, Saleh MN, Shaw DR, LoBuglio AF. Platelet surface-bound IgG in patients with immune and nonimmune thrombocytopenia. Blood 1987; 69: 278-83.
5 Tani P, Berchtold P, McMillan R. Autoantibodies in chronic ITP. Blut 1989; 59: 44-6.
6 Pfueller SL, Cosgrove L, Firkin BG, Tew D. Relationship of raised platelet IgG in thrombocytopenia to total platelet protein content. Br J Haematol 1981; 49: 293-302.
7 Heyns Ad, Lötter MG, Badenhorst PN, van Reenen OR, Pieters H, Minnaar PC, Retief FP. Kinetics, distribution and sites of destruction of ¹¹¹Indiumlabelled human platelets. Br J Haematol 1980; 44: 269-80.
8 Schmidt KG, Rasmussen JW. Kinetics and distribution in vivo of ¹¹¹Inlabelled autologous platelets in idiopathic thrombocytopenic purpura. Scand J Haematol 1985; 34: 47-56.
9 Stratton JR, Ballem PJ, Gernsheimer T, Cerqueira M, Slichter SJ. Platelet destruction in autoimmune thrombocytopenic purpura: Kinetics and clearance of Indium-111-labeled autologous platelets. The Journal of Nuclear Medicine 1989; 30: 629-37.
10 Elkon KB, Ferjencik PP, Walport MJ, Peters AM, Lewis SM, Hughes GRV. Evaluation of heat-damaged and IgG-coated red cells for testing reticuloendothelial function. Journal of Immunological Methods 1982; 55: 253-63.
11 Peters AM, Walport MJ, Elkon KB, Reavy HJ, Ferjencik PP, Lavender JP, Hughes GRV. The comparative blood clearance kinetics of modified radiolabelled erythrocytes. Clinical Science 1984; 66: 55-62.
12 Schreiber AD, Frank MM. Role of antibody and complement in the immune clearance and destruction of erythrocytes. J Clin Invest 1972; 51: 575-82.
13 Spiegelberg AL. Biological role of different antibody classes. Int Arch Allergy Appl Immunol 1989; 90: 22-7.
14 Maran R, Dueymes M, Le Corre R, Renaudineau Y, Shoenfeld YaYP. IgG subclasses of human autoantibodies. Ann Med Interne (Paris) 1997; 148: 29-38.
15 Deckmyn H, Stanssens P, Hoet B, Declerck PJ, Lauwereys M, Gansemans Y, Torna 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.
16 Liu LX, Nardi MA, Nierodzik ML, Karpatkin S. Heterogenous inhibition of platelet aggregation by monoclonal antibodies binding to multiple sites on GPIIIa. Br J Haematol 1995; 91: 976-82.
17 Bhattacharya S, Jordan R, Machin S, Senior R, Mackie I, Smith CR, Schaible TF, Weisman HF, Lahiri A. Blockade of the human platelet GPIIb/IIIa receptor by a murine monoclonal antibody Fab fragment (7E3): Potent dose-dependent inhibition of platelet function. Cardiovasc Drugs Ther 1995; 09: 665-75.
18 Hanson SR, Pareti FI, Ruggeri ZM, Marzec UM, Kunicki TJ, Montgomery RR, Zimmerma TS, Harker LA. Effects of monoclonal antibodies against the platelet glycoprotein IIb/IIIa complex on thrombosis and hemostasis in the baboon. J Clin Invest 1988; 81: 149-58.
19 Krupski WC, Bass A, Kelly AB, Ruggeri ZM, Harker LA, Hanson SR. Interruption of vascular thrombosis by bolus anti-platelet glycoprotein IIb/IIIa monoclonal antibodies in baboons. J Vasc Surg 1993; 17: 294-304.
20 Cadroy YC, 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.
21 Kaku S, Kawasak T, Sakai Y, Taniuch Y, Yano S, Suzuki K, Terazaki C, Kawamura K, Masuho Y, Satoh N, Takenaka T, Yanagi K, Ohsima N. Antithrombotic effect of a humanized anti-GPIIb/IIIa monoclonal antibody, YM207, in a photochemically induced thrombosis model in monkeys. Eur J Pharmacol 1995; 279: 115-21.
22 Hosono M, Sone N, Endo K, Saga T, Kobayashi H, Hosono MN, Sakahara H, Yasunaga K, Konishi J. Kinetics of platelets in dogs with thrombocytopenia induced by antigycoprotein IIb/IIIa receptor monoclonal antibody. Nucl Med Biol 1995; 22: 71-6.
23 Galfre G, Milstein C. Preparation of monoclonal antibodies: Strategies and procedures. Methods Enzymol 1981; 73: 1-46.
24 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.
25 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.
26 Salacinski PRP, McLean C, Sykes JEC, Clement JVV, Lowry PJ. Iodination of proteins, glycoproteins and peptides using a solid-phase oxidizing agent, 1,3,4,6-tetrachloro-3α, 6α -diphenyl glycoluril (Iodogen). Anal Biochem 1981; 117: 131-46.
27 Sawatzke CLaSCC. Fixation and embedding of small volumes of platelets for transmission electron microscopy. J Clin Pathol 1980; 33: 600-2.
28 Dewanjee MK, Rao SA, Didisheim P. Indium-111 tropolone, a new highaffinity platelet label: Preparation and evaluation of labeling parameters. The Journal of Nuclear Medicine 1981; 22: 981-7.
29 Kotzè HF, Heyns Ad, Lötter MG, Pieters H, Roodt JP, Sweetlove A, Badenhorst PN. Comparison of oxine and tropolone methods for labeling human platelets with indium-111. The Journal of Nuclear Medicine 1991; 32: 62-6.
30 Kotzè HF, Lötter MG, Badenhorst PN, Heyns Ad. Kinetics of In-111-platelets in the baboon: I. Isolation and labelling of a viable and representative platelet population. Thromb Haemost 1985; 53: 404-7.
31 van Rensburg AJ, Lötter MG, Heyns Ad, Minnaar PC. An evaluation of four methods of ¹¹¹In planar image quantification. Med Phys 1988; 15: 853-61.
32 Naude H, van Aswegen A, Herbst C, Lötte MG, Pretorius PH. A Monte Carlo evaluation of the channel ratio scatter correction method. Phys Med Biol 1996; 41: 1059-66.
33 ICSH Recommended methods for radioisotope platelet survival studies. Blood 1977; 50: 1137-44.
34 Lötter MG, Rabè Wl, van Zyl JM, Heyns Ad, Wessels P, Kotzè HF, Minnaar PC. A computer program in compiled BASIC for the IBM personal computer to calculate the mean platelet survival time with the Multiple- Hit and Weighted Mean methods. Comp Biol Med 1988; 18: 305-15.
35 Branehog I, Ridel B, Weinfeld A. On the analysis of platelet survival curves and the calculation of platelet production and destruction. Scand J Haematol 1977; 19: 230-41.
36 Lötter MG, Heyns Ad, Badenhorst PN, Wessels P, van Zyl JM, Kotzè HF, Minnaar PC. Evaluation of mathematic models to assess platelet kinetics. J Nucl Med 1986; 27: 1192-201.
37 Suzuki M, Kawakatsu T, Nagata H, Hamamoto K, Iwata K, Ohga S, Nomura S, Kokawa T, Yasunaga K. Effects of injected antibody against the platelet glycoprotein IIb/IIIa complex on monkey platelet fibrinogen. Thromb Haemost 1992; 67: 578-81.
38 McMillan R, Longmire RL, Tavassoli M. In vitro platelet phagocytosis by splenic leukocytes in idiopathic thrombocytopenic purpura. N Engl J Med 1974; 290: 249-51.
39 Tardio DJ, McFarland JA, Gonzalez MF. Immune thrombocytopenic purpura: Current concepts. J Gen Int Med 1993; 08: 160-3.
40 Kaplan C. Idiopathic thrombocytopenic purpura, autoantibodies, autoantigens. An overview. Ann Med Interne (Paris) 1992; 06: 371-3.
41 Moisan A, Le Prise PY, Le Cloirec J, Legall E, Ghandour C, Le Blay R, Herry JY. 111-Indium labeled platelets in thrombocytopenic purpura. Survival and biodistribution studied with scintillation camera. A review of 485 patients. In: Clinical Application of Radiolabelled Platelets. Kessler C. The Netherlands: Kluwer Academic Publishers; 1990: 248-57.
42 Heyns Ad. Platelet kinetics and imaging: techniques and clinical applications. Hematology Reviews 1990; 04: 97-112.
43 Heyns Ad. Thrombopoiesis and platelet kinetics. In: Haemostasis and Thrombosis. Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. New York: Churchill Livingstone; 1994: 31-47.
44 Heyns Ad, Lötter MG, Badenhorst PN, de Kock F, Pieters H, Herbst C, van Reenen OR, Kotzè HF, Minnaar PC. Kinetics and sites of destruction of 111Indium-oxine-labeled platelets in idiopathic thrombocytopenic purpura: a quantitative study. Am J Hematol 1982; 12: 167-77.
45 Heyns Ad. The autoimmune purpuras – a methodological approach. Hematology Reviews 1990; 04: 113-23.
46 Kotzè HF, Heyns Ad, Wessels P, Pieters H, Badenhorst PN, Lötter MG. Evidence that ¹¹¹In-labelled platelets pool in the spleen, but not in the liver of normal humans and baboons. Scand J Haematol 1986; 37: 259-64.
47 Savolainen S, Syrjälä MT, Liewendahl K, Gripenberg J, Nieminen U. Compartmental analysis of short-lived platelet dynamics. Scand J Clin Lab Invest 1990; 50: 697-86.
48 Peters AM, Saverymuttu SH, Bell RN, Lavender JP. The kinetics of short-lived Indium-111 radiolabelled platelets. Scand J Haematol 1985; 34: 137-45.
49 Klonizakis I, Peters AM, Fitzpatrick ML, Kensett MJ, Lewis SM, Lavender JP. Spleen function and platelet kinetics. J Clin Pathol 1981; 34: 377-80.
50 Syrjälä MT, Savolainen S, Nieminen U, Gripenberg J, Liewendahl K, Ikkala E. Splenic dynamics of indium-111 labeled platelets in idiopathic thrombocytopenic purpura. The Journal of Nuclear Medicine 1989; 30: 1546-9.
51 Peters AM, Lavender JP. Platelet kinetics with Indium-111 platelets: comparison with Chromium-51 platelets. Semin Thromb Hemost 1983; 09: 100-14.
52 Nomura S, Yanabu M, Kido H, Fukuroi T, Yamaguchi K, Soga T, Nagata H, Kokawa T, Yasunaga K. Antiplatelet autoantibody-related microparticles in patients with idiopathic (autoimmune) thrombocytopenic purpura. Ann Hematol 1991; 62: 103-7.
53 Nomura S, Kido H, Yamaguchi K, Fukuroi T, Yanabu M, Kawakatsu T, Suzuki M, Kokawa T, Yasunaga K. Platelet activation by antiplatelet autoantibodies in immune thrombocytopenic purpura. Eur J Haematol 1992; 49: 109-10.
54 Nomura S, Yanabu M, Fukuroi T, Kido H, Kawakatsu T, Yamaguchi K, Suzuki M, Kokawa T, Yasunaga K. Anti-glycoprotein IIb/IIIa autoanti-bodies are reversibly internalized into platelets in idiopathic (autoimmune) thrombocytopenic purpura. Autoimmunity 1992; 13: 133-40.
55 Heaton WA, Holme S, Hartman P. Elevated levels of PAIgG in thrombocytopenic patients are not related to the presence of microthrombocytes or megathrombocytes. Am J Clin Pathol 1988; 89: 88-94.
56 Kokawa T, Nomura S, Yasunaga K. Relationship between platelet volume and anti-platelet autoantibodies in idiopathic thrombocytopenic purpura. Eur J Haematol 1991; 47: 104-8.
57 Hattori A, Soga N, Mito M, Koike T, Shibata A. Stress platelets in normal individuals and patients with idiopathic thrombocytopenic purpura. Blood Cells 1992; 18: 281-94.
58 Hauch TW, Rosse WF. Platelet-bound complement (C3) in immune thrombocytopenia. Blood 1977; 50: 1129-36.
59 Kurata Y, Curd JG, Tamerius JD, McMillan R. Platelet-associated complement in chronic ITP. Br J Haematol 1985; 60: 723-33.
60 Kayser W, Mueller-Eckhardt C, Budde U, Schmidt RE. Complement-fixing platelet autoantibodies in autoimmune thrombocytopenia. Am J Hematol 1981; 11: 213-9.
61 Myers TJ, Kim BK, Steiner M, Baldini MG. Platelet-associated complement C3 in immune thrombocytopenic purpura. Blood 1982; 59: 1023-8.
62 Panzer S, Niessne H, Lechner K, Dudcza R, Jäger U, Mayr WR. Plateletassociated immunoglobulins IgG, IgM, IgA and complement C3c in chronic idiopathic autoimmune thrombocytopenia: relation to the sequestration pattern of ¹¹¹Indium labelled platelets. Scand J Haematol 1986; 37: 97-102.