Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates

Nancy Cauwenberghs, Muriel Meiring, Stephan Vauterin, Veronika Van Wyk, Seb Lamprecht, Jan P. Roodt, Levente Novák, J. Hársfalvi, Hans Deckmyn, Harry F. Kotzé

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Platelet adhesion in arterial blood flow is mainly supported by the platelet receptor glycoprotein (GP) Ib, which interacts with von Willebrand factor (vWF) that is bound to collagen at the site of vessel wall injury. Antibody 6B4 is a monoclonal antibody (MoAb) raised against purified human GPIb. MoAb 6B4 inhibits both ristocetin- and botrocetin-induced, vWF- dependent human platelet agglutination. MoAb 6B4 furthermore blocks shear- induced adhesion of human platelets to collagen I. We studied the antithrombotic effect of this inhibitory murine MoAb 6B4 in a baboon model of arterial thrombosis. When injected into baboons, intact IgG and its F(ab')2 fragments caused almost immediate thrombocytopenia, whereas injection of the Fab fragments alone did not. Fab fragments were subsequently used to investigate their in vivo effect on platelet deposition onto a thrombogenic device, consisting of collagen-rich, glutaraldehyde-fixed bovine pericardium (0.6 cm2), at a wall shear rate ranging from 700 to 1000 s-1. Baboons were either pretreated with Fabs to study the effect of inhibition on platelet adhesion or treated 6 minutes after placement of the thrombogenic device to investigate the effect on interplatelet cohesion. Pretreatment of the animals with bolus doses ranging from 80 to 640 μg/kg Fab fragments significantly reduced 11 In-labeled platelet deposition onto the collagen surface by ≃43% to 65%. Only the highest dose caused a significant prolongation (doubling) of the bleeding time. Ex vivo ristocetin-induced platelet agglutination was equally reduced. Treatment with a bolus of 110 μg/kg Fab fragments after a thrombus was allowed to form for 6 minutes had no effect on further platelet deposition. We therefore conclude that Fab fragments or derivatives of inhibitory anti-GPIb antibodies may be useful compounds to prevent thrombosis.

Original languageEnglish
Pages (from-to)1347-1353
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume20
Issue number5
Publication statusPublished - May 2000

Fingerprint

Platelet Glycoprotein GPIb-IX Complex
Platelet Membrane Glycoproteins
Immunoglobulin Fragments
Immunoglobulin Fab Fragments
Blocking Antibodies
Primates
Blood Platelets
Monoclonal Antibodies
Papio
Collagen
Ristocetin
Thrombosis
Agglutination
von Willebrand Factor
Equipment and Supplies
Bleeding Time
Pericardium
Glutaral
Thrombocytopenia
Anti-Idiotypic Antibodies

Keywords

  • Glycoprotein Ib
  • Monoclonal antibodies
  • Platelet adhesion
  • Platelet aggregation
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Cauwenberghs, N., Meiring, M., Vauterin, S., Van Wyk, V., Lamprecht, S., Roodt, J. P., ... Kotzé, H. F. (2000). Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. Arteriosclerosis, Thrombosis, and Vascular Biology, 20(5), 1347-1353.

Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. / Cauwenberghs, Nancy; Meiring, Muriel; Vauterin, Stephan; Van Wyk, Veronika; Lamprecht, Seb; Roodt, Jan P.; Novák, Levente; Hársfalvi, J.; Deckmyn, Hans; Kotzé, Harry F.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 20, No. 5, 05.2000, p. 1347-1353.

Research output: Contribution to journalArticle

Cauwenberghs, N, Meiring, M, Vauterin, S, Van Wyk, V, Lamprecht, S, Roodt, JP, Novák, L, Hársfalvi, J, Deckmyn, H & Kotzé, HF 2000, 'Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 5, pp. 1347-1353.
Cauwenberghs, Nancy ; Meiring, Muriel ; Vauterin, Stephan ; Van Wyk, Veronika ; Lamprecht, Seb ; Roodt, Jan P. ; Novák, Levente ; Hársfalvi, J. ; Deckmyn, Hans ; Kotzé, Harry F. / Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2000 ; Vol. 20, No. 5. pp. 1347-1353.
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