Comparison of common platelet receptors between the chacma baboon (Papio ursinus) and human for use in pre-clinical human-targeted anti-platelet studies

Abstract

Anti-platelet agents play a central part in the treatment and prevention of acute thrombotic events. Discriminating animal models are needed for the development of novel agents. The chacma baboon has been extensively used as a model to evaluate anti-platelet agents. However, limited data exist to prove the translatability of this species to humans. We aimed to determine the suitability of the chacma baboon in preclinical human targeted GPIIb/IIIa, GPIbα and P2Y12 studies. Light-transmission platelet aggregometry (LTA), whole blood impedance aggregometry, receptor number quantification and genomic DNA sequencing were performed. Baboon ADP and arachidonic acid-induced LTA aggregation results differed significantly from human values, even at increased concentrations. LTA ristocetin-induced agglutination was comparable between species, but baboon platelets needed twice the concentration of ristocetin to elicit a similar response. Citrated baboon blood had significantly less aggregation than humans when evaluated with impedance aggregometry. However, hirudinised baboon whole blood gave similar aggregation as humans at the same agonist concentrations. GPIIb, GPIIIa and GPIbα numbers were significantly more on the baboon platelets. None of the amino acids deemed vital for receptor function, ligand binding or receptor inhibition, were radically different between the species. However, a conservative change in a calcium-binding region of GPIIb may render the baboon platelets more sensitive to calcium-binding agents. The chacma baboon may be used for the evaluation of human-targeted GPIIb/IIIa-, GPIbα- and P2Y12-inhibiting agents. However, the best anticoagulant, optimal agonist concentrations, increase in receptor number and sequence differences must be considered for any future studies.

Keywords:

• Anti-platelet studies
• chacma baboon
• platelet receptors

Acknowledgements

The author acknowledges Dr. Daleen Struwig, medical writer, Faculty of Health Sciences, University of the Free State, for assistance with technical and editorial preparation of the manuscript; and Ms Marissa Butler and Mr Riaan van Zyl for assisting with the laboratory work; and Mr Jan Roodt and Mr Seb Lamprecht for animal handling. Dr. Mike Mitchell is acknowledged for his assistance with sequencing. Prof. Karen Vanhoorelbeke is acknowledged for graciously supplying the 6B4 antibody.

Declaration of interests

The authors have no conflict of interest to declare. The research was funded by a National Health Laboratory Services (NHLS) Research Trust grant.

Human subject statement

Ethics approval was granted by the Ethics Committee at the Faculty of Health Sciences of the University of the Free State, Bloemfontein, South Africa (ECUFS #134/2011). All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all participants for being included in the study.

Animal subject statement

Animal ethics approval was granted by the Interfaculty Control Committee on Animal Experimentation of the University of the Free State, Bloemfontein, South Africa (Animal Experiment #18/2011 and #21/2013). The guidelines and requirements of this committee are in accordance with the South African National Standard for the care and use of animals for scientific research (document SANS 10386 of 2008).