Clofazimine, but not isoniazid or rifampicin, augments platelet activation in vitro

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dc.contributor.author Anderson, Ronald
dc.contributor.author Theron, Annette J.
dc.contributor.author Nel, Jan Gert
dc.contributor.author Durandt, Chrisna
dc.contributor.author Cholo, Moloko C.
dc.contributor.author Feldman, Charles
dc.contributor.author Tintinger, Gregory Ronald
dc.date.accessioned 2019-10-07T15:08:42Z
dc.date.available 2019-10-07T15:08:42Z
dc.date.issued 2018-11-20
dc.description.abstract Although the inclusion of the cationic amphiphilic, anti-mycobacterial agent, clofazimine, in the chemotherapeutic regimens of patients with multidrug-resistant tuberculosis (TB) has contributed to improved outcomes, concerns remain about the cardiotoxic potential of this agent. Accordingly, the current study was undertaken with the primary objective of investigating the effects of clofazimine, on the reactivity of human platelets in vitro, a seemingly unexplored, mechanism of cardiotoxicity. Platelet-rich plasma (PRP) prepared from the blood of healthy, adult humans was treated with clofazimine (0.625– 10 mg/L), or the primary anti-TB agents, isoniazid and rifampicin (at final concentrations of 5 and 10 mg/L), followed by addition of either adenosine 50-diphosphate (ADP) or thrombin and measurement of platelet activation according to the magnitude of expression of CD62P (P-selectin), as well as the CD62P-mediated formation of heterotypic neutrophil:platelet (NP) aggregates, using flow cytometry. Clofazimine, but neither isoniazid nor rifampicin, caused dose-related potentiation of both ADP- and thrombin-activated expression of CD62P by platelets, achieving statistical significance at threshold concentrations of 0.625 and 2.5 mg/L, respectively, as well as significant formation of N:P aggregates. These stimulatory effects of clofazimine on platelet activation were partly attenuated by pre-treatment of PRP with the membrane-stabilizing agent, a-tocopherol, possibly consistent with a membrane-disruptive mechanism. In conclusion, clofazimine, at concentrations within the therapeutic range, augments platelet activation in vitro, probably by a mechanism linked to membrane destabilization. If operative in vivo, these pro-thrombotic activities of clofazimine may predispose for development of microvascular occlusion, exacerbating an already existing high risk for development of TB-associated cardiovascular disease. en_ZA
dc.description.department Haematology en_ZA
dc.description.department Immunology en_ZA
dc.description.department Internal Medicine en_ZA
dc.description.librarian am2019 en_ZA
dc.description.sponsorship The National Research Foundation of South Africa (CF, ongoing support) and The National Health Laboratory Service of South Africa Research Trust (MC, Grant 004 94648). en_ZA
dc.description.uri http://www.frontiersin.org/Pharmacology en_ZA
dc.identifier.citation Anderson R, Theron AJ, Nel JG, Durandt C, Cholo MC, Feldman C and Tintinger GR (2018) Clofazimine, but Not Isoniazid or Rifampicin, Augments Platelet Activation in vitro. Front. Pharmacol. 9:1335. DOI: 10.3389/fphar.2018.01335. en_ZA
dc.identifier.issn 1663-9812 (online)
dc.identifier.other 10.3389/fphar.2018.01335
dc.identifier.uri http://hdl.handle.net/2263/71605
dc.language.iso en en_ZA
dc.publisher Frontiers Media en_ZA
dc.rights © 2018 Anderson, Theron, Nel, Durandt, Cholo, Feldman and Tintinger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). en_ZA
dc.subject Adenosine 50-diphosphate en_ZA
dc.subject Clofazimine en_ZA
dc.subject Isoniazid en_ZA
dc.subject Neutrophils en_ZA
dc.subject Platelets en_ZA
dc.subject P-selectin en_ZA
dc.subject Rifampicin en_ZA
dc.subject Thrombin en_ZA
dc.subject Tuberculosis (TB) en_ZA
dc.title Clofazimine, but not isoniazid or rifampicin, augments platelet activation in vitro en_ZA
dc.type Article en_ZA


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