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.
