Perspective: Collagen induced platelet activation via the GPVI receptor as a primary target of colchicine in cardiovascular disease

Abstract

Colchicine has been demonstrated to reduce cardiovascular death, myocardial infarction (MI), ischemic stroke, and ischemia-driven coronary revascularization in people with coronary artery disease (CAD). These reductions were observed even in patients already taking antiplatelet therapy. As well as having anti-inflammatory effects, colchicine demonstrates antiplatelet effects. We propose that colchicine's antiplatelet effects primarily target collagen-induced platelet activation via the collagen receptor, glycoprotein (GP)VI, which is critical for arterial thrombosis formation. In settings such as stroke and MI, GPVI signaling is upregulated. We have demonstrated in vitro that therapeutic concentrations of colchicine lead to a decrease in collagen-induced platelet aggregation and alter GPVI signaling. Clinical studies of colchicine given for 6 months lead to a significant reduction in serum GPVI levels in CAD patients, which may ameliorate thrombotic risk. Future evaluation of the effects of colchicine in clinical trials should include assessment of its effects on collagen-mediated platelet activation, and consideration be given to quantifying the contribution of such antiplatelet effects additional to the known anti-inflammatory effects of colchicine.

Keywords: GPVI; cardiovascular disease (CVD); colchicine; platelet activation; stroke.

Figure 1

Schematic of the inhibitory role of colchicine in platelet activation. Colchicine modulates microtubule polymerization, but also leads to a reduction in platelet activation and aggregation. Colchicine does not change GPVI surface expression levels but does result in reduced ROS generation by platelets in response to stimulation of the GPVI receptor by CRP-XL; however, it is not known at what point within the GPVI signaling pathway ROS generation is affected. While the reduction in ROS generation in response to colchicine is specific to the GPVI signaling pathway, reduced activation by colchicine, particularly after stimulation with other agonists such as ADP, may be a microtubule depolymerization dependent effect. Whether colchicine directly interacts with the platelet GPVI receptor or acts exclusively downstream of this receptor is unknown. Created with Biorender.com (, , –58).