Platelets and Microtubules

Abstract

A B S T R A C T We examined the role of microtubules in platelet aggregation and secretion (release reaction) induced by the calcium ionophore A23187 (0. 8-5 ,uM). At these concentrations, platelet aggregation was preceded by a lag period of -1 min. Colchicine (an agent that disrupts microtubule assembly-disassembly) was shown to bind to platelet microtubules by employing [3H]colchicine at a concentration that is specific for microtubules in other tissues (10 nM). Colchicine prolonged the lag period, inhibited the secondary wave of platelet aggregation, and inhibited the release reaction (release of[14C]serotonin). Platelets were next incubated with 20-60% D20, an agent that stabilizes microtubules. D20 overcame colchicineinduced inhibition of the lag period, aggregation, and release. D20 alone enhanced platelet aggregation by 59+14% (SEM) and shortened the lag period by 43+10%. We conclude that functioning microtubules are required for platelet aggregation and release, and that microtubules of platelet preparations are functioning submaximally.

Effect of Colchicine on Platelet-Platelet and Platelet-Leukocyte Interactions: a Pilot Study in Healthy Subjects

“…This finding is consistent with a study by Karpatkin et al that demonstrated a decrease in platelet aggregation in response to ADP, epinephrine, and collagen when PRP was pre-incubated for 2 minutes with 250 μM to 2000 μM colchicine but not at lower concentrations [4]. Moreover, Bouaziz et al observed a decrease in microtubular content and tubulin polymerization when thrombin-stimulated platelets were pre-incubated for a longer time period (120 minutes) with 10 μM to 1000 μM colchicine, but demonstrated a modest 20% decrease in platelet aggregation only when these platelets were treated with 100 μM to 1000 μM colchicine [14].…”

“…Mechanistic in vitro studies suggest that therapeutic concentrations of colchicine bind to platelet tubulin and modulate microtubular associated protease, which in turn either prevents phosphoprotein synthesis or degrades existing phospoproteins required for microtubular polymerization [4,15]. Based on our study, this putative mechanism of action may not translate into functional effects on platelet aggregation in the setting of therapeutic oral colchicine administration.…”

“…The cardioprotective mechanisms of colchicine have not been fully elucidated. Microtubules support the discoid shape of platelets and may play a role in platelet activation [4–8]. Colchicine disrupts microtubule polymerization and dissociation, and thus may inhibit platelet activation.…”

“…Colchicine disrupts microtubule polymerization and dissociation, and thus may inhibit platelet activation. The effect of colchicine on platelet activity is currently limited to in vitro studies or examination of platelet aggregation in clinical models [4–8]. The aim of the current study was to evaluate the effects of colchicine both in vitro and in vivo in healthy human subjects, with particular regard to homotypic versus platelet-leukocyte interactions.…”

Anti-inflammatory therapy for COVID-19 infection: the case for colchicine

“…29 47 At supratherapeutic concentrations, colchicine, through its microtubule effects, converts normal discoid platelets to rounded, irregular structures and inhibits platelet activation by decreasing calcium entry. 48 These mechanisms diminish in vitro platelet-to-platelet aggregation. In contrast, we demonstrated that standard clinical doses of colchicine do not decrease platelet-to-platelet aggregation but do diminish neutrophil-toplatelet aggregation, 49 suggesting that colchicine at physiological doses may provide an inhibitory role at the inflammation/ thrombosis interface without comprising homeostatic plateletto-platelet function.…”