Dissociating mechanical from biochemical platelet activation: dimethyl sulfoxide modulates the platelet membrane to attenuate shear-mediated activation

Abstract Patients supported by implantable cardiovascular devices, including stents, prosthetic valves, and mechanical circulatory support systems, remain vulnerable to thromboembolic complications despite modern antithrombotic therapy. A central contributor is shear-mediated platelet activation, which differs in phenotype and pharmacologic sensitivity from activation induced by conventional biochemical agonists. Here we tested whether the platelet membrane can be perturbed to reduce shear-mediated activation, using dimethyl sulfoxide (DMSO) as a membrane-active probe. Gel-filtered platelets treated with DMSO were exposed to constant, dynamic ventricular-assist-device, and hyper-shear waveforms and assessed for thrombin generation, phosphatidylserine externalization, morphology, ultrastructure, and membrane probe anisotropy. DMSO at concentrations of 15% (v/v) or less reduced the measured shear-induced Platelet Activity State (PAS) across the tested shear regimes without overt membrane fragmentation under the tested conditions. Membrane anisotropy changed in a concentration-dependent, nonmonotonic pattern that coincided with the inhibitory concentration range. After shear exposure, DMSO-treated platelets retained a measurable arachidonic-acid-induced aggregatory response under the conditions tested. These findings provide functional evidence that shear-induced procoagulant activity can be attenuated while arachidonic-acid-induced activity remains detectable in the same platelet population, and they support membrane perturbation as a general strategy for studying, and potentially targeting, mechanically induced platelet responses, with membrane lipids such as cholesterol representing a plausible next class of fluidity-modulating agents.