Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation - mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device - ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers - before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device 'thrombogenic footprint', indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops - before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology - demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization - indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.