Over the past decade, continuous-flow rotary pumps have dramatically improved survival for patients with advanced systolic heart failure. Bleeding and thrombosis, however, continue to be the Achilles heel of left ventricular assist device (LVAD) therapy. There is a dynamic and complex interaction between the patient and pump. The net effect of a variety of hematologic derangements, such as hemolysis, high-molecular-weight von Willebrand degradation, platelet activation and diminished pulsatility, is poorly understood. A combination of these factors mediates the common adverse events of gastrointestinal bleeding, device thrombosis and stroke. In this review we incorporate information from translational investigations in LVAD patients to understand how continuous-flow pumps activate the coagulation system and platelets predisposing to thrombosis, while, in parallel, degrade high-molecular-weight von Willebrand factor and trigger abnormal angiogenesis predisposing to bleeding. Finally, we propose novel strategies to develop a personalized approach to anti-thrombotic monitoring and titration of anti-coagulants to minimize the bleeding and thrombotic event rates of future LVAD recipients.