Heart failure (HF) is a public health burden. In the next ten years, 8 million Americans are expected to have HF. A subset of these patients will develop advanced HF. They are refractory to medical therapies and have limited treatment options, including heart transplantation or a left ventricular assist device (LVAD). Heart transplants for all advanced HF patients are impractical due to the scarcity of donors. LVAD therapy is the sole viable option for advanced HF patients as a bridge to transplant, a temporary treatment while the heart recovers, and a long-term destination therapy. Over the last two decades, significant progress in LVADs have been made through various iterations. Advances in LVADs have been due to redesign focused on lowering adverse events. However, bleeding and infections are still the most prevalent adverse complications. LVADs and other mechanical circulatory support devices induce damage to blood cells and plasma components due to the high mechanical shear stress (HMSS) generated. Therefore, there must be a link between LVAD-induced cellular damage and the adverse events experienced in LVAD patients. This dissertation aimed to investigate the relationship between cellular blood damage and LVAD-associated complications and qualify the extent of cellular damage/defects and functional alterations.The overall objective of this dissertation was to investigate the acquired cellular defects of platelets and neutrophils in blood after shear stress exposure. This objective was accomplished through in-vivo, in-vitro, and in-silico studies. The in-vivo studies examined the shear stress-induced injury of platelets in LVAD recipients and linked the adverse bleeding events (Chapter 3). The in-vitro studies explored the shear stress-induced injury of leukocytes (Chapter 4). The extent of the structural damage and functional alterations related to shear stress level and the exposure time was quantified (Chapter 5 and Chapter 6). Finally, the in-silico studies developed a simulation of leukocyte function with experimental data that was used to predict the extent of the shear stress-induced leukocyte function change (Chapter 6). The damaging effects of the high shear stress produced by mechanical circulatory support devices such as LVADs were conveyed through an integrated biological and engineering approach.