The blood coagulation system plays a critical role in maintaining the delicate thrombohemorrhagic balance in the body. Nanoparticles in the bloodstream can encounter and interact with one or more components of the coagulation system, which potentially interfere with the hemostatic balance in unintended ways, causing lethal complications. A thorough understanding of the interface between nanoparticles and the coagulation system is valuable for the engineering and the successful translation of nanoparticles into the clinic. Herein, we discuss the roles of each component of the coagulation system and possible influences of nanoparticles on them, focusing on underlying molecular mechanisms. We also cover common in vitro methods to access the effect of nanoparticles on coagulation as well as changes in nanoparticles parameters that are correlated to alterable interference in blood coagulation. Further, engineered nanoparticles with their two-side effects for the desirable alteration of hemostasis have been briefly addressed.