Inflammation involves multiple molecular, humoral and cellular mechanisms that aim to protect the body from injury or infection by the tight orchestration of immune cell trafficking, interactions and activation. Platelets and neutrophils are major players in the initial thromboinflammatory response by rapidly responding to a variety of danger signals. When the intensity, timing or locations of these responses are uncontrolled, however, they can trigger localized or systemic injury. Studies over the past decades have revealed that during the normal inflammatory response, blood elements frequently interact with each other to form heterotypic aggregates. The formation of these aggregates within blood vessels, in turn, underlies injury in several models of acute inflammation and can in some instances lead to death. These phenomena are likely to have a bigger contribution to the outcome of inflammatory processes than previously expected, not only in acute scenarios but also in those that involve chronic vascular damage, such as atherosclerosis. We will review here the molecular mediators of these interactions and their consequences in the context of cardiovascular injury.