Thromboinflammation: an important pathogenic process linked to a diverse range of human diseases. (A) A broad spectrum of human disorders is associated with thromboinflammatory complications, many of which have microvascular dysfunction. It is likely that the level of α-thrombin generation is a key determinant of the extent of the thromboinflammatory response. For example, diseases such as sepsis, ischemia reperfusion (IR) injury (the focus of this review), and organ transplant rejection are associated with widespread activation of coagulation throughout the microcirculation, which is accompanied by an intense thrombotic and inflammatory response. At the extremes of this spectrum, the microvascular thrombotic disorder thrombotic thrombocytopenia purpura (TTP) exhibits limited α-thrombin generation and is associated with a limited inflammatory response in the early phase of the disease. At the other end of the spectrum, autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), are primarily considered inflammatory disorders, with a limited role for α-thrombin. Nonetheless, other hemostatic components appear to contribute to the pathogenesis of these diseases. (B) Tissue or organ injury by diverse pathogenic mechanisms is commonly associated with microvascular thromboinflammatory responses. Microvascular obstruction can be mediated by all cellular elements in blood, including platelets, neutrophils, and red blood cells (RBCs), with stable occlusion typically linked to the activation of coagulation and fibrin generation. Regardless of the primary insult to tissues or organs (infection, ischemia, or trauma), the ultimate outcome of these disorders is heavily influenced by the extent of the microvascular thrombotic and inflammatory responses. EC, endothelial cell; HUS, hemolytic-uremic syndrome; NO, nitric oxide; TRALI, transfusion-related acute lung injury.