Thrombosis with associated inflammation (thromboinflammation) occurs commonly in a broad range of human disorders. It is well recognized clinically in the context of superficial thrombophlebitis (thrombosis and inflammation of superficial veins); however, it is more dangerous when it develops in the microvasculature of injured tissues and organs. Microvascular thrombosis with associated inflammation is well recognized in the context of sepsis and ischemia-reperfusion injury; however, it also occurs in organ transplant rejection, major trauma, severe burns, the antiphospholipid syndrome, preeclampsia, sickle cell disease, and biomaterial-induced thromboinflammation. Central to thromboinflammation is the loss of the normal antithrombotic and anti-inflammatory functions of endothelial cells, leading to dysregulation of coagulation, complement, platelet activation, and leukocyte recruitment in the microvasculature. α-Thrombin plays a critical role in coordinating thrombotic and inflammatory responses and has long been considered an attractive therapeutic target to reduce thromboinflammatory complications. This review focuses on the role of basic aspects of coagulation and α-thrombin in promoting thromboinflammatory responses and discusses insights gained from clinical trials on the effects of various inhibitors of coagulation on thromboinflammatory disorders. Studies in sepsis patients have been particularly informative because, despite using anticoagulant approaches with different pharmacological profiles, which act at distinct points in the coagulation cascade, bleeding complications continue to undermine clinical benefit. Future advances may require the development of therapeutics with primary anti-inflammatory and cytoprotective properties, which have less impact on hemostasis. This may be possible with the growing recognition that components of blood coagulation and platelets have prothrombotic and proinflammatory functions independent of their hemostatic effects.