Alpha-2-macroglobulin (A2M) is an antiproteinase that plays different roles in hemostasis. A2M is a homo-tetrameric glycoprotein of high molecular weight highly conserved throughout evolution. Proteinase inhibitor activity of A2M is possible via a unique cage structure able to trap proteinase without having any direct inhibition regarding enzymatic activity. Clearance of trapped proteinase is achieved through A2M binding to the low-density lipoprotein receptor-related protein 1: LRP1. A2M synthesis is controlled by pro-inflammatory cytokines and increases in several chronic or acute inflammatory diseases and also varies with age. A2M can trap several proteinases involved in both coagulation and fibrinolysis, thus acting as a trigger and inhibitor of hemostasis. A2M is able to inhibit thrombin, factor Xa, activated protein C, plasmin, tissue-plasminogen activator and urokinase. A2M is usually poorly envisioned in hemostasis balance regulation. A2M plasma concentration are differently regulated during inflammatory-related diseases. It can also neutralize cytokines that are known to modify hemostasis as well. In this review, we propose to summarize known functions of A2M focusing on the roles of this antiproteinase in hemostasis and thrombosis.