Hirudin is the most potent and specific thrombin inhibitor and is derived from the medicinal leech. It is reported to inhibit thrombin with an equilibrium dissociation constant (K.sub.i) value of 2.2.times.10.sup.-14 M. synthetic thrombin inhibitors have been designed based on the hirudin sequence but with a dramatically reduced size. The bulky active site inhibitor segment, hirudin.sup.1-48, has been substituted by small non-substrate type active site inhibitors of thrombin, e.g., dansyl-Arg-(D-pipecolic acid). The linker segment has also been modified using a combination of .omega.-amino acids to reduce the molecular weight but retaining sufficient length to span the two principal binding domains. Among the inhibitors designed, dansyl-Arg-(D-pipecolic acid)-(12-aminododecanoic acid)-4-aminobutyric acid)-Asp-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-(L-.beta.-cyclohexylalamine)-(D-Glu)-OH (SEQ ID NO:45) showed the highest affinity and displays a competitive-type inhibition. The incorporation of the non-substrate type active site inhibitor segment and the linker of .omega.-amino acids into the bivalent thrombin inhibitors not only improved in vitro thrombin inhibitory activity to the pM level, overcame proteolytic susceptibility at the level of the "normal" scissile bond and confered high in vivo activity.