The tetrapeptide Phe-Asn-Pro-Arg (SEQ ID NO: 3) is a structurally-optimized sequence for binding to the active site of thrombin. By conjugating this tetrapeptide or variants thereof to a C-terminal fragment of hirudin, we were able to generate a series of new multivalent inhibitors of thrombin containing only genetically encodable natural amino acids. We found that synergistic binding to both the active site and an exosite of thrombin can be enhanced through substitutions of amino acid residues at the P.sub.4, P.sub.3 and P.sub.3' sites of the active-site directed sequence, Xaa (P.sub.4)-Yaa (P.sub.3)-Pro (P.sub.2)-Arg (P.sub.1)-Pro(P.sub.1')-Gln(P.sub.2')-Zaa(P.sub.3'). Complementary to rational design, a phage library was constructed to explore further the residue requirements at the P.sub.4, P.sub.3 and P.sub.3' sites for multivalent and optimized bridge-binding. Panning of the phage library has led to thrombin-inhibitory peptides possessing strong anti-cloning activities in the low nanomolar range and yet interfering only partially with the catalytic active site of thrombin. In all, the availability of potent and genetically-encodable polypepticle inhibitors of thrombin opens the door for much wider applications of this clinically-successful class of anticoagulants, e.g. through more cost-effective recombinant peptide production, in areas such as gene therapy as well as to improve clinical efficacy/safety through the incorporation of homing peptides for targeted delivery.