The present invention relates to analogues of anti-thrombin polypeptides and to a process for their preparation. The analogues have been obtained by a C-terminal modification of anti-thrombin polypeptides isolated from the leech Hirudinaria manillensis and are characterized by an improved biological activity in comparison to the polypeptides from which they are derived. The analogues of the invention may be prepared by: 1) isolating the anti-thrombin polypeptide from the tissue or secretions of the leech Hirudinaria manillensis and 2) subsequently modifying the C-terminal end of such polypeptide. Alternatively, the analogues may also be synthetized by recombinant DNA methods. According to this latter aspect, the invention provides DNA sequences, expression vectors and host cell lines for the recombinant preparation of the analogues. The analogues of the invention find a useful application in the treatment of venous thrombosis, vascular shunt occlusion and thrombin-induced disseminated intravascular coagulation.