Direct and indirect antithrombins: Heparins, low molecular weight heparins, heparinoids, and hirudin

With the eclipse of UH by newer anticoagulants, the field has opened up to search for new and better drugs. Hirulog or bivalirudin is another direct antithrombin that has been used in initial trials. It is smaller than hirudin, at 20 amino acids. Currently under investigation, it seems to have a short half-life, a narrow therapeutic window, and a reverse dose effect, with lower levels achieving better cardiac post-thrombolysis patency than higher doses. Other antithrombins being examined are the hirudisins, where four amino acids of hirudin have been replaced by the RGDS integrin-binding sequence and thrombin receptor antagonist peptides. In addition, many other inhibitors of activated clotting factors are being studied for future therapeutic value. Tick anticoagulant protein studies are underway, as are studies on a group of benzamidine isoxazoline derivates, which are direct Xa inhibitors. We are truly at an age of discovery with the newer anticoagulants and it may take many years until we can distinguish the advantages and disadvantages of all the newer therapies. It looks like an ever more real possibility that medicine may find an antithrombotic regimen that is highly effective, highly reversible, and nontoxic.