**3.3. Irudin, lepirudin, desirudin, bivalirudin, and argatroban**

Hirudin is a direct thrombin inhibitor (DTI) derived from the salivary secretions of leech (*Hirudo medicinalis*). Lepirudin and desirudin are two forms of recombinant hirudin, structurally identical except for minute differences in the amino-terminus sequence [59]. Unlike heparin and others anticoagulants, DTIs do not need antithrombin to perform its anticoagulant action: epirudin and desirudin form a bivalent irreversible complex with thrombin, while hirudin binds to both the active site as well as to exosite I on thrombin.

Lepirudin and desirudin have been evaluated for the prevention and treatment of VTE and in patients with acute coronary syndrome (ACS). These drugs are generally more effective than heparin in prevention of thrombosis but lead to more bleeding complications possibly related to their irreversible binding to thrombin [60]. Their indications of use comprehend: treatment and prevention of suspected or proven HIT; VTE prophylaxis after hip or knee arthroplasty. Lepirudin and desirudin are administered intravenously or subcutaneously and have a half-life of 80 and 60–120 minutes, respectively. The excretion is totally renal. Due to their narrow therapeutic range, therapy monitoring should be done regularly through aPTT, activated clotting time (ACT), and anti-Xa assay evaluation.

Bivalirudin is used in treatment of patients with unstable angina undergoing PCI even if at risk of HIT. This is a synthetic analog of hirudin that forms a reversible, high-affinity complex with thrombin [61]. Consequently, bivalirudin has a shorter half-life (25 minutes) and is a weaker thrombin inhibitor compared to hirudin, with a potentially larger therapeutic window. Its clearance is for 80% enzymatic and for 20% renal. Bivalirudin is now one of the preferred drugs for patients undergoing PCI in American and European guidelines, and it has become one of the most widely used antithrombotics in the USA for PCI [62].

Argatroban is a small, univalent competitive inhibitor of thrombin. It binds selectively and reversibly to the active site of thrombin and has a short elimination half-life of 50 min through hepatobiliary clearance. Since it is metabolized in the liver, it should be used with caution in patients with liver failure. Argatroban has been approved for the prevention and treatment of VTE in patients with HIT [46, 47] and for patients with (a history of) HIT who need to undergo PCI [46, 63].
