What does Bivalirudin (direct thrombin inhibitor) inhibit?

Bivalirudin Mechanism of Action

Bivalirudin directly inhibits thrombin (factor IIa) by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. 1

Direct Thrombin Inhibition

• Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin and inhibits clot-bound thrombin, distinguishing it from indirect thrombin inhibitors like heparin that require cofactors. 2

• The drug binds bivalently to thrombin at two distinct sites: the active catalytic site and the fibrinogen-binding site (anion-binding exosite I), providing high affinity and specificity for thrombin. 1, 3

• Unlike heparin-based anticoagulants, bivalirudin does not require plasma cofactors such as antithrombin for its anticoagulant effect, making it a true direct thrombin inhibitor with predictable pharmacokinetics. 4

Reversible Binding Mechanism

• The binding of bivalirudin to thrombin is reversible because thrombin slowly cleaves the bivalirudin-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions after drug discontinuation. 1

• This reversible mechanism allows for gradual restoration of thrombin activity, with coagulation times returning to baseline approximately 1 hour following cessation of bivalirudin administration. 1

Clinical Implications of Mechanism

• Bivalirudin inhibits both free circulating thrombin and fibrin-bound thrombin, a critical advantage over heparin which cannot effectively inhibit thrombin once it is bound to fibrin or subendothelial collagen. 5, 3

• The drug effectively inhibits thrombin-mediated platelet aggregation by blocking both protease activated receptor 1 and 4 (PAR 1 and PAR 4). 3

• Bivalirudin does not bind to plasma proteins (except thrombin) or red blood cells, contributing to its predictable anticoagulant response without the variability seen with heparin. 1, 4

Pharmacodynamic Effects

• Bivalirudin exhibits dose- and concentration-dependent anticoagulant activity as evidenced by prolongation of ACT, aPTT, PT, TT, and INR. 1

• Intravenous administration produces an immediate anticoagulant effect with onset of action at 2-4 minutes. 6

• The drug has a short half-life of approximately 25 minutes in patients with normal renal function, with elimination occurring predominantly through proteolytic cleavage (80% enzymatic, 20% renal). 6, 1