Bivalirudin is a synthetic, bivalent direct thrombin inhibitor peptide. It was rationally designed based on the structure of hirudin, the potent natural thrombin inhibitor found in leech saliva, to create a more controllable anticoagulant for clinical use. Its development represented a significant advance in anticoagulant therapy, offering a reversible, short-acting alternative to heparin with a potentially improved safety profile regarding heparin-induced thrombocytopenia. Bivalirudin has become a significant peptide drug, primarily used as an anticoagulant during percutaneous coronary interventions (PCI) and in patients with acute coronary syndromes.
Quick Facts
| Also Known As | Angiomax, Hirulog, BG8967 |
|---|---|
| Sequence | H-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH |
| Molecular Formula | C98H138N24O33 |
| Molecular Weight | 2180.3 Da |
| PubChem CID | 16129704 |
Research Parameters
| Half-Life | ~25 minutes in patients with normal renal function. |
|---|---|
| Stability | Lyophilized powder is stable when stored as recommended. After reconstitution with Sterile Water for Injection, the solution is stable for up to 24 hours at 2-8°C. Solutions diluted in infusion fluids are stable for up to 24 hours at room temperature. |
| Solubility | Sterile Water for Injection, 0.9% Sodium Chloride Injection (normal saline) |
| Vial Size | 250 mg |
| Storage (Lyophilized) | Store at 2-8°C (36-46°F). Protect from light. |
| Storage (Reconstituted) | Store at 2-8°C (36-46°F) and use within 24 hours. Do not freeze. |
| Typical Research Dose | Clinical dosing is in mg/kg. Research animal model doses vary widely and are species-specific (e.g., in rodent thrombosis models, doses may range from 1-10 mg/kg). |
| Cycle Parameters | In clinical research (PCI), administration is a single bolus plus continuous infusion for the duration of the procedure (typically 1-2 hours). For medical management studies, continuous infusion may last up to 72 hours. No cyclical 'on/off' protocol is used. |
| Amino Acid Count | 23 |
Mechanism of Action
Bivalirudin is a bivalent direct thrombin inhibitor that binds simultaneously to both the active catalytic site and the substrate recognition exosite 1 of thrombin. This dual binding results in potent, specific, and reversible inhibition of both circulating (fluid-phase) and clot-bound (fibrin-bound) thrombin.
Catalytic Site Inhibition: The N-terminal D-Phe-Pro-Arg-Pro segment binds reversibly to the active catalytic site of thrombin, competitively inhibiting its enzymatic activity on substrates like fibrinogen.
Exosite 1 Inhibition: The C-terminal segment, which is derived from hirudin, binds with high affinity to anion-binding exosite 1 (ABE-1) of thrombin. This binding disrupts thrombin's interaction with its physiological substrates, such as fibrinogen and platelet thrombin receptors.
Reversible Action: Unlike hirudin, bivalirudin's interaction with the catalytic site is reversible. Thrombin slowly cleaves the Arg-Pro bond within the bivalirudin sequence, releasing the N-terminal fragment and restoring active site function, while the C-terminal fragment remains weakly bound to exosite 1. This provides a transient, self-reversing anticoagulant effect.
Research Applications
Cardiovascular Research: Bivalirudin is extensively studied as an anticoagulant in models of percutaneous coronary intervention (PCI), acute coronary syndromes, and coronary artery bypass grafting. Research focuses on its efficacy compared to heparin plus glycoprotein IIb/IIIa inhibitors, particularly in reducing bleeding complications and the risk of heparin-induced thrombocytopenia (HIT).
Thrombosis Models: Used in preclinical and clinical research to understand the dynamics of thrombin inhibition, especially regarding the inhibition of clot-bound thrombin, which is less effectively targeted by heparin. Studies investigate its role in preventing arterial and venous thrombosis.
Coagulation Biochemistry: Serves as a key tool compound in biochemical research to dissect the structure-function relationships of thrombin, the kinetics of bivalent inhibition, and the physiological roles of thrombin's exosite interactions.
Safety & Side Effects
The primary risk from clinical studies is bleeding, consistent with its anticoagulant mechanism. Major bleeding events are reported but generally at a lower rate compared to heparin-based regimens. Other reported side effects include back pain, nausea, headache, and hypotension. In patients with renal impairment, clearance is reduced, requiring dose adjustment. Anecdotal reports are minimal as it is a clinically regulated drug. Theoretical concerns include the risk of thrombosis if infusion is stopped abruptly in certain high-risk settings (e.g., PCI without adequate antiplatelet cover).
Dosage Information
The following information is derived from clinical and research studies and is presented for educational purposes only. In clinical studies for PCI, bivalirudin is typically administered as an intravenous bolus (0.75 mg/kg) followed by a continuous infusion (1.75 mg/kg/hr for the duration of the procedure). For medical management of unstable angina, an infusion may be continued for up to 72 hours. In research settings, dosing in animal models varies significantly based on species and the thrombosis or injury model being studied.
References
Bittl, J.A., et al. 'Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina.' The New England Journal of Medicine, 1995.
Lincoff, A.M., et al. 'Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial.' JAMA, 2003.
Stone, G.W., et al. 'Bivalirudin during primary PCI in acute myocardial infarction.' The New England Journal of Medicine, 2008.
Warkentin, T.E., et al. 'Bivalirudin.' Thrombosis and Haemostasis, 2008.
White, H.D., et al. 'Effect of bivalirudin on vascular complications after percutaneous coronary intervention: a meta-analysis of randomized trials.' The American Heart Journal, 2009.
Kastrati, A., et al. 'Bivalirudin versus unfractionated heparin during percutaneous coronary intervention.' The New England Journal of Medicine, 2008.