Key result
Anti-thrombin combined with anti-V/Va or anti-IX/IXa shows promising dose-dependent anticoagulation in vitro.
Why the study?
Novel anticoagulant drugs and combinations targeting coagulation factors require evaluation to identify promising dual target treatment strategies and therapeutic windows.
Do combinations of thrombin inhibitors with other coagulation factor inhibitors provide promising therapeutic windows in human blood plasma?
Do combinations of thrombin inhibitors with other coagulation factor inhibitors provide promising therapeutic windows in human blood plasma?
In vitro thrombin generation testing suggests that combining thrombin inhibitors with inhibitors of factors V/Va or IX/IXa may offer promising therapeutic windows for novel anticoagulant strategies.
Many anticoagulant drugs inhibiting proteins of the coagulation cascade have been developed. The main targets of anticoagulant drugs are thrombin and factor Xa; inhibiting these factors delays thrombus growth, thus preventing thrombosis while increasing bleeding risk. A balance between thrombosis and bleeding is ensured in the 'therapeutic window' of the anticoagulant drug concentration range. Novel anticoagulant drugs and combinations thereof are being developed. We rank coagulation factors as potential anticoagulant drug targets in combination with thrombin inhibitors, aptamer HD1 and bivalirudin, providing a background for several promising dual target treatment strategies. The thrombin generation test was used to assess the whole coagulation cascade in normal and factor-deficient human blood plasma. Potential therapeutic windows were estimated for coagulation factors, ranking them as targets for anticoagulant drugs. Thrombin and factor Xa have been revealed as the most promising targets, which fully agrees with the current drug development strategy. Inhibitors of factors Va and VIIa are expected to have narrow therapeutic windows. Inhibitors of factors VIIIa and IXa are expected to have a moderate anticoagulant effect. Factors XI and XII are poor targets for anticoagulant drugs. Compared with plasma that is deficient in factor II, the thrombin inhibitors bivalirudin and aptamer HD1 had increased activity. Both inhibitors were tested in deficient plasma providing a model of potential drug combination. The most promising combinations were anti-thrombin with anti-V/Va and also anti-thrombin with anti-IX/IXa. Each combination had an incremental dose-effect dependence that is promising from the standpoint of the therapeutic window.
No takes yet. Share an insight, caveat, or question.
Zavyalova et al. (2015) studied Thrombosis. Thrombin inhibitors (aptamer HD1 and bivalirudin) and coagulation factor deficiencies vs. Normal plasma or single targets was evaluated on Thrombin generation and therapeutic window estimation. The most promising anticoagulant combinations were anti-thrombin with anti-V/Va and anti-thrombin with anti-IX/IXa, which demonstrated incremental dose-effect dependence in vitro.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: