Influence of bivalirudin on tissue factor-triggered coagulation

Abstract

Bivalirudin, a synthetic analog of the carboxy-terminus of hirudin, is a reversible thrombin inhibitor used during coronary balloon angioplasty. The objective of this study was to evaluate the influence of bivalirudin on thrombin generation. Three in-vitro models (numerical simulations, synthetic coagulation proteome and whole blood) of contact pathway-independent blood coagulation triggered with tissue factor were used in this study. Increasing concentrations of bivalirudin prolong the initiation phase of thrombin generation in a concentration-dependent manner. At subpharmacologic bivalirudin concentrations (0.5-2 micromol/l), total thrombin generation was significantly increased. At a pharmacologic concentration (5 micromol/l), bivalirudin suppressed thrombin generation in the synthetic coagulation proteome; in numerical simulations and contact pathway-inhibited whole blood, no thrombin generation was detected over 1200-2000 s and platelet activation was inhibited by 80%. The addition of a pharmacologic concentration (9 micromol/l) of a naturally occurring protease inhibitor aprotinin in the presence of at least 0.5 micromol/l bivalirudin provided limited enhancement of the bivalirudin inhibitory effect. In conclusion, bivalirudin at pharmacologic concentrations is an efficient inhibitor of thrombin generation, platelet activation and clot formation, which acts not as a modulator but as an 'on-off' switch of blood coagulation.

The effect of high circulating estradiol levels on thrombin generation during in vitro fertilization

“…The numerical model that was used for these studies includes key plasma pro- and anti- coagulants of the TF pathway to thrombin generation that are evaluated in clinical laboratories. This model correlates well to empirical models describing the TF pathway [18,22–24]. …”

Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation

“…Thrombin itself has a role in both primary hemostasis, with respect to platelet activation, and secondary hemostasis, in which fibrin is crosslinked to form a stable hemostatic clot, which is later degraded by fibrinolysis. Previously, bivalirudin, a synthetic analog of hirudin currently in use in cardiac surgery, which is most analogous to the active element of TLN, has been demonstrated to decrease thrombin‐induced platelet activation . The importance of platelet deposition in TMA has previously been demonstrated with CD61 staining of platelets, which was positive in TMA induced by calcineurin inhibitor toxicity in kidney transplant recipients .…”

Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants

“…A cell-based model of blood coagulation has been proposed based on in vitro studies in whole blood and reconstituted systems. [1][2][3] Upon exposure to blood, the membrane-anchored TF binds circulating factor VII/VIIa. The resulting TF/VIIa complex initiates coagulation by activating factor IX and factor X to generate small amounts of IXa and Xa.…”