Whole blood clots are more resistant to lysis than plasma clots--greater efficacy of rivaroxaban.

INTRODUCTION: Defective thrombolysis, a thrombotic risk factor, can be attributed to the formation of a compact clot poorly accessible to fibrinolytic enzymes. Venous thrombi, rich in red blood cells (RBCs), and arterial thrombi containing various amounts of RBCS, plasma and whole blood (WB) clot permeability and degradability were compared. The effect of rivaroxaban, a potent direct factor Xa inhibitor, was also evaluated. MATERIALS AND METHODS: Fibrin permeability was determined by flow measurement through the clot. Clot degradability was evaluated by the amount of D-dimer generated by clot perfusion with plasminogen and tissue plasminogen activator. Fibrin clot structure was assessed by confocal microscopy. RESULTS: WB clot permeability (KS) and degradability were 6.7- and 38-fold lower, respectively, compared with plasma clots. This is attributed to 1) occlusion of fibrin pores by RBCs and 2) a consistent increase in thrombin generation due to platelets and RBCs inducing formation of a tighter clot. Rivaroxaban added to plasma or WB before clotting, in reducing thrombin generation, led to the formation of a looser clot that is more degradable by fibrinolytic enzymes. Permeability and degradability of whole blood clots formed in the presence of rivaroxaban were very similar to those of plasma clots. CONCLUSION: The resistance to fibrinolysis of WB clots was reduced considerably when clots were formed with rivaroxaban. These results may have implications for the development of antithrombotic agents.

Clot structure modification by fondaparinux and consequence on fibrinolysis: a new mechanism of antithrombotic activity.

Fondaparinux is a synthetic pentasaccharide consisting of the minimal sequence of heparin which interacts with antithrombin (AT). It represents a new class of selective factor Xa inhibitors without any antithrombin activity. It has been shown to exhibit potent antithrombotic properties in clinical studies. However, the mechanism of its antithrombotic action has not yet been fully established. In the present study it was shown that fondaparinux, used at pharmacological concentration (500 ng/ml), rendered the clot more susceptible to fibrinolysis induced by t-PA: plasma fibrin clots formed in the presence of fondaparinux and perfused with t-PA were degraded at a faster rate than those formed in the absence of fondaparinux. This fibrinolytic activity of fondaparinux is mainly due to a modification of clot structure characterized by a loose fibrin conformation with less branched fibers and the presence of large pores in comparison to control clots which present a tighter conformation. The difference in fibrin structure was responsible for an increase in clot porosity leading to a better availability of t-PA to the fibrin network. It is related to the decrease in thrombin generation, in an AT-dependent pathway. It was also demonstrated that in the presence of exogenous thrombomodulin, the inhibition of TAFI activation by fondaparinux could contribute, to a lesser extent, to the increased thrombus lysis. The increase in t-PA induced thrombus lysis could contribute to the antithrombotic activity of fondaparinux.