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.
Varin
Rémi
R
Groupe de Recherche MERCI, EA 3829, Faculté de Médecine et de Pharmacie, Boulevard Gambetta, Rouen Cedex, France.
Mirshahi
Shahsultan
S
Mirshahi
Pezhman
P
Kierzek
Gerald
G
Sebaoun
David
D
Mishal
Zohar
Z
Vannier
Jean-Pierre
JP
Yvonne Borg
Jeanne
J
Simoneau
Guy
G
Soria
Claudine
C
Soria
Jeannette
J
D000990:Antithrombin III; D001777:Blood Coagulation; D005337:Fibrin / Q000737:chemistry / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D000077425:Fondaparinux; D007700:Kinetics; D011134:Polysaccharides / Q000494:pharmacology*; D011487:Protein Conformation / Q000187:drug effects; D013917:Thrombin / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D005343:Fibrinolytic Agents; D011134:Polysaccharides; D000990:Antithrombin III; D005337:Fibrin; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D000077425:Fondaparinux