Effects of fondaparinux and a direct factor Xa inhibitor TAK-442 on platelet-associated prothrombinase in the balloon-injured artery of rats.
Endothelial damage triggers platelet adhesion and platelet-associated prothrombinase formation at the point of injury, resulting in the progression of thrombus formation. The present study compared the inhibitory effects of fondaparinux, an indirect factor Xa (FXa) inhibitor, and TAK-442, a direct FXa inhibitor, on platelet-associated prothrombinase activity in the balloon-injured rat artery. TAK-442 and fondaparinux inhibited endogenous FXa activity in platelet-poor human [half-maximal inhibitory concentration (IC(50)): 53 nM, TAK-442; 11 nM, fondaparinux] and rat (IC(50): 32 nM, TAK-442; 19 nM, fondaparinux) plasma. TAK-442 inhibited in vitro reconstituted human prothrombinase (system included FXa, calcium, and washed platelets) with an IC(50) value of 51 nM, whereas fondaparinux exhibited only weak inhibition (IC(50): 1700 nM). In a rat model of balloon injury, thrombin activity on the surface of injured vessels increased to 3.2-, 22-, and 5.8-fold the activity on the surface of the intact aorta at 5 minutes, 1 hour, and 24 hours after the injury, respectively. At approximately 1 hour after the injury, TAK-442 blocked platelet-associated thrombin generation on the surface of injured aortas with an IC(50) value of 19 nM, whereas fondaparinux showed no significant inhibition at the highest concentration tested (IC(50): >300 nM). These results suggest a possible limitation of fondaparinux in inhibiting platelet-associated prothrombinase activity and resultant thrombus formation as compared with TAK-442.
Pharmacology Research Laboratories, Takeda Pharmaceutical Company Ltd., Osaka, Japan.
Noriko
N
Konishi
Katsuhiko
K
Hiroe
Masaki
M
Kawamura
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006801:Humans; D008297:Male; D011134:Polysaccharides / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism
C553657:1-(1-(3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoyl)piperidin-4-yl)tetrahydropyrimidin-2(1H)-one; D065427:Factor Xa Inhibitors; D011134:Polysaccharides; D011744:Pyrimidinones; D013450:Sulfones; D013925:Thromboplastin; D000077425:Fondaparinux