Flavone-8-Acetic Acid (Flavonoid) Profoundly Reduces Platelet-Dependent Thrombosis and Vasoconstriction After Deep Arterial Injury In Vivo

Abstract

Background —Flavone-8-acetic acid (FAA; [Flavonoid]), an adjuvant antitumor drug, inhibits ristocetin-induced aggregation of human platelets. The effect of FAA on platelet-dependent thrombosis was studied in vivo in the porcine carotid artery after deep arterial injury by balloon angioplasty. Methods and Results — 111 In-labeled autologous platelet and 125 I-labeled porcine fibrin(ogen) deposition, and the incidence of macroscopic mural thrombosis onto deeply injured artery (tunica media) were compared in 20 pigs (40±1 kg [mean±SEM], body surface area=1.0±0.1 m 2 ), randomized to FAA bolus (n=10) of 5.5g/m 2 , followed by an infusion at 0.14g · m −2 · min −1 or placebo (n=10). Vasoconstriction was measured immediately beyond the dilated segment using quantitative angiography. Platelet deposition (×10 6 /cm 2 of carotid artery) was reduced over 12-fold in pigs treated with FAA (13±3 versus 164±51, P =0.001) compared with placebo. Fibrin(ogen) deposition (×10 12 molecules/cm 2 of carotid artery) did not significantly differ in FAA-treated pigs versus placebo (40±8 versus 140±69, P =0.08). Large mural thrombi were present in 100% of placebo-treated pigs versus very small thrombi in 40% of FAA-treated pigs ( P =0.005). Vasoconstriction was reduced from 46±6% in the placebo group to 15±3% in the FAA group ( P <0.001). Plasma level of FAA before angioplasty was 515±23 μg/mL. The activated partial thromboplastin time was unchanged. The bleeding time was >2SD above the normal mean in 4 of 5 treated pigs (increased from 157±29 to 522±123 s). Conclusions —FAA markedly reduced platelet deposition, mural thrombi, and injury-induced vasoconstriction after deep arterial injury, suggesting that a major inhibition of platelet glycoprotein Ibα may be beneficial therapy.