Heras, Magda

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.

Background Thrombolysis to normal flow in patients with acute myocardial infarction preserves left ventricular function and decreases mortality. Failure of early reperfusion, reocclusion, or residual thrombus may be due to concurrent activation of the platelet-coagulation system. Thus, we hypothesized that the best concomitant antithrombotic therapy (recombinant [r]-hirudin, heparin, or aspirin) will maximally accelerate thrombolysis by r–tissue-type plasminogen activator (rTPA) and reduce residual thrombus. Methods and Results Occlusive thrombi were formed in the carotid arteries of 29 pigs (by balloon dilatation followed by endarterectomy at the site of injury-induced vasospasm) and matured for 30 minutes before rTPA was started, with or without antithrombotic therapy. Thrombolysis was assessed with the use of angiography and measurement of residual thrombus. Pigs were allocated to one of five treatments: placebo, rTPA, rTPA plus r-hirudin, rTPA plus heparin, or rTPA plus intravenous aspirin. No placebo-treated pig reperfused. Two of six animals treated with rTPA alone reperfused compared with seven of seven animals treated with rTPA plus r-hirudin (reperfusion time, 33±10 minutes), six of seven animals treated with rTPA plus heparin (reperfusion time, 110±31 minutes), and two of six animals with rTPA plus aspirin. The activated partial thromboplastin time was prolonged in only the rTPA plus r-hirudin group (25±0.1 times baseline) and the rTPA plus heparin group (5.3±0.2 times baseline). Residual 111 In-platelet and 125 I-fibrin(ogen) depositions were lower in the heparin-treated group and lowest in the r-hirudin–treated group (heparin versus hirudin, respectively; incidence of residual macroscopic thrombus was six of six animals versus two of seven [ P =.01]; 125 I-fibrin(ogen), 170±76 versus 48±6 ×10 6 molecules/cm 2 [ P =.02]; 111 In-platelets, 47±15 versus 13±2 ×10 6 /cm 2 , P =.10). No pigs developed spontaneous bleeding. Conclusions Thrombin inhibition with heparin or r-hirudin significantly accelerated thrombolysis of occlusive platelet-rich thrombosis, but only the best antithrombotic therapy (r-hirudin) eliminated or nearly eliminated residual thrombus.