Acute myocardial infarction is triggered by coronary artery occlusion that may be recanalized by thrombolytic therapy with a success rate of up to 75% only. The resistance of coronary artery occlusion to thrombolysis may either be due to obstruction of the lumen by a nonthrombotic mechanism or by intrinsic resistance of thrombus to dissolution. Coronary arterial thrombi are composed of platelet-rich and erythrocyte-rich material in variable proportions. To evaluate the relative sensitivity of these thrombus components to thrombolysis, we have used two femoral arterial thrombosis models in the rabbit, consisting of erythrocyterich clot produced by injecting whole blood and thrombin in an isolated segment and of platelet-rich thrombus spontaneously formed on an everted (inside out) femoral arterial segment. Intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) at a rate of 30 ,ug/kg/min consistently reperfused arteries occluded with erythrocyte-rich clot (six of six animals compared with zero of six placebo-treated animals, p=0.002), whereas infusion of 30 or 100 ,g/kg/min was significantly less efficient for reperfusion of everted segments occluded with platelet-rich material (only four of 12 animals, p=0.01). Intra-arterial infusion proximal to the occlusion, at a rate of 20 ,ug/kg/min reperfused six of seven rabbits with erythrocyte-rich clots but only one of seven rabbits with occluded everted segments (p=0.03). A dose of 100 ,ug/ kg/min was necessary to reperfuse platelet-rich occlusions in five of six rabbits. We conclude that platelet-rich arterial thrombus is much more resistant to thrombolysis with rt-PA than erythrocyte-rich clot. This differential sensitivity to lysis may explain the failure of thrombolytic therapy in a significant percentage of patients with acute myocardial infarction who may have a predominantly platelet-rich occlusion. The rabbit femoral arterial eversion graft model may represent a useful tool for developing strategies directed at the dissolution of platelet-rich thrombus. (Circulation 1989;79:920-928) Presented in part at the 61st Scientific Meetings of the American Heart Association, Washington, DC, November 14-17, 1988. Supported in part by ISCHEMIA SCOR Grant (HL-25215) and THROMBOSIS SCOR Grant
The disproportionate elevation of PAI-1 compared with u-PA observed in atheromatous material extracted from vessels of diabetic subjects is consistent with increased gene expression of PAI-1 in vessels as well as the known increase of PAI-1 in blood, presumably reflecting increased synthesis. The increased PAI-1 detected in the atheroma may contribute in vivo to accelerated or persistent thrombosis underlying acute occlusion and to vasculopathy exacerbated by clot-associated mitogens in the vessel wall. Because the changes were observed to be associated with insulin resistance and type 2 diabetes mellitus, they may be modifiable by reduction of insulin resistance with insulin sensitizers and stringent control of hyperglycemia.
The pharmacodynamics of intravenous bolus injections of 0.05, 0.10, 0.15, and 0.20 mg/kg of F(ab')2 fragments of the murine monoclonal antibody 7E3, 7E3-F(ab')2, directed against the glycoprotein Ilb/Illa (GPIIb/IIIa) receptor of human platelets, were studied in groups of four patients with unstable angina pectoris. With 0.20 mg/kg, the template bleeding time prolonged from 6.3±1.9 (mean±SD) to > 30 min; it subsequently decreased to 13±7.8 min after 12 h and to 8.3±1.5 min after 24 h. The number of unblocked GPIIb/IIIa receptors (preinfusion value, 32,000±3,000 per platelet) decreased to 13±7% of the preinfusion value 1 h after infusion, and then increased to 33±10% at 12 h, 44±8% at 24 h and 67±7% at 72 h. The logarithm of the bleeding time was inversely proportional with the residual GPIIb/IIIa receptors (r = 0.73, P < 0.0001). ADP-induced platelet aggregation (measured by changes in light transmittance in percent) decreased from 60±5% before infusion to 1.5±3% 1 h after infusion; it then increased to 29±3% after 24 h and 39±6% after 72 h. Platelet counts decreased by 16% at 1 h and returned to control values within 24 h. Proportionally smaller effects were seen at lower doses of 7E3-F(ab')2. Antibody injection did not induce spontaneous bleeding. Angina was not observed during the first 12 h when the bleeding time was significantly prolonged, but occurred in 6 of the 16 patients within the next 3 d. 2 of the 16 patients developed low titers of IgG antibodies specific for 7E3-F(ab')2. Thus 7E3-F(ab')2 induces dose-related inhibition of platelet function; at a dose of 0.20 mg/kg, it causes profound inhibition of platelet aggregation and prolongation of the bleeding time, but no spontaneous bleeding. (J. Clin. Invest.
Resistance of coronary occlusive thrombus to thrombolytic therapy, found in some patients with acute myocardial infarction, may be due to the presence of platelet-rich coronary clot. Reperfusion therapy in such patients may require the development and evaluation of alternative strategies in animal models. Therefore, platelet-rich coronary artery thrombus was developed by excision, eversion (inside out) and reanastomosis of a 1 cm segment of the left circumflex coronary artery in anesthetized dogs maintained on heparin antiocoagulation. Blood flow was restored in 25 of 27 dogs. Thrombotic occlusion of the everted segment graft with primarily platelet-rich thrombus or thrombus containing platelet-rich and erythrocyte-rich zones, persisting for at least 30 min, occurred within 4.5 +/- 3.5 min (mean +/- SD) in 20 of these 25 dogs. In 5 of these 20 dogs (group I, control), stable occlusion, as monitored with an ultrasound flow probe and coronary angiography, was maintained during a 2 h observation period. In group II (n = 5), intravenous bolus injections of recombinant tissue-type plasminogen activator (rt-PA) at a dose of 0.45 mg/kg body weight at four 15 min intervals did not cause reperfusion in four dogs and produced cyclic reperfusion and reocclusion in one dog. In group III (n = 5), a single intravenous bolus injection of 0.8 mg/kg of the F(ab')2 fragment of a murine monoclonal antibody (7E3) against the human platelet GPIIb/IIIa receptor [7E3-F(ab')2] produced stable reperfusion in two of the five dogs, whereas occlusion persisted in the other three. In group IV (n = 5), injection of 7E3-F(ab')2 (0.8 mg/kg) followed by rt-PA (0.45 mg/kg) caused stable reperfusion without reocclusion in all dogs (p less than 0.05 versus rt-PA alone and p less than 0.01 versus control). This study confirms that platelet-rich occlusive coronary thrombus is very resistant to lysis with intravenous rt-PA. However, this resistance may be overcome by the combined use of a reduced dose of rt-PA and the antiplatelet GPIIb/IIIa receptor antibody 7E3. The results indicate that platelet-rich thrombus resistant to thrombolytic agents may be dispersed pharmacologically without resort to mechanical recanalization. The present dog model may be useful in investigating specific strategies for the dispersion of resistant platelet-rich coronary thrombus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.