Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis.

Abstract

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

Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance

“…In response to a tPA infusion rate of 20 g ⅐ kg Ϫ1 ⅐ min Ϫ1 we observed carotid artery reperfusion in only 1 of 5 wild-type mice, results consistent with those of Jang et al, 1 who initially described the resistance of platelet-rich thrombi to lysis in rabbits. In contrast, thrombolysis was observed in 5 of 5 PAI-1 Ϫ/Ϫ mice.…”

“…However, platelet-rich thrombi are highly resistant to lysis by tPA. 1 Plasminogen activator inhibitor-1 (PAI-1), 2 the primary endogenous inhibitor of tPA and urokinase, may play an important role in inhibiting arterial clot lysis. Platelets and arterial thrombi contain high concentrations of PAI-1, [3][4][5] and antibodies to PAI-1 accelerate clot lysis in vitro.…”

Enoxaparin therapy for arterial thrombosis in infants with congenital heart disease

“…Increasing evidence suggests that the anticoagulant effect of UFH is impaired by platelets to a greater extent than LMWH, and that platelet interaction is much more inhibited by LMWH than UFH [16][17][18]. In addition, animal models have shown that platelet-rich thrombi are particularly resistant to thrombolysis, and that platelets and fibrin still accumulate on lysing thrombi during effective thrombolytic therapy [19].…”

Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.

“…We used a rabbit femoral artery eversion graft model in which we have previously shown that stable thrombosis primarily by PR material occurs spontaneously. 21 Attempts to prevent thrombotic occlusion in this model with the use of aspirin or heparin, alone or in combination, have failed. 6 With a specific thrombin inhibitor, however, especially when combined with aspirin, it was possible not only to prevent platelet-mediated eversion graft thrombosis but also to maintain patency after disappearance of the inhibitor from blood.…”