Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin.

Cercek, Bojan; Lew, Allan S.; Hod, Hanoch; Yano, Juliana; Reddy, N K; Ganz, William

doi:10.1161/01.cir.74.3.583

Cited by 136 publications

(32 citation statements)

References 18 publications

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“…Blood was collected at baseline (before treatment allocation) and 45 minutes, 3 hours (end of alteplase infusion), 12 Figure 1. Median FPA plasma levels (with their 10th to 90th percentiles) at baseline were 21 ng/ml (2-390 ng/ml) in placebo-allocated patients (n = 166) and 18 ng/ml (2-210 ng/ml) in heparin-allocated patients (n=168) (p=NS).…”

Section: Blood Sampling and Handlingmentioning

confidence: 99%

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Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

et al. 1992

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Section: Blood Sampling and Handlingmentioning

confidence: 99%

“…In placebo-treated patients, no significant correlation between plasma FPA levels and coronary patency was observed. (1-110) 23 8 ( (1-60) 25 8 (1-140) 98 25 (5-350) 40 28 (2-300) 12 hr 114 4 (1-56) 26 11 (2-240) 94 …”

Section: Blood Sampling and Handlingmentioning

confidence: 99%

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

et al. 1992

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“…Clot lysis and recanalization of the occluded coronary artery induced in vivo by t-PA can be accelerated by adjunctive ther apy with antiplatelet agents such as aspirin or antithrombin agents such as heparin and hiru din (28,29). It has been reported that heparin enhances thrombolysis and maintains coronary artery-patency after the administration of t-PA (6,30). As the balance between fibrin deposi tion and lysis is a key factor for thrombosis, we administered heparin to prevent the forma tion of fibrin and its incorporation into the thrombus during thrombolysis by plasminogen activators.…”

Section: Discussionmentioning

confidence: 99%

Thrombolytic Effects of a Novel Modified Tissue Plasminogen Activator, E6010, on Coronary Thrombosis in the Pig.

et al. 1992

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-This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical sti mulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respec tively. The time to recanalization after 0.4 mg/kg of E6010 was 22 ± 11 min (mean ± S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 ± 0.3 vs. 9.4 ± 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, a 2-plasmin inhibitor and plas minogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic ac tion of E6010 following single intravenous bolus injection.A number of clinical studies have confirmed the effectiveness of recombinant tissue plasmi nogen activator (t-PA) as a thrombolytic agent in the treatment of acute myocardial infarction (1 3). One disadvantage associated with t-PA is its very rapid elimination from the systemic circulation by clearance in the liver, resulting in an initial plasma half-life in the order of a few minutes (4, 5). This rapid clearance of t PA necessitates intravenous or intracoronary infusion of a relatively high dose in order to maintain therapeutic plasma levels. The rapid decrease in plasma level of t-PA after the ter mination of infusion may result in coronary reocclusion (6), and overdose of t-PA, which may occur with continuous infusion, may in crease the risk of hemorrhagic complications (7) t-PA derivatives with slower clearance from plasma would be effective by intravenous bolus injection and provide advantages over conventional t-PA in the treatment of acute myocardial infarction and other thrombotic diseases. E6010 is a novel modified human t PA, in which cysteine 84 in the epidermal growth factor domain is replaced by serine (8). A slower rate of clearance of E6010 from plasma compared to that of t-PA has been dem

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“…The canine model with a copper coil-induced femoral artery thrombus that was developed by Bush et al (25) and Cercek et al (26) was modified and used to examine the efficacy of the thrombolytic agents. Mongrel dogs (body weight: 9-15 kg) were anesthetized with sodium pentobarbital and artificially ventilated.…”

Section: Induction Of Thrombusmentioning

confidence: 99%

“…The blood concentrations of rt-PA and E6010 were measured by ELISA with a polyclonal antibody specific for t-PA (26,27 …”

Section: Administration Of Rt-pa and E6010mentioning

confidence: 99%

Thrombolysis of Canine Femoral Artery Thrombus by a Novel Modified Tissue-Type Plasminogen Activator (E6010).

Suzuki

Nagaoka

et al. 1994

Jpn.J.Pharmacol

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ABSTRACT-The thrombolytic activity of a novel modified tissue-type plasminogen activator (t-PA) (E6010) was examined in a canine model with copper coil-induced femoral artery thrombus. This model, in which thrombolytic activity can be easily and directly quantified by determining changes in thrombus weight, should be useful for comparing the activities of various thrombolytic agents. Using this model, the present study showed that the thrombolytic activity of bolus intravenous injection of E6010 was identical to that of continuous intravenous infusion of recombinant t-PA at the same dose. This thrombolytic activity can be explained by changes in blood concentrations of the administered thrombolytic agents. On the other hand, administration of the thrombolytic agents dose-dependently caused significant changes in the levels of hemostatic and fibrinolytic factors. These changes were not so marked with administration of E6010, and therefore we concluded that E6010 is unlikely to cause bleeding complications after administration Keywords: E6010 (novel modified t-PA), Plasminogen activator (tissue-type), Femoral artery thrombus model, Thrombolytic activity, Plasma concentrationRecently, coronary artery angiography has been com monly used and safely performed during early stages of acute myocardial infarction.As a result, coronary thrombi have been found in many patients with acute myocardial infarction, suggesting its involvement in the pathogenesis of myocardial infarction (1). In 1979, Rentrop et al. succeeded in lysing a coronary thrombus by direct intracoronal infusion of streptokinase (2). In Japan, percutaneous transluminal coronary recanaliza tion (PTCR) with urokinase has been commonly per formed (3). These drugs can lyse fibrin that is a compo nent of thrombi by converting plasminogen into the ac tive form, plasmin, in the circulating blood. The resulting plasmin lyses not only fibrin but also fibrinogen. The effect of plasmin is regulated by a2-plasmin inhibitor, which binds to plasmin to inactivate it. The increase in plasmin caused by these drugs results in the subsequent decrease in blood concentrations of fibrinogen and a2 plasmin inhibitor, frequently leading to bleeding compli cations. Therefore, it is necessary to develop drugs that have a high affinity with thrombi so that the production of plasmin will be localized near the thrombi.Compared to intracoronary administration, intra venous administration has been found to produce more rapid recanalization of the coronary artery by throm bolytic therapy. A large dose of urokinase must be admin istered for thrombolysis, with a high risk of bleeding com plications. In 1982, tissue-type plasminogen activator (t-PA), which has a high affinity to thrombi, was isolated and purified from human melanoma cells (4). The genetic recombinant technology has enabled the large-scale production of t-PA (5). T-PA has been used as an effective thrombolytic agent against acute myocardial infarction (6 8) and other diseases (9). However, pharmacokinetic studies revealed th...

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Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin.

Cited by 136 publications

References 18 publications

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

Thrombolytic Effects of a Novel Modified Tissue Plasminogen Activator, E6010, on Coronary Thrombosis in the Pig.

Thrombolysis of Canine Femoral Artery Thrombus by a Novel Modified Tissue-Type Plasminogen Activator (E6010).

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