TP-9201, A Glycoprotein IIb/IIIa Platelet Receptor Antagonist, Prevents Rethrombosis After Successful Arterial Thrombolysis in the Dog
Background and Purpose We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog.
Methods Occlusive thrombosis was induced by electrolytic injury of the left carotid artery. Thirty minutes later, 0.05 U/kg of anisoylated plasminogen streptokinase activator complex (APSAC) was infused locally to achieve clot lysis. Carotid artery recanalization was followed immediately by the infusion of either saline (10 mL/h, 240 minutes; n=9), low-dose TP-9201 (120 μg/kg plus 3 μg · kg–1 · min–1, 240 minutes; n=7), or high-dose TP-9201 (185 μg/kg plus 5 μg · kg–1 · min–1, 240 minutes; n=7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined.
Results TP-9201 produced complete inhibition of platelet aggregation in citrated platelet-rich plasma but a partial and dose-dependent inhibition in heparinized platelet-rich plasma. A twofold and eightfold increase in the template bleeding time was associated with the infusion of low-dose and high-dose TP-9201, respectively. There were frequent cyclic flow reductions in both the saline and low-dose TP-9201–treated groups after thrombolysis. However, the high-dose TP-9201–treated group exhibited a sustained flow with minimal evidence of cyclic flow reductions. At the conclusion of the protocol, patent vessels were found more frequently in the high-dose TP-9201 (5/7; P=.0048) than in the low-dose TP-9201 treatment group (2/7; P=.17) when compared with the saline group (0/9). Infusion of high-dose TP-9201 was associated with a significant reduction in the thrombus mass as compared with the control vessels.
Conclusions Administration of TP-9201 in conjunction with successful thrombolysis inhibited ex vivo platelet aggregation and prevented rethrombosis of the canine carotid artery. This study demonstrates that TP-9201, an inhibitor of the platelet GPIIb/IIIa receptor, can inhibit platelet–vessel wall interaction and thus prevent rethrombosis.
Reocclusion after successful arterial recanalization remains a clinical problem with all the available thrombolytic regimens.1 The circulating blood platelet represents a major component in both arterial thrombosis and rethrombosis.2 3 The binding of fibrinogen to the platelet surface is necessary for platelet aggregation induced by all of the agonists believed to operate in vivo.4 5 6 Therefore, the final common step in platelet aggregation, regardless of the agonist involved, requires the interaction of the adhesive protein fibrinogen with the heterodimeric platelet membrane integrin receptor GPIIb/IIIa (αIIbβ3). The platelet-specific GPIIb/IIIa receptor consists of α and β transmembrane subunits. The GPIIIa (β3) can form a complex with another α-subunit, αv, to form the αvβ3 vitronectin receptor7 that is present on endothelial cells and osteoclasts.8 Although ex vivo studies indicate that the GPIIb/IIIa receptor can bind to vWF, the relative significance of this interaction in vivo remains to be established.9
After the recanalization that follows the use of a thrombolytic agent, the presence of a residual thrombus and the associated shear forces, along with the release of mediators promoting further platelet aggregation and vasoconstriction, present a thrombogenic environment for recruitment of new platelets and fibrin deposition, which lead to rethrombosis.10 Therefore, an inhibitor of the platelet GPIIb/IIIa receptor represents a rational approach for reducing the incidence of rethrombosis.9
TP-9201 is a synthetic RGD-containing cyclic peptide that inhibits the interaction between GPIIb/IIIa and fibrinogen. TP-9201 inhibits ADP-induced platelet aggregation in humans, baboons, and dogs with a similar potency (IC50=1-3 μmol/L), and is less potent in rabbits (IC50=45 μmol/L) and rats (IC50=20 μmol/L).11 Inhibition of human platelet adhesion to fibrinogen and vWF coated surfaces under static and high shear conditions was demonstrated with TP-9201.11 In vitro assays with purified integrin receptors and ligands have shown TP-9201 to be 14- to 200-fold-more selective for GPIIb/IIIa over the vitronectin (αvβ3 and αvβ5) and fibronectin receptors (α5β1).12
The antithrombotic efficacy of TP-9201 has been demonstrated in femoral vein thrombosis in hamsters,13 canine arterial eversion graft thrombosis,13 and coronary artery rethrombosis in dogs.14 In the present study, we used TP-9201 in conjunction with APSAC to assess its efficacy as adjunctive therapy in the prevention of arterial rethrombosis.
This study conforms to the position of the American Heart Association on research animal use adopted November 11, 1984, by the American Heart Association. The procedures followed in this study were in accordance with the guidelines of the University of Michigan (Ann Arbor) Committee on the use and care of animals, and with the Guide for Care and Use of Laboratory Animals, US Department of Health, Education, and Welfare Publication No. NIH 78-23.
TP-9201 and APSAC were supplied by Telios Pharmaceuticals, Inc. The chemical structure of TP-9201 is shown in Fig 1⇓. Sodium citrate, ADP, arachidonic acid, epinephrine, and other standard reagents were purchased from Sigma Chemical Co.
Model of Vessel Occlusion
The model used in this study is a modification of one developed by our laboratory for the study of experimentally induced coronary artery thrombosis and has been used successfully for related studies by several investigators.15 16 17 18 19 The model makes use of anodal current–induced electrolytic injury to the intimal surface of the arterial wall that invariably results in the formation of a platelet-dependent, occlusive intravascular thrombus.17 19
Healthy, male and female purpose-bred beagle dogs (9 to 13 kg) were anesthetized with sodium pentobarbital (30 mg/kg, IV), intubated, and ventilated with room air at a tidal volume of 30 mL/kg at a rate of 12 breaths per minute (Harvard Apparatus). The left common carotid artery was exposed by blunt dissection with care not to injure the vessel. Catheters were inserted into the right and left femoral veins for blood sampling and drug administration, respectively. Arterial blood pressure was monitored from the cannulated femoral artery with a blood pressure transducer (Gould Inc, Cardiovascular Product). The standard limb lead II of the electrocardiograph was recorded continuously and used to monitor heart rate. A calibrated flow probe (model 2RB907, Transonic Systems Inc) was placed on the carotid artery to continuously monitor blood flow (mL/min). The point of insertion of an intravascular electrode for anodal current application and positioning of the mechanical constrictor was downstream relative to the flow probe. The mechanical constrictor on the carotid artery was constructed of stainless steel, shaped to fit around the vessel. A nylon screw (2 mm in diameter) threaded through the C-shaped metal band was adjusted to decrease the circumference of the vessel and produce a regional stenosis. The vessel was constricted to a point where the pulsatile flow pattern was reduced by approximately 50% without altering the mean carotid artery blood flow.
Anodal current–induced electrolytic injury to the intimal surface of the vessel was accomplished with the use of an intravascular electrode composed of a Teflon-insulated, silver-coated, copper wire. Penetration of the vessel wall by the electrode was facilitated by attaching the tip of a 25-gauge hypodermic needle to the uninsulated part of the electrode. The intravascular electrode was connected to the positive pole (anode) of a dual-channel square wave generator (Grass S88 stimulator and a Grass Constant Current Unit, model CCU1A, Grass Instrument Co). The cathode was connected to a distant subcutaneous site. The current delivered to each vessel was monitored continuously on separate ammeters and maintained at 300 μA. The anodal electrode was positioned to have the uninsulated portion (3 to 4 mm) in intimate contact with the endothelial surface of the vessel. Proper positioning of the electrode in the vessel was confirmed by visual inspection at the conclusion of each experiment.
Local administration of APSAC was achieved by using a C-shaped 25-gauge needle cannula attached to a polyethylene tubing. The needle cannula was inserted into the lumen of the carotid artery 1 cm proximal to the electrode and distal to the flow probe. APSAC was infused immediately proximal to the formed thrombus.
Anodal current was applied to the carotid artery and terminated 30 minutes after the flow signal had remained stable at zero blood flow, indicating formation of an occlusive thrombus. Thirty minutes after occlusion occurred in the carotid artery, APSAC (0.05 U/kg) was infused locally, directly proximal to the occlusive intravascular thrombus to achieve clot lysis. APSAC was administered over 60 seconds in a dose selected to achieve thrombolysis without altering the plasma clotting factors as determined by measurement of the aPTT and PT. Immediately after the administration of APSAC, the animals were randomized to receive the intravenous infusion of either saline (10 mL/h; n=9), low-dose TP-9201 (120 μg/kg plus 3 μg · kg–1 · min–1 for 240 minutes; n=7), or high-dose TP-9201 (185 μg/kg plus 5 μg · kg–1 · min–1 for 240 minutes; n=7). Vessel patency was defined as blood flow of ≥10 mL/min for >1 minute. Blood pressure, heart rate, and blood flow were monitored for 4 hours after administration of saline or TP-9201. All the data were stored on computer disk using a MacLab data acquisition system (MacLab) and software interfaced with a Macintosh Power Book 140 (Apple Computer).
At the end of the experimental protocol, the injured vessel segment of the carotid artery was ligated both proximal and distal to the point of injury and removed without disturbing the intravascular thrombus. The vessel segment was opened longitudinally to allow removal of the intact thrombus. The weight of each thrombus was determined using an analytical balance.
Determinations of the aPTT, PT, tongue-template bleeding time, and ex vivo platelet aggregation were made at baseline and repeated at 60, 120, and 240 minutes after the administration of saline or TP-9201. Blood (10 mL) was withdrawn from the right femoral vein cannula into a plastic syringe containing 3.7% sodium citrate as the anticoagulant (1:10 citrate to blood [vol/vol]) for the ex vivo platelet aggregation determinations. In addition, a second blood specimen of heparinized blood (10 mL; 10 U of heparin/mL blood) was collected for platelet aggregation studies. The whole blood cell count was determined with an H-10 cell counter (Texas International Laboratories, Inc). PRP, the supernatant present after centrifugation of anticoagulated (citrate or heparin) whole blood at 1000 rpm for 5 minutes (140g), was diluted with PPP to achieve a platelet count of 200 000/mm3. PPP was prepared after the PRP was removed by centrifuging the remaining blood at 2000g for 10 minutes and discarding the bottom cellular layer. Ex vivo platelet aggregation was assessed by established spectrophotometric methods with a 4-channel aggregometer (BioData-PAP-4, Bio Data Corp) by recording the increase in light transmission through a stirred suspension of PRP maintained at 37°C. Aggregation was induced with ADP (20 μmol/L) and AA (0.65 mmol/L). A subaggregatory concentration of epinephrine (550 nmol/L) was used to prime the platelets before addition of the agonists to induce platelet aggregation. Values for platelet aggregation are expressed as percentage of light transmission standardized to PRP and PPP samples yielding 0% and 100% light transmission, respectively.
The anticoagulation state of the animals was assessed by determining aPTT and PT with a Hemochron (Technidyne) and reagents supplied by the manufacturer. Citrated whole blood (2 mL) was used for the determination.
Bleeding times were determined with the use of a Simplate device (Simplate-R, Organon Teknika Corp), which made a uniform incision 5 mm long and 1 mm deep on the upper surface of the tongue. The tongue lesion was blotted with a filter paper every 30 seconds until the transfer of blood to the filter paper ceased.
The data are expressed as mean±SEM. A one-way ANOVA (repeated measures) was used to assess differences over time within groups. The data were analyzed by one-way ANOVA (factorial) for group comparisons. Fisher’s protected least significant difference and Bonferroni/Dunn post hoc analyses were used to determine significance at P<.05. A paired t test was used to assess the differences over time within a group, and values were determined to be statistically different at a level of P<.05. Fisher’s exact test was used to examine significance in vessel patency between treatment groups. A nonparametric (Kruskal-Wallis) test was used to compare the median patency scores between groups. The Kruskal-Wallis test is basically calculated as a regular ANOVA, but it uses the ranks of the data and is resistant to outliers.
Animals that were to be included in the protocol satisfied the following preestablished criteria: (1) a circulating platelet count of not less than 100 000 per mm3; (2) a demonstrated ability of epinephrine-primed platelets to aggregate in response to both AA and ADP before administration of TP-9201; (3) a thrombotic occlusion of the carotid artery within 3 hours from the onset of vessel wall injury with a 300 μA direct anodal current; (4) an absence of heart worms on final postmortem examination; and (5) an ability of APSAC to successfully lyse the thrombus. In the current study, all of the purpose-bred animals initially selected met the inclusion criteria, and therefore there was no need to exclude any animal retrospectively.
TP-9201 administration did not produce any change in the blood pressure or heart rate throughout the experimental protocol (Table 1⇓).
Blood Coagulation Parameters
Local administration of APSAC (0.05 U/kg) at a site proximal to the carotid artery thrombus had no effect on the aPTT, PT, or bleeding times, indicating lack of a systemic lytic action (Table 1⇑). As expected, infusion of either dose of TP-9201 did not alter the aPTT or PT values from the baseline. However, TP-9201 did prolong the template bleeding times. Infusion of low-dose TP-9201 increased the template bleeding time from 116±8 to 223±30 seconds (twofold), whereas the high-dose TP-9201 increased the bleeding time from 129±24 to 938±264 seconds (eightfold). There was moderate bleeding from the carotid artery incision site in 2 of 7 animals treated with the high dose.
In the APSAC plus saline group, ADP- and AA-induced platelet aggregations at baseline in citrated samples were 74±6% and 76±3%, respectively, and at 4 hours the aggregations were 74±10% and 63±7%, respectively. Similar results were obtained when aggregation was studied in heparinized samples, indicating that local administration of APSAC did not affect the platelets. During TP-9201 infusion, the ex vivo platelet aggregation in response to ADP or AA in citrated blood samples was inhibited by >90% in both the low- and high-dose groups (Fig 2⇓). In heparinized blood samples, however, the low-dose TP-9201 produced a 21% inhibition of platelet aggregation in response to ADP or AA. On the other hand, the high-dose TP-9201 produced 45% and 31% inhibition of platelet aggregation in response to ADP and AA, respectively. Thus, TP-9201 in both the low- and high-dose regimens was less effective in inhibiting ex vivo platelet aggregation in PRP prepared from blood anticoagulated with heparin compared with PRP samples prepared from citrate anticoagulated whole blood.
Patency Status of the Carotid Artery
The carotid artery blood flow during the experimental protocol is depicted in Fig 3⇓. The baseline flows, determined before the initiation of electrolytic injury, were 90±5 mL/min (saline group), 90±4 mL/min (low dose), and 103±13 mL/min (high dose). Electrolytic injury of the endothelium caused a progressive decrease in blood flow, finally culminating in an occlusive thrombus. The time to occlusion was similar in all the treatment groups (Table 2⇓). In the absence of APSAC, saline alone does not result in recanalization. Instead, there is continuous accretion of platelets on the primary thrombus that leads to larger and stable thrombi (data not shown). Local injection of APSAC lysed the thrombus in all the animals included in the study. Infusion of TP-9201 did not produce a statistically significant effect on the mean time to reperfusion of the carotid artery (saline group, 44±11 minutes; low-dose group, 43±5 minutes; high-dose group, 35±16 minutes). The median times to reperfusion were 50, 45, and 21 minutes for the saline, low-dose, and high-dose groups, respectively (P=.32; Kruskal-Wallis test). Animals treated with the high dose, but not the low dose, of TP-9201 showed significantly higher flow in the injured carotid artery compared with the saline group. The patency status (presence or absence of a flow signal of 10 mL/min) of the carotid artery after the local administration of APSAC combined with the intravenous administration of vehicle or TP-9201 is represented graphically in Fig 4⇓. All the animals in the saline group progressed to reocclusion after thrombolysis. However, there were 2 of 7 (P=.17) and 5 of 7 (P=.0048) patent vessels at the end of the protocol, in the low- and high-dose TP-9201 groups, respectively.
Qualitative Analysis of Oscillatory Flow in the Carotid Artery
To assess the degree of maintenance of blood flow qualitatively, criteria were developed (Fig 5⇓) and applied every 60 minutes after the administration of vehicle or TP-9201. The established criteria were as follows: (1) A rating of 0 indicates an absence of blood flow. When reflow occurs, but the flow declines to 0, a score of 1 is assigned. (2) A rating of 2 indicates a decline in blood flow that is restored spontaneously before it reaches 0. (3) A rating of 3 is applied when the blood flow is maintained relatively constant in a nonoscillatory manner.
Recanalization was associated with a characteristic blood flow pattern in the carotid artery termed cyclic flow variations (reocclusion and reflow, or decrease in flow). Representative examples of oscillatory variations in carotid artery blood flow after recanalization are shown in Fig 5⇑.
Administration of APSAC resulted in thrombolysis and restoration of carotid artery blood flow in all of the animals in each group. When the scoring method described above was used, the median patency score for the control group was 1 (Fig 6⇓). Similarly, the median patency score in the low-dose TP-9201 group was 1. A sustained nonoscillatory flow was observed in the high-dose TP-9201 group, accompanied by a significant (P<.05, Kruskal-Wallis test) improvement of patency scores compared with the control animals. The median patency score was 2 initially and reached a value of 3 during the infusion of high-dose TP-9201.
At the conclusion of the experimental protocol, thrombi were removed from the carotid artery and weighed. No significant change in carotid artery thrombus weight was noted in the low-dose TP-9201 group as compared with the vehicle-treated group (Table 2⇑). In the high-dose TP-9201 group, however, there was a significant reduction in the thrombus weight.
Upon activation by a diverse group of agonists, the platelets undergo shape change accompanied by changes in actin cytoskeleton, which lead to surface expression of adhesive molecules termed integrins. GPIIb/IIIa is a member of the integrin family of cell adhesion molecules, and it binds to a number of adhesive proteins such as fibrinogen, vWF, vitronectin, and fibronectin.9 The platelet GPIIb/IIIa binds to fibrinogen by specific-binding sequences, either the tetrapeptide sequence containing RGD (Aα95-98) or the dodecapeptide sequence (γ400-411) in the ligand molecule. The interaction of GPIIb/IIIa with fibrinogen represents the final event in platelet aggregation and thrombus formation. Several linear peptides20 21 and synthetic peptides22 23 24 containing the RGD sequence have been shown to inhibit platelet aggregation and prevent thrombus formation.
Experimental25 26 and clinical27 28 29 30 evidence supports a significant role for platelet- and thrombin-mediated mechanisms in the pathogenesis of abrupt vessel closure and acute ischemic complications after percutaneous transluminal angioplasty. A number of physiological agonists can cause platelet activation in vivo. These include collagen exposed on the surface of a ruptured plaque, ADP (which may be released from platelet-dense granules or during the lysis of red blood cells subjected to high shear forces at the site of arterial stenosis), and thrombin (which is generated as a thrombus is formed and lysed). In addition, thrombolytic agents can activate platelets, either directly or indirectly, via thrombin generation and thereby establish a local environment at the site of vessel wall injury in which the fibrinolytic action is countered by enhanced platelet reactivity and deposition at the site of the residual thrombus mass.31 32 Antiplatelet agents currently in use are effective against one of the multiple agonists capable of aggregating platelets in vitro. These agents include aspirin, which inhibits the cyclooxygenase-mediated metabolism of AA leading to platelet-derived thromboxane A2; ticlopidine and clopidogrel, which inhibit ADP-mediated ex vivo platelet aggregation; thromboxane synthetase or receptor antagonists; and thrombin inhibitors that act at specific platelet receptor sites to induce aggregation. Clinical benefit with these agents when used alone in the acute setting is less than ideal.
TP-9201 is a synthetic peptidic molecule (molecular weight=1135.5) that acts as an antagonist of the GPIIb/IIIa receptor and inhibits platelet aggregation.13 14 33 In the present study we used a canine model of platelet-dependent arterial rethrombosis to evaluate the efficacy of TP-9201. Administration of TP-9201 as an adjunct to thrombolysis resulted in maintenance of vessel patency despite the presence of deep vessel wall injury. This effect was accomplished by inhibition of platelet–vessel wall interaction and was correlated with inhibition of ex vivo platelet aggregation in response to both ADP and AA. A typical feature of the experimental model is the CFRs that occur after local application of a thrombolytic agent at the site of the occlusive thrombus and its subsequent lysis. The CFRs are characteristic of ongoing platelet–vessel wall interaction.34 Infusion of TP-9201 not only reduced the CFRs but also increased the quantity and improved the quality of blood flow in the carotid artery. It was shown earlier that TP-9201 enhanced rTPA-induced thrombolysis in a canine model of coronary artery rethrombosis.14 Although not statistically significant, TP-9201 exhibited slight enhancement of thrombolysis as reflected by the median time to reperfusion. Whereas the model for induction of arterial thrombosis is similar in both of the studies, the lytic agent and the route of its administration were different. Tschopp et al14 administered rTPA as a continuous 90-minute infusion, whereas we administered APSAC as a local intra-arterial infusion over 60 seconds. The latter represents a greater challenge for the antithrombotic potential of the drug under study. Moreover, limiting the thrombolytic agent to the site of the thrombus avoids development of a systemic lytic state that would otherwise contribute to the overall efficacy of the thrombolytic agent. Although APSAC-induced thrombolysis was moderately enhanced, rethrombosis was inhibited by TP-9201, indicating that despite the increased thrombogenic stimulus of the arterial wall injury and residual thrombus, it could limit further recruitment of platelets at the site of injury.
The in vivo efficacy of TP-9201 correlated well with the aggregation profile in the heparinized PRP but not with that in citrated PRP. Both the low and high doses of TP-9201 produced >90% inhibition of platelet aggregation in citrated PRP. However, in heparinized PRP the low and high doses produced 21% and 45% inhibition of platelet aggregation, respectively. This apparent inconsistency can be explained as follows. Sodium citrate is used routinely in standard platelet aggregation assays. However, the presence of citrate decreases the concentration of ionized Ca2+.11 35 The concentration of ionized calcium influences the in vitro aggregation response. Furthermore, the presence of a positively charged arginine following the RGDX sequence in TP-9201 may allow it to compete with Ca2+ and thereby affect its binding to the GPIIb/IIIa receptor. The presence of citrate and the resulting decrease in Ca2+ may artificially increase the degree of ex vivo inhibition of platelet aggregation by a given dose of TP-9201. Dosing regimens based on the degree of ex vivo platelet aggregation in citrated PRP may provide misleading information regarding an effective dose for in vivo prevention of platelet reactivity. Ex vivo platelet aggregation responses conducted in PRP, prepared from heparinized blood, should provide a more accurate assessment of the dose needed for in vivo efficacy. A similar phenomenon and conclusion were reported recently with respect to the GPIIb/IIIa receptor antagonist integrilin.36
There appears to be a correlation between the pharmacokinetic half-life (2.5 to 2.6 hours) and the pharmacodynamic half-life (3 hours) of TP-9201,37 indicating that its action is related directly to the concentration in the circulation. This property confers a significant advantage, since it may result in rapid resolution of the platelet inhibitory effects once the drug infusion is terminated. This may also allow for rapid normalization of any bleeding problems associated with TP-9201 infusion.
The present study confirms previously reported investigations that showed antithrombotic efficacy of TP-9201 in hamsters with a standardized femoral vein endothelial injury predisposing to platelet-rich mural thrombosis, in dogs with a carotid arterial eversion graft inserted into the femoral artery,13 and in a canine model of thrombolysis.14 Low-molecular-weight RGD peptides bind reversibly and competitively to the GPIIb/IIIa receptors and are eliminated rapidly from the plasma compartment, giving rise to a shorter duration of pharmacodynamic response. This can be an advantage over agents that bind irreversibly to the platelet receptors and/or have protracted effects of immunogenicity. The in vivo potency of linear RGD peptides was low.20 High doses of a tetrapeptide, acetyl-Arg-Gly-Asp-Ser-NH2 (Bitistatin), were required to prevent coronary artery thrombosis, and the duration of effect was brief.21 In contrast, cyclic peptides including MK-0552,22 SK&F106760 and SK&F107260,23 24 and TP-920113 14 appear to have an advantage over linear peptides in terms of potency and pharmacological half-life. The cyclic conformation renders RGD analogues more stable in blood and imparts a higher affinity for the integrin receptor.23 The short half-life of TP-9201 provides a means of titrating the platelet-inhibitory effect or terminating the action of the drug by stopping the infusion.
The primary antiplatelet agents currently available for the treatment of stroke include aspirin, ticlopidine, and prostacyclin. Aspirin and ticlopidine, although effective when used long term, have an unpredictable effect when administered during the acute phase.38 Prostacyclin analogues when administered during acute thrombosis rapidly inhibit the platelet activity but have adverse effects, particularly hypotension. The potential role of GPIIb/IIIa receptor inhibition in the prophylaxis of cerebrovascular thrombosis and thromboembolic events remains to be explored. The ability of TP-9201 to achieve rapid inhibition of platelet reactivity and maintain arterial blood flow may allow the drug to be used as an adjunctive agent in the management of stroke patients. The limited duration of action upon termination of its administration provides TP-9201 with a reasonable safety margin relative to other inhibitors of the platelet GPIIb/IIIa receptor. It must be cautioned, however, that the incidence of reocclusion after successful thrombolysis of human cerebral vascular lesions is not known. It is possible that this is not as major a problem in the cerebral circulation as it is in the coronary circulation. The major limiting factor in thrombolysis for cerebral infarction is intracranial bleeding, and perhaps reocclusion. The propensity for antiplatelet therapy to affect hemostasis and exacerbate intracranial bleeding would be a distinct negative aspect of combined thrombolysis and inhibition of the platelet glycoprotein IIb/IIIa receptor.
Selected Abbreviations and Acronyms
|APSAC||=||anisoylated plasminogen streptokinase activator complex|
|aPTT||=||activated partial thromboplastin time|
|CFRs||=||the cyclic flow reductions|
|vWF||=||von Willebrand factor|
This study was supported in part by a grant from the National Institutes of Health, Heart, Lung and Blood Institute, HL-19782-16, and by The Cardiovascular Research Fund, University of Michigan. The authors wish to thank Dr Michael D. Pierschbacher from Telios Pharmaceuticals for providing TP-9201.
- Received January 9, 1997.
- Revision received May 16, 1997.
- Accepted May 28, 1997.
- Copyright © 1997 by American Heart Association
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