Anistreplase Research Articles

FcγRIIa - dependent platelet activation identified in COVID-19 vaccine-induced immune thrombotic thrombocytopenia-, heparin-induced thrombocytopenia, streptokinase- and anisoylated plasminogen-streptokinase activator complex-induced platelet activation.

Coronavirus disease 2019 (COVID-19), which was caused by the coronavirus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was globally responsible for remarkable morbidity and mortality. Several highly effective vaccines for COVID-19 were developed and disseminated worldwide within an unprecedented timescale. Rare but dangerous clotting and thrombocytopenia events, and subsequent coagulation abnormalities, have been reported after massive vaccination against SARS-CoV-2. Soon after their global rollout, reports of a morbid clinical syndrome following vaccination with adenovirus-DNA-based vaccines appeared. In the spring of 2021, reports of a novel, rare and morbid clinical syndrome, with clinically devastating and fatal complication after vaccination with adenovirus-based coronavirus vaccines (Janssen/Johnson & Johnson and Astra-Zeneca vaccines) led to a brief suspension of their use by several countries. Those complications were associated with unusual cerebral and splanchnic venous thrombosis, and circulating autoantibodies directed against anti-platelet factor 4 (PF4), a protein secreted from platelets, leading to the designation: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT). The reported VITT incidence remains very low and does not affect the overall benefit of immunization, however, if left untreated, VITT can be debilitating or even fatal. VITT resembled specific adverse drugs' reactions that also involved the production of autoantibodies and subsequent abnormal platelet activation through platelet FcγRIIa. These unusual but well-documented drug reactions were heparin-induced thrombocytopenia (HIT), streptokinase- (SK), and anisoylated plasminogen-streptokinase activator complex- (APSAC) associated with platelet-activating antibodies. There was considerable overlapping of clinical features between VITT, COVID-19 and these adverse drugs' reactions. We review the phenomenon of VITT against the backdrop of shared and common mechanisms that underlie HIT-, SK-, and APSAC-platelet FcγRIIa-dependent platelet activation. An understanding of VITT's pathogenesis may be achieved by comparing and contrasting VITT-, HIT-, SK- and APSAC-induced platelet activation mechanisms, their respective physiopathology and similarities. Discussing these conditions in parallel provides insight into complex immunological disorders and diseases associated with abnormal hemostasis and thrombosis in particular.

Duration of Symptoms Is Not Always the Key Modulator of the Choice of Reperfusion for ST-Elevation Myocardial Infarction

Fibrinolytic therapy (FT) and primary percutaneous coronary intervention (PCI) are both well-accepted reperfusion therapies in ST-segment elevation myocardial infarction (STEMI). The evidence of randomized clinical trials indicates a relatively modest difference in 30-day mortality (≈1%) in favor of primary PCI over fibrin-specific FT and was based on very timely primary PCI (ie, a primary PCI–related delay of 40 minutes [door-to-balloon less door-to-needle time]).1 Longer delays to primary PCI, which are far more frequent in clinical practice,2 are associated with attenuated benefit or no benefit at all, particularly when compared with fibrin-specific FT.3,4 The benefit of timely primary PCI over FT is likely to especially apply to higher-risk patients.5,6 Irrespective of the method of reperfusion, the potential for myocardial salvage and better clinical outcome is inversely proportional to ischemic time or its only available clinical surrogate, symptom duration.7–12 These considerations underpin the notion expressed in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of STEMI that timely reperfusion therapy is likely more important in determining outcome than whether FT or primary PCI is the chosen reperfusion method.13 Response by Armstrong et al p 1310 The ACC/AHA STEMI guidelines highlight the time point of 3 hours of symptom duration in guiding the choice of reperfusion therapy. They state that if symptom duration is <3 hours, no preference exists between FT and primary PCI provided that treatment is timely (for FT, door-to-needle time <30 minutes; for primary PCI, door-to-balloon time <90 minutes and ≤60 minutes between estimated needle time and estimated balloon time). However, if symptom duration exceeds 3 hours, these guidelines favor primary PCI over FT, again provided that primary PCI can be performed in a timely fashion.13 This article reexamines the evidence that may or may not be the basis …

Thrombolytic Therapy in Dogs and Cats

Abstract Objective: To review the thrombolytic agents most commonly used in humans, their mechanisms of action, potential uses, adverse effects, and reports of their use in dogs and cats. Human data synthesis: Thrombolytic agents avaliable in human medicine include streptokinase, urokinase, tissueplasminogen activator (t‐PA), single‐chain urokinase plasma activator (scu‐PA) and anisoylated plasminogen‐strep‐tokinase activator complex (APSAC). These agents were originally used for the management of proximal deep vein thrombosis and severe pulmonary embolism but more recently, use of these drugs has been extended to include the treatment of acute peripheral arterial disease, cerebrovascular disease (stroke) and acute coronary thrombosis. The most predictable side effect associated with the use of thrombolytic therapy is hemorrhage. Veterinary data synthesis: Clinical experience with thrombolytic agents in small animals is limited to streptokinase and t‐PA. It is possible, that as in humans, canine and feline patients with PTE and right ventricular dysfunction may benefit from thrombolytic therapy but there are no veterinary studies to support this theory to date. Successful use of streptokinase has been documented in a small number of canine patients with systemic thromboembolism. 63 Thrombolytic therapy is relatively efficacious in cats with aortic thromboemboli but is associated with a high mortality rate. 59,60,64 With regard to use of t‐PA in veterinary medicine, the small number of animals treated with varying protocols makes it impossible to provide safe and effective dose recommendations at this time. Conclusions: Future goals for thrombolytic therapy in veterinary medicine include determination of more specific clinical indications, as well as design of effective protocols that minimize mortality and morbidity.

Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens

Background In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction. Methods and Results The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of ≤3 hours and >3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76.3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P = .09), anisoylated plasminogen streptokinase activator complex (59.5% vs 34.8%, P = .004), and urokinase (62.3% vs 41.7%, P = .03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy. Conclusions We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset. (Am Heart J 1999;137:34-8.)

TP-9201, a glycoprotein IIb/IIIa platelet receptor antagonist, prevents rethrombosis after successful arterial thrombolysis in the dog.

We examined the ability of TP-9201, a platelet glycoprotein IIb/IIIa receptor antagonist, to prevent carotid artery rethrombosis in the anesthetized dog. 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 micrograms/kg plus 3 micrograms.kg-1.min-1, 240 minutes; n = 7), or high-dose TP-9201 (185 micrograms/kg plus 5 micrograms.kg-1.min-1, 240 minutes; n = 7). Ex vivo platelet aggregation responses to ADP or arachidonic acid were determined. 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. 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.

Platelet aggregation by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex: heterogenous responses in platelet-rich plasma but not in washed platelets

Platelet aggregation by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex: heterogenous responses in platelet-rich plasma but not in washed platelets

TIMI grade 3 flow and reocclusion after intravenous thrombolytic therapy: A pooled analysis

Early and sustained flow of grade 3 according to Thrombolysis in Myocardial Infarction (TIMI) criteria and reocclusion rates are the key measures that define the physiologic efficacy of thrombolytic agents in the treatment of acute myocardial infarction. We performed a systematic overview of angiographic studies after intravenous thrombolysis with accelerated and standard-dose tissue-plasminogen activator (TPA), anisoylated plasminogen streptokinase activator complex (APSAC), and streptokinase. There were 5475 angiographic observations from 15 studies for TIMI flow analysis and 3147 angiographic observations from 27 studies for reocclusion. At 60 and 90 minutes, the rates of TIMI grade 3 flow were 57.1% and 63.2%, respectively, with accelerated TPA, 39.5% and 50.2% with standard-dose TPA, 40.2% and 50.1% with APSAC, and 31.5% at 90 minutes with streptokinase. Overall reocclusion with standard-dose TPA was 11.8% versus 6.0% for accelerated TPA, 4.2% for streptokinase, and 3.0% for APSAC. Although the incidence of TIMI grade 3 flow increased over time with all thrombolytic regimens, decreased patency was observed at 180 minutes with accelerated TPA. Still, accelerated TPA is the most effective agent to establish early (90-minute) TIMI grade 3 flow. (Am Heart J 1997;133:273-82.)

Evaluation of Thrombolytic Agents

The mechanism of action of currently available thrombolytic agents, such as streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) and anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC), involves conversion of inactive plasminogen to plasmin, a potent fibrinolytic. However, the relatively weak substrate specificity of first generation agents (streptokinase and urokinase) can result in a state of systemic fibrinolysis and associated bleeding complications. The second generation drugs such as alteplase were developed in an attempt to enhance fibrin specificity, so that only enzymatic conversion of fibrin-complexed plasminogen would take place, thus avoiding systemic fibrinolysis. Results from large clinical trials have failed to consistently show any significant differences between first and second generation thrombolytic agents in the incidence of bleeding. In the clinical setting, thrombolytic agents have been evaluated primarily in patients with acute myocardial infarction and have been shown to significantly reduce morbidity and mortality compared with conservative treatment. The focus of current and future research is to investigate these agents in patients with other vaso-occlusive or ischaemic conditions (e.g. stroke), and also to evaluate different drug administration regimens and the use of adjunctive therapies such as aspirin (acetylsalicylic acid) and heparin.

Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex

Streptokinase (SK) is one of the plasminogen activators currently used in therapeutics. SK antibodies may appear in the blood after thrombolytic therapy with SK or after ß-hemolytic streptococci infection. Such antibodies may both activate platelets and neutralize the ability of SK to convert plasminogen into plasmin. We previously demonstrated that platelet activation induced by the combination of IgG anti-SK and anisoylated plasminogen-SK activator complex (APSAC) is mediated by Fγ7RIIal receptor. However, the mechanism by which IgG anti-SK and APSAC (or SK) transduce an activating signal across the platelet plasma membrane remains unknown. We have demonstrated in the present study that the platelet aggregation induced by the combination of IgG anti-SK and APSAC is accompanied by an increase in inositol phosphate, Ca2+ mobilization and thromboxane (Tx) A2 generation. Neomycin, erbstatin and GF 109203X, which inhibit phospholipase C (PLC), protein tyrosine kinase (PTK) and protein kinase C (PKC) activities, respectively, abolished platelet aggregation induced by IgG anti-SK plus APSAC, indicating the pivotal roles of the PLC, PTK and PKC pathways in this immunological activation. In addition, TxA2 generation is also important since aspirin, a cyclo-oxygenase inhibitor and SQ 29548, a TxA2 receptor antagonist, showed significant inhibition of the platelet response. The contribution of released ADP was confirmed using apyrase, which significantly inhibited IgG anti-SK plus APSAC-induced platelet aggregation. Finally, WEB 2086, a platelet-activating factor (PAF) receptor antagonist, was not effective, indicating that PAF is not involved in this process. APSAC- or SK-induced platelet activation may limit the therapeutic effectiveness of the drug and may contribute to the pathogenesis of early reocclusion. The study of the mechanism leading to APSAC-induced platelet activation could be relevant for a better understanding of the physiopathology of immune complex disorder diseases and thrombolytic treatment failure.

Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex

Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex

Signal transduction in the platelet activation induced by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex

Streptokinase (SK) is one of the plasminogen activators currently used in therapeutics. SK antibodies may appear in the blood after thrombolytic therapy with SK or after-hemolytic streptococci infection. Such antibodies may both activate platelets and neutralize the ability of SK to convert plasminogen into plasmin. We previously demonstrated that platelet activation induced by the combination of IgG anti-SK and anisoylated plasminogen-SK activator complex (APSAC) is mediated by Fc gamma RIIa1 receptor. However, the mechanism by which IgG anti-SK and APSAC (or SK) transduce an activating signal across the platelet plasma membrane remains unknown. We have demonstrated in the present study that the platelet aggregation induced by the combination of IgG anti-SK and APSAC is accompanied by an increase in inositol phosphate, Ca2+ mobilization and thromboxane (Tx) A2 generation. Neomycin, erbstatin and GF 109203X, which inhibit phospholipase C (PLC), protein tyrosine kinase (PTK) and protein kinase C (PKC) activities, respectively, abolished platelet aggregation induced by IgG anti-SK plus APSAC, indicating the pivotal roles of the PLC, PTK and PKC pathways in this immunological activation. In addition, TxA2 generation is also important since aspirin, a cyclooxygenase inhibitor and SQ 29548, a TxA2 receptor antagonist, showed significant inhibition of the platelet response. The contribution of released ADP was confirmed using apyrase, which significantly inhibited IgG anti-SK plus APSAC-induced platelet aggregation. Finally, WEB 2086, a platelet-activating factor (PAF) receptor antagonist, was not effective, indicating that PAF is not involved in this process. APSAC- or SKinduced platelet activation may limit the therapeutic effectiveness of the drug and may contribute to the pathogenesis of early reocclusion. The study of the mechanism leading to APSAC-induced platelet activation could be relevant for a better understanding of the physiopathology of immune complex disorder diseases and thrombolytic treatment failure.

233 Signal transduction of platelet activation induced by IgG anti-streptokinase and by apsac (anisoylated-plasminogen streptokinase activator complex)

233 Signal transduction of platelet activation induced by IgG anti-streptokinase and by apsac (anisoylated-plasminogen streptokinase activator complex)

A randomized factorial trial of reperfusion strategies and aspirin dosing in acute myocardial infarction

The focus of new research efforts to improve the morbidity and mortality associated with acute myocardial infarction (AMI) has turned to adjuvant agents that show promise of improving outcomes following coronary thrombolysis. We enrolled 162 patients with AMI in a randomized trial comparing front-loaded tissue-plasminogen activator (t-PA) plus weight-adjusted heparin with anisoylated plasminogen streptokinase activator complex (APSAC) without heparin as well as standard-dose (325 mg) and low-dose (81 mg) aspirin. The primary end point was an in-hospital morbidity profile; secondary end points were clinical and angiographic potency and hemorrhagic events. Selected sites performed an electrocardiographic substudy to determine the time to 50% ST-segment recovery and the time to steady state. Although the trial was terminated when the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I trial showed that t-PA had a significant mortality advantage over streptokinase, important trends were evident. Patients given t-PA and heparin were better anticoagulated (p = 0.001), yet AP-SAC-treated patients had more bleeding complications. The primary end point favored t-PA (25.4% vs 31.3%), and the secondary end points were similar in both groups. In the electrocardiographic substudy, the t-PA group achieved both 50% ST-segment recovery and steady-state recovery sooner than the APSAC group. Patients taking low-dose aspirin had lower in-hospital mortality and less recurrent ischemia but more strokes than the standard-dose aspirin group. Thus, this trial demonstrated trends favoring front-loaded t-PA with weight-adjusted heparin over APSAC without heparin in the treatment of AMI. The use of low-dose aspirin did not appear to impose a loss of protection from adverse events, nor did standard-dose aspirin increase serious bleeding.

Medical therapy for ischemic stroke.

Therapy for stroke is undergoing major changes. Many of the changes parallel the advances made in the therapy for myocardial infarction. Acute intervention with cytoprotective and thrombolytic agents is undergoing active investigation. Cytoprotective therapy includes drugs that act to prevent cell death during ischemia and reperfusion. These agents include calpain inhibitors, voltage-sensitive calcium- and sodium-channel antagonists, receptor-mediated calcium-channel antagonists [including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonists], glutamate-synthesis inhibitors, glutamate-release antagonists, gamma-aminobenzoic acid (GABA) antagonists, 5-HT (serotonin) receptor agonists, gangliosides, antioxidants, growth factors, antiapoptotic agents, and antiadhesion molecules. Thrombolysis is effective in myocardial infarction. Thrombolysis is undergoing evaluation in stroke with streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), tissue plasminogen activator (t-PA; including recombinant t-PA), urokinase, and single-chain urokinase (scu-PA). Both systemic and selective administration are being evaluated. Preventive therapy with both antiplatelet and anticoagulant drugs sheds new light on how best to stratify patients in terms of a risk-benefit ratio. Continuing public education will be essential as stroke therapy advances.

Antithrombotic effect of GYKI-14766 in a canine model of arterial and venous rethrombosis: a comparison with heparin.

We compared the antithrombotic effects of the thrombin inhibitor, D-methyl-phenylalanyl-prolyl-arginal (GYKI-14766) with those of heparin in a canine model of arterial and venous rethrombosis. Thrombogenesis was induced by electrolytic injury to the endothelial surface of the carotid artery and jugular vein. Either heparin (300 U/kg, n = 7), GYKI-14766 (0.5 mg/kg/h, n = 7), or saline (n = 10) was administered intravenously (i.v.) immediately after the local administration of anisoylated plasminogen streptokinase activator complex (APSAC 0.1 U/kg). Supplemental doses of heparin (100 U/kg) were administered at 1-h intervals. Infusion of GYKI-14766 was maintained for 5 h throughout the experiment. Ex vivo platelet aggregation in response to ADP or arachidonic acid (AA) was not changed in any of the experimental groups. Both GYKI-14766 and heparin increased the activated partial thromboplastin time (aPTT) over their respective baseline values. Heparin, but not GYKI-14766, increased the bleeding time. After successful thrombolysis, arterial and venous rethrombosis occurred in all saline-treated dogs. GYKI-14766 prevented cyclic flow variations and reocclusion in the artery and the vein (p < 0.01). Heparin had only minimal effects on the artery and no effect on the vein. Arterial thrombus weights were reduced by GYKI-14766 [saline control = 24 +/- 4 mg, GYKI-14766 = 9 +/- 3 mg, (p < 0.05); heparin = 14 +/- 2 mg, p = NS]. The venous thrombus weights were reduced slightly by GYKI-14766 and were unchanged by heparin (saline = 25 +/- 5 mg, GYKI-14766 = 13 +/- 4 mg, heparin = 26 +/- 3 mg). The data suggest that GYKI-14766 is effective in preventing occlusive rethrombosis in both the arterial and venous circulation after thrombolysis without augmenting bleeding time. GYKI-14766 may represent an alternative to heparin as an adjunctive agent during thrombolytic therapy.

Fibrin-selective thrombolytic therapy for acute myocardial infarction.

Thrombolytic therapy of acute myocardial infarction is based on the premise that coronary artery thrombosis is its proximate cause. Rupture of atheromatous plaque leads to occlusive thrombosis that produces myocardial ischemia and cell necrosis, leading to loss of ventricular function and possibly death.1 2 One approach to the treatment of established thrombosis consists of pharmacological dissolution of the blood clot by intravenous infusion of plasminogen activators that activate the fibrinolytic system (Fig 1⇓). The fibrinolytic system includes a proenzyme, plasminogen, which is converted by plasminogen activators to the active enzyme plasmin, which in turn digests fibrin to soluble degradation products. Inhibition of the fibrinolytic system takes place at the level of both the plasminogen activators (mainly by plasminogen activator inhibitor-1) and plasmin (mainly by α2-antiplasmin).3 Thrombolytic agents that are either approved for clinical use or under clinical investigation in patients with acute myocardial infarction include streptokinase, recombinant tissue-type plasminogen activator (rTPA, prepared either as alteplase or as duteplase), rTPA derivatives such as reteplase and TNK-rTPA, anisoylated plasminogen streptokinase activator complex, two-chain urokinase-type plasminogen activator (UPA), recombinant single-chain UPA (prourokinase), and more recently, recombinant staphylokinase and derivatives. The hypothesis underlying thrombolytic therapy in acute myocardial infarction is that early and sustained recanalization prevents cell death, reduces infarct size, preserves myocardial function, and reduces early and late mortality. Figure 1. Schematic representation of the fibrinolytic system. The proenzyme plasminogen is activated to the active enzyme plasmin by plasminogen activators. Plasmin degrades fibrin into soluble fibrin degradation products. Inhibition of the fibrinolytic system may occur at the level of the plasminogen activators by plasminogen activator inhibitors (PAI) or at the level of plasmin, mainly by α2-antiplasmin. SK indicates streptokinase. The beneficial effects of thrombolytic therapy in acute myocardial infarction are now well established, and it has become routine …

Overview of randomized trials of intravenous heparin in patients with acute myocardial infarction treated with thrombolytic therapy

Intravenous heparin is routinely given after thrombolytic therapy for patients with acute myocardial infarction in the United States and in some, but by no means all, other countries. Several trials have documented improved infarct-artery patency in patients treated with heparin; however, none was large enough individually to assess the effect of heparin on clinical outcomes. We performed a systematic overview of the 6 randomized controlled trials (1,735 patients) to summarize the available data concerning the risks and benefits of intravenous heparin versus no heparin after thrombolytic therapy. Mortality before hospital discharge was 5.1% for patients allocated to intravenous heparin compared with 5.6% for controls (relative risk reduction of 9%, odds ratio 0.91, 95% confidence interval 0.59 to 1.39). Similar rates of recurrent ischemia and reinfarction were observed among those allocated to heparin therapy or control. The rates of total stroke, intracranial hemorrhage, and severe bleeding were similar in patients allocated to heparin; however, the risk of any severity of bleeding was significantly higher (22.7% vs 16.2%; odds ratio 1.55, 95% confidence interval 1.21 to 1.98). There was no significant difference in the observed effects of heparin between patients receiving tissue-type plasminogen activator and those receiving streptokinase or anisoylated plasminogen streptokinase activator complex, or between patients who did and did not receive aspirin. The findings of this overview demonstrate that insufficient clinical outcome data are available to support or to refute the routine use of intravenous heparin therapy after thrombolysis. It is not known if these findings are due to lack of statistical power, inappropriate levels of anticoagulation, or lack of benefit of intravenous heparin. Large randomized studies of heparin (and of newer antithrombotic regimens) are needed to establish the role of such therapy.

Fibrolase, an active thrombolytic enzyme in arterial and venous thrombosis model systems.

Pharmacologic dissolution of an established thrombus has become an accepted therapeutic approach for many patients who develop thrombotic occlusive disease (1). Intravenous infusion of plasminogen activators, including recombinant tissue plasminogen activator (rt-PA), urokinase (UK), streptokinase (SK), and anisoylated plasminogen streptokinase-activator complex (APSAC), is effective in restoring blood flow in occluded arteries and veins (1,2). SK, APSAC, and UK activate circulating plasminogen as well as fibrin-bound plasminogen within the thrombus. The widespread systemic activation of the fibrinolytic system, leads to the depletion of α2-antiplasmin (α2-AP), and generation of free plasmin that degrades several plasma proteins, including fibrinogen, and factors V and VIII. On the other hand, rt-PA and recombinant single-chain urokinase-type plasminogen activator (scu-PA), activate plasminogen preferentially on the fibrin surface, where the fibrin associated plasmin is protected from rapid inactivation by α2-AP. Despite the availability of fibrin-specific thrombolytic agents, currently available therapy has a number of important limitations. A significant percentage (25–30%) of patients with acute myocardial infarction are resistant to reperfusion within 90 minutes despite the use of the most potent thrombolytic agents or combinations (3) and systemic fibrinogenolysis with accompanying bleeding is encountered frequently (4). Further, 10–30% of patients experience acute coronary reocclusion following thrombolytic therapy (5). There is also a small but significant risk of neurological complications (6) including stroke (7) and intracranial hemorrhage (8). Additionally, there is concern about the rapidly acting plasma inhibitor of t-PA, PAI-1 (9), which is significantly increased in myocardial infarction (10), and may, with other factors, predispose patients to reinfarction (11).KeywordsHigh Performance Liquid ChromatographyBlood Flow VelocitySnake VenomThrombolytic AgentFibrinolytic EnzymeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Flow cytometry reveals activated GP IIb-IIIa complexes on platelets from patients undergoing thrombolytic therapy after acute myocardial infarction.

We report the detection of activated GP IIb-IIIa complexes on platelets of patients undergoing thrombolytic therapy after acute myocardial infarction. Protocols were established for the monoclonal antibodies (mAbs): VH10, anti-P-selectin, a marker of platelet secretion; 9F9 and F26, two anti-RIBS (receptor-induced binding sites) mAbs specific for fibrinogen (Fg) bound to the GP IIb-IIIa receptor. Of ten patients studied: two were treated with streptokinase, four with APSAC (anisoylated plasminogen-streptokinase activator complex), and three with rt-PA. Platelets were tested on at least five occasions in the week following therapy. The percentage of platelets positive with 9F9 was often high, and reached a maximum within three days. By this time, plasma Fg levels, which fell during fibrinolysis, had begun to return to normal. Levels of activated platelets had fallen to baseline after 7 days. PAC-1, a mAb which binds directly to the activated GP IIb-IIIa complex, confirmed the results with 9F9, but F26 was a less sensitive probe. Binding of the anti-P-selectin mAb (VH10) was low, showing that little secretion had occurred. A concentration-dependent inhibition of 9F9 binding by RGDW peptide, a competitive inhibitor for Fg on GP IIb-IIIa, confirmed that Fg (or epitope-containing degradation products) were being located by the antibody. The activation of GP IIb-IIIa occurred despite the patients receiving aspirin and heparin. Thus platelets of some fibrinolytic patients have an increased tendency for surface activation within the first 72 h after treatment, a finding which would be compatible with an increased thrombotic tendency.

Current issues concerning thrombolytic therapy for acute myocardial infarction

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States—tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)—all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by ∼20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by ∼23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive. At present, any small differences in safety, efficacy and ease of administration of different thrombolytic agents are far outweighed by the large benefits that would accrue from earlier administration and wider utilization of any of these drugs.