Fibrin-specific Thrombolytic Agent Research Articles

Intracoronary thrombolysis in ST-elevation myocardial infarction: a systematic review and meta-analysis

BackgroundDespite restoration of epicardial blood flow in acute ST-elevation myocardial infarction (STEMI), inadequate microcirculatory perfusion is common and portends a poor prognosis. Intracoronary (IC) thrombolytic therapy can reduce microvascular thrombotic...

Fibrin-Specific Thrombolytic Therapy for Acute CVA within 6 Hours of Onset, Systematic Review and Meta-analysis

Objective: Cerebrovascular Accident (CVA) remains a major cause of disability and death and fibrinolytic agents might reduce long-term disability. We sought to determine whether patients receiving fibrin-specific thrombolytic agents acutely (within 6 h) following CVA had improved functional outcome, or decreased mortality or increased intracerebral bleeding at 6-months than patients receiving placebo. Materials and Methods: We conducted a systematic review of randomized controlled clinical trials that assessed 6-months functional outcome, mortality and intracranial hemorrhage and compared thrombolytic therapy with placebo in patients randomized within the first 6 hours following CVA. We searched these databases: MEDLINE (1990-2018), Cochrane Central Register of Controlled Trials, and Cochrane Database for Systematic Reviews. Two blinded reviewers reviewed the eligible articles and rated study quality using the Jadad score. We calculated pooled Odds Ratios (ORs) using a random effect model. Results: We included 9 studies with 6523 enrolled participants and had 673 deaths. Compared with placebo, thrombolytic therapy within 6 hours of CVA did not result in a statistically significant reduction in 6-month mortality (OR 1.21, 95% confidence interval [CI] 0.94–1.55). More patients in the thrombolytic therapy group had favorable functional outcome (OR 1.20 confidence interval [CI] 1.07–1.35). Thrombolytic therapy caused more fatal intracerebral bleeding than placebo (OR 5.61 confidence interval [CI] 3.40-9.24). Conclusion: Fibrin-Specific thrombolytic within 6 hours of CVA improves functional outcome at the expense of increasing symptomatic and fatal intracerebral bleed. Future studies are required before extending the thrombolytic window to 6-hours.

Early Fibrinogen Depletion and Symptomatic Intracranial Hemorrhage After Reperfusion Therapy.

Background and Purpose- We aimed to thoroughly investigate the relationship between early fibrinogen depletion and symptomatic intracranial hemorrhage (sICH) in patients receiving reperfusion therapy including intravenous thrombolysis (IVT) with or without endovascular thrombectomy (EVT). Methods- This study included 1135 stroke patients with baseline and follow-up fibrinogen levels at 2 hours after the beginning of alteplase infusion for those with IVT only or immediately after the end of EVT for those with combined IVT and EVT. Patients received alteplase up to 9 hours after the onset or on awakening based on automated perfusion imaging. sICH was ascertained using ECASS II (The Second European-Australasian Acute Stroke Study) criteria. Δfibrinogen was calculated as follow-up fibrinogen minus baseline fibrinogen. Results- In patients with IVT only, baseline fibrinogen level was 3.36±0.94 g/L and decreased to 2.47±0.80 g/L at 2 hours after the beginning of alteplase infusion. In patients with IVT followed by EVT, baseline fibrinogen level was 3.35±0.82 g/L and decreased to 2.52±0.83 g/L immediately after the end of EVT. sICH was observed in 44 (3.9%) patients. The extent of Δfibrinogen was associated with sICH in patients with IVT only (odds ratio, 1.929; 95% CI, 1.402-2.654; P<0.001) and in those with IVT followed by EVT (odds ratio, 1.765; 95% CI, 1.135-2.743; P=0.012). Conclusions- An early decrease in fibrinogen levels was related to sICH after reperfusion therapy with alteplase. More fibrin-specific thrombolytic agents are warranted to be tested in acute ischemic stroke patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03367286.

Long-Term Outcomes of Pharmacoinvasive Reperfusion Strategy Depending on the Choice of Thrombolytic Agent in ST-Segment Elevation Myocardial Infarction

There is limited information on the comparative results of using different thrombolytic drugs for pharmacoinvasive reperfusion in acute ST-segment elevation myocardial infarction (STEMI). There is special interest in comparing the efficacy of fibrin-selective and fibrin-non-selective thrombolytics. Aim. To study the prevalence of major adverse cardiovascular events and the status of patients who had STEMI and pharmacoinvasive reperfusion a year ago, depending on the choice of thrombolytic drug. Material and methods . 240 STEMI-patients undergoing pharmacoinvasive reperfusion (reference event) were divided into 4 groups depending on the choice of the thrombolytic drug (alteplase [group 1], teneteplase [group 2], fortetelizin [group 3], streptokinase [group 4]) as well as into 2 groups depending on the fibrin-specificity of thrombolytics. One year after the reference event the prevalence of major cardiovascular events (death, repeated myocardial infarction, stroke, repeated revascularization of the target vessel, and their combination) was assessed. Data of echocardiography and 24-hour ECG monitoring, indicis of rating scale of clinical state in patients with heart failure (RSCS, Mareev V.Y, 2000), results of determination of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and of six-minute walk test were also analyzed. Results. One year after the reference event, patients who received fibrin-selective thrombolytics (groups 1,2, 3) compared with patients treated with fibrin-non-selective drug (group 4) had a higher left ventricular ejection fraction (49.8±7.4% vs 47,4±6.8%; p=0.048), lower index of impaired local contractility (1.19 [1.06; 1.38] vs 1.25 [1.175; 1.5], p=0.029), an end-diastolic volume (1 39.1 ±28.6 ml vs 148.7±23.9 ml; p=0.027), the size of the left atrium (39.0±4.6 mm vs 41.1 ±3.1 mm, p=0.007 ), and insignificantly lower prevalence of atrial fibrillation (1.5% vs 6.7%, p=0.068). They also showed a lower prevalence of supraventricular tachycardia (4.5% vs 13.3%, p=0.049) and ventricular extrasystoles (54.5% vs 76.7%, p=0.022) as well as the daily number of ventricular extrasystoles (4.5 [0; 32.0] vs 34, 0 [2.25; 80.25], p=0.001) with more favorable gradations and indicators of heart rate variability. Statistically significantly lower NT-proBNP level (148 [1 20; 208.5] pg/ml vs 241 [189; 287] pg/ml; p=0.000) and chronic heart failure manifestation according to RSCS (p=0.033), as well as a longer distance in the six-minute walk test (p=0.000) were found in patients treated with fibrin-selective drugs. Statistically significant differences between groups 1, 2, 3 for the study period were not found. Significant differences in the prevalence of hard clinical endpoints (death, repeated myocardial infarction, stroke, repeated revascularization of the target artery) were not found in all groups. Conclusion. More favorable clinical, laboratory and instrumental parameters were found one year after STEMI and pharmacoinvasive reperfusion with fibrin-specific thrombolytic agents as compared with fibrin-non-specific thrombolytic. All groups had no statistically significant differences in the effect on hard clinical endpoints during the entire observation period.

Activity Regulation by Fibrinogen and Fibrin of Streptokinase from Streptococcus Pyogenes.

Streptokinase is a virulence factor of streptococci and acts as a plasminogen activator to generate the serine protease plasmin which promotes bacterial metastasis. Streptokinase isolated from group C streptococci has been used therapeutically as a thrombolytic agent for many years and its mechanism of action has been extensively studied. However, group A streptococci are associated with invasive and potentially fatal infections, but less detail is available on the mechanism of action of streptokinase from these bacteria. We have expressed recombinant streptokinase from a group C strain to investigate the therapeutic molecule (here termed rSK-H46A) and a molecule isolated from a cluster 2a strain from group A (rSK-M1GAS) which is known to produce the fibrinogen binding, M1 protein, and is associated with life-threatening disease. Detailed enzyme kinetic models have been prepared which show how fibrinogen-streptokinase-plasminogen complexes regulate plasmin generation, and also the effect of fibrin interactions. As is the case with rSK-H46A our data with rSK-M1GAS support a “trigger and bullet” mechanism requiring the initial formation of SK•plasminogen complexes which are replaced by more active SK•plasmin as plasmin becomes available. This model includes the important fibrinogen interactions that stimulate plasmin generation. In a fibrin matrix rSK-M1GAS has a 24 fold higher specific activity than the fibrin-specific thrombolytic agent, tissue plasminogen activator, and 15 fold higher specific activity than rSK-H46A. However, in vivo fibrin specificity would be undermined by fibrinogen stimulation. Given the observed importance of M1 surface receptors or released M1 protein to virulence of cluster 2a strain streptococci, studies on streptokinase activity regulation by fibrin and fibrinogen may provide additional routes to addressing bacterial invasion and infectious diseases.

Fibrinogen degradation coagulopathy and bleeding complications after stroke thrombolysis

Prominent fibrinogen cleavage by recombinant tissue plasminogen activator and formation of fibrinogen degradation products with anticoagulant properties was proposed to amplify the risk of thrombolysis-related bleeding complications, but supportive evidence mainly derived from studies on myocardial infarction. This study included 547 consecutive stroke patients treated with recombinant tissue plasminogen activator, who underwent repeated assessment of fibrinogen levels before and 6 hours after thrombolysis. Symptomatic intracranial hemorrhages were ascertained using National Institute of Neurological Disorders and Stroke criteria. Intracranial hemorrhage or systemic bleeding events manifested in 47 patients (8.6%). A decrease ≥200 mg/dL in the fibrinogen level 6 hours after thrombolysis emerged as a significant and independent predictor for bleeding risk (multivariable odds ratio [95% confidence interval] 4.53 [2.39-8.60], p < 0.001). The population-attributable risk was 39.9% (95% confidence interval, 19.0-60.2) for any major bleeding, causality assumed, and surpassed 50% in patients with less severe strokes (NIH Stroke Scale score ≤16). Quantification of fibrinogen depletion after stroke thrombolysis significantly improved routine risk prediction of bleeding complications as indicated by an increase in the C-statistics from 0.712 to 0.798 (p = 0.015) and a net reclassification index of 0.341 (p < 0.001). A prospective bicenter validation sample (n = 148) corroborates the key findings of this study and suggests positive and negative predictive values of fibrinogen depletion for any major bleeding of 29.2% and 93.5%. This study lends strong support to the concept that prominent fibrinogen turnover after IV stroke thrombolysis-a condition termed "early fibrinogen degradation coagulopathy"-is a relevant cause of major bleeding complications. Rigorous testing of more fibrin-specific thrombolytic agents in the setting of acute stroke is warranted.

The Desmoteplase in Acute Ischemic Stroke (DIAS) Clinical Trial Program

Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In comparison to alteplase, it has high fibrin selectivity, is associated with minimal or no neurotoxicity, and has no apparent negative effect on the blood-brain barrier. The safety and efficacy of desmoteplase is being studied in the Desmoteplase in Acute Ischemic Stroke clinical trial program. Three studies (Dose Escalation Study of Desmoteplase in Acute Ischemic Stroke, Desmoteplase in Acute Ischemic Stroke, and Desmoteplase in Acute Ischemic Stroke-2) have been completed, two large randomized, double-blind, placebo-controlled, phase III trials are ongoing at >200 sites worldwide (Desmoteplase in Acute Ischemic Stroke-3 and Desmoteplase in Acute Ischemic Stroke-4, n = 800; DIAS-3 and DIAS-4), and a randomized, double-blind, placebo-controlled, dose-escalation phase II trial is ongoing in Japan (Desmoteplase in Acute Ischemic Stroke-Japan, n = 48; DIAS-J). The objective of DIAS-3 and DIAS-4 is to evaluate the safety and efficacy of a single IV bolus injection of 90 μg/kg desmoteplase given three- to nine-hours after onset of ischemic stroke (National Institutes of Health Stroke Scale 4-24, age 18-85 years). The objective of DIAS-J is to evaluate the safety and tolerability of desmoteplase 70 and 90 μg/kg three- to nine-hours after ischemic stroke onset in Japanese patients. Patients are included with occlusion or high-grade stenosis (thrombolysis in myocardial infarction 0-1) in proximal cerebral arteries on magnetic resonance or computed tomography angiography but excluded with extended ischemic edema on computed tomography or diffusion-weighted imaging. Desmoteplase is the only thrombolytic agent in late-stage development for acute ischemic stroke that is now tested in patients with proven stroke pathology. The results of the Desmoteplase in Acute Ischemic Stroke clinical trial program will show whether patients with major artery occlusions but not extended ischemic brain damage can be safely and effectively treated up to nine-hours after onset.

Vascular Occlusion Enables Selecting Acute Ischemic Stroke Patients for Treatment With Desmoteplase

Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS]). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA. Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40-12.23; P=0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109). In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable.

Abstract 2595: Vascular Occlusion as an Imaging Biomarker for Selecting Acute Ischemic Stroke Patients for Treatment with Desmoteplase

Desmoteplase is a novel, highly fibrin-specific and non-neurotoxic thrombolytic agent. Evidence of safety and efficacy was obtained in two phase II trials (DIAS and DEDAS). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post-hoc analyses were performed with the aim of predicting treatment responders based on CT and MR angiography. The predictive value of infarct volume and TIMI grade at baseline with respect to drug response measured by clinical outcome at Day 90 was investigated using DIAS-2 data. Patients were grouped according to vessel status (TIMI grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2. In DIAS-2, a substantial number of mismatch-selected patients (126/179, 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, the majority having a favorable outcome at Day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect size based on the pooled data from DIAS, DEDAS, and DIAS-2 was borderline statistically significantly different (P=0.05) in the TIMI 0-1 and TIMI 2-3 subgroups. It was favorable for desmoteplase-treated patients presenting with TIMI 0-1 at baseline (odds ratio, 4.144; 95% CI, 1.40-12.23; P=0.010), while there was no desmoteplase treatment benefit in patients presenting with TIMI 2-3 (odds ratio, 1.109). In this sample of patients diagnosed with a mismatch, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CT or MR angiography in clinical trials of thrombolytic therapy is justifiable.

The Tissue-Type Plasminogen Activator Story

Milestones in the development of tissue-type plasminogen activator (t-PA) as a fibrin-specific thrombolytic agent include: purification of human t-PA from the culture fluid of the Bowes melanoma cell line, elucidation of the molecular basis of fibrin-specific plasminogen activation, first experimental animal models of thrombosis, first patient (renal allograft) treated with melanoma t-PA, pilot studies in patients with acute myocardial infarction, cloning and expression of recombinant t-PA providing sufficient amounts for large scale clinical use, and demonstration of its therapeutic benefit in large multicenter clinical trials.

Spotlight on Reteplase in Thrombotic Occlusive Disorders1

Reteplase (Retavase) is a plasminogen activator, mimicking endogenous tissue plasminogen activator (t-PA), a serine protease, converting plasminogen to plasmin and thereby precipitating thrombolysis. It is a third-generation recombinant form of t-PA that operates in the presence of fibrin (i.e. it is fibrin specific). Reteplase can be administered as a bolus dose (nonweight-based), rather than an infusion, which promotes rapid and safe administration. The ease of administration of this reteplase dosage regimen (two 10U bolus doses, each over 2 minutes, 30 minutes apart) is conducive to prehospital initiation of thrombolytic treatment in patients with ST-segment elevation myocardial infarction (STEMI), which reduces the time to treatment, a critical factor in improving long-term survival. In large randomized clinical trials of patients with STEMI, reteplase was superior to alteplase for coronary artery patency (according to TIMI [thrombolysis in myocardial infarction] flow) at 60 and 90 minutes, but there was no significant difference between agents for mortality rate and incidence of intracranial bleeding. The 35-day mortality rates were equivalent for reteplase and streptokinase recipients; there was reduced incidence of some cardiac events with reteplase versus streptokinase, but a greater incidence of hemorrhagic stroke. Reteplase has also shown thrombolytic efficacy (in nonapproved indications) as a catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions, as 5-minute bolus doses (in 1U increments) for acute ischemic stroke, as a low-dose solution for occluded catheters or grafts, and as an intravenous double bolus for massive pulmonary embolism. Across studies in these indications, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other fibrin-specific thrombolytic agents. With its efficacy, and the ease of administration of the bolus doses potentially minimizing dosage errors when treatment is administered under time pressure, reteplase is a valuable option for pre- or in-hospital thrombolytic treatment in patients with STEMI, and is a useful thrombolytic for the treatment of the other thrombotic occlusive disorders described.

Thrombolytics, Anticoagulants, and Antiplatelet Agents

More than 250 articles regarding thrombolytic therapy in acute ischemic stroke were published in the first 10 months of 2005 (Source PubMed). In this section we will focus on some reports that directly affect and improve the treatment of stroke patients, that led to further phase III trials, or that represent a great disappointment after several years of investigation. The key publication on thrombolytic therapy in acute ischemic stroke using recombinant tissue plasminogen activator was published almost 10 years ago, which led to the approval of this drug in many countries.1 Since then, considerable knowledge has been gained about the risks and benefits of thrombolytic therapy. However, 1 major concern is still the limited time window of 3 hours. Many studies have been conducted to extend this time window without increasing the risk for the patients. In addition, more pathophysiologically oriented imaging techniques, such as diffusion- and perfusion-weighted imaging, seemed to be able to detect tissue at risk for further infarction. In January 2005, the results of the Desmoteplase In Acute Ischemic Stroke trial (DIAS) were published.2 DIAS was a dose-finding, phase II, randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. It was the first randomized, double-blind, placebo-controlled thrombolysis trial using MRI-based criteria for patient selection and also as an end point. The efficacy end points were rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by National Institutes of Health Stroke Scale Score (NIHSSS; ≥8-point improvement or scoring of 0 or 1), modified Rankin scale (0 to 2), and Barthel Index (75 to 100) at 90 days. Safety …

Tissue-type plasminogen activator: a historical perspective and personal account

Over the past two decades tissue-type plasminogen activator (t-PA), the main physiological plasminogen activator, has been developed as a fibrin-specific thrombolytic agent for the treatment of various thromboembolic diseases. Milestones in this development include: first purification of human t-PA from uterine tissue, elucidation of the interactions regulating physiological fibrinolysis, thus providing a molecular basis for the concept of fibrin-specific plasminogen activation, first animal models of thrombosis and pilot studies in patients supporting the therapeutic potential of t-PA, cloning and expression of recombinant t-PA providing sufficient amounts for large scale clinical use, and demonstration of its therapeutic benefit in large multicenter clinical trials, mainly in patients with acute myocardial infarction (AMI), but also in patients with massive pulmonary embolism, ischemic stroke, deep vein thrombosis and peripheral arterial occlusion. Genetically modified variants of t-PA have been developed for bolus administration in patients with AMI.

Editor’s Commentary: One Size Does Not Fit All

In this present series of “Mini-Review: Expert Opinions,” leading clinical investigators present their cases for treatment of acute ST-segment elevation myocardial infarction with thrombolytic therapy or percutaneous coronary intervention (PCI). The investigators review relevant studies and their own experience that support their positions. A review of information provided by Drs Armstrong, Collen, and Antman1 and Grines, Serruys, and O’Neill,2 as well as other relevant literature related to the treatment of acute ST-elevation myocardial infarcts, would lead the unbiased reviewer to conclude that the optimal therapy presently available is an acute intervention, ie, PCI (or surgical revascularization), if that procedure can be done by experts within at least 90 minutes of the event. One obtains the most rapid opening of the infarct-related artery and the best perfusion of the infarct-injured zone associated with no or little risk of intracerebral hemorrhage with PCI. However, this is not always possible to do. Many infarcts occur in the early morning hours in patients at considerable distances from a hospital where such therapy is available. In other cases, the necessary facility may not be available in a timely …

Thrombolytic fibrin specificity influences activated partial thromboplastin time prolongation in vitro.

Despite limited comparative data, guidelines suggest the same concomitant unfractionated heparin (UFH) dose for all fibrin-specific thrombolytic agents in acute myocardial infarction. Since a supratherapeutic activated partial thromboplastin time (aPTT) correlates with adverse outcomes, clarifying effects of various agents on aPTT are needed. The present in vitro study evaluated the influence of alteplase (rt-PA), reteplase (r-PA), and tenecteplase (TNK) on aPTT prolongation. Blood samples from healthy volunteers (n = 12) were treated with equipotent concentrations of rt-PA, r-PA, and TNK, with and without UFH. Samples of each treatment group were incubated at 37 degrees C; aPTT and fibrinogen activity were measured after 4 h. Mean aPTT values for rt-PA alone and r-PA alone were prolonged versus those of TNK alone (P = 0.001 for both). Combined with UFH, rt-PA and r-PA increased the aPTT versus UFH alone (P < 0.05 for both). Interestingly, TNK + UFH reduced the aPTT versus UFH alone (P < 0.001). A negative correlation existed between fibrinogen activity and aPTT for all treatments, except TNK alone. The present investigation illustrates that an agent with maximal fibrin specificity (TNK) has minimal effect on the aPTT, while agents with less fibrin specificity are more likely to prolong the aPTT, with and without UFH present.

Emerging anticoagulant and thrombolytic drugs

Since its discovery, heparin has been used intensely as an anticoagulant for several medical and surgical indications. However, efforts are in progress to replace heparin because of its serious complications, such as intraoperative and postoperative bleeding, osteoporosis, alopecia, heparin resistance, heparin rebound, heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS), and other disadvantages. Significant developments in the field of new anticoagulants have resulted in the evaluation and introduction of low molecular weight heparins (LMWHs) and heparinoids, hirudin, ancrod, synthetic peptides and peptidomimetics. However, despite significant progress in the development of these new anticoagulants, a better or an ideal anticoagulant for cardiovascular patients is not yet available and heparin still continues to amaze both basic scientists and the clinicians. To minimise the adverse effects of heparin, newer approaches to optimise its use in combination with the new anticoagulants may provide better clinical outcome. In our experience, the off-label use of argatroban at a dose of 300 microg/kg iv. bolus followed by 10 microg/kg/minute infusion in combination with aggrastat (a glycoprotein [GP] IIb/IIIa inhibitor) at a dose of 10 microg/kg iv. bolus followed by an infusion of 0.15 microg/kg/minute in patients with HIT undergoing percutaneous coronary interventions resulted in elevation of celite activated clotting time (ACT) to 300 seconds followed by a gradual decline and the ACT remained above 200 seconds even after 200 min of drug administration. A bewildering array of newer anticoagulants now exist, such as LMWHs and heparinoids, indirect or direct thrombin inhibitors, oral thrombin inhibitors, such as melagatran (AstraZeneca) and HC-977 (Mitsubishi Pharmaceuticals), Factor IXa inhibitors, indirect or direct Factor Xa inhibitors, Factor VIIa/tissue factor (TF) pathway inhibitor, newer antiplatelet agents, such as GPIIb/IIIa inhibitors, fibrin specific thrombolytic agent, such as tenecteplase and modulation of the endogenous fibrinolytic activity by thrombin activatable fibrinolytic inhibitor (TAFI), Factor XIIIa inhibitors and PAI-1 inhibitors. The quest for newer anticoagulant, antiplatelet and fibrinolytic agents will continue until ideal agents are found.

A review of available fibrin-specific thrombolytic agents used in acute myocardial infarction.

Thrombolytic agents are a first-line therapeutic option for establishing coronary artery patency in acute myocardial infarction. Three fibrin-specific thrombolytics--alteplase, reteplase, and tenecteplase--are available in the United States and have undergone preliminary patency trials and large randomized, comparative, survival studies. Patency rates differ among them, although overall mortality benefit is similar. Because of this fact and the economic impact of the drugs, competition in this market is significant. Distinguishing features of the drugs will likely influence selection. Reteplase and tenecteplase offer ease of administration with bolus dosing. Increased fibrin specificity appears to play a significant role in separating them. Tenecteplase, the most highly fibrin specific, is associated with decreased risk of noncerebral bleeding and reduced need for blood transfusions in all patients, as well as longer survival in those with late presentation acute myocardial infarction. Current trials will reveal the role of these agents in combination with glycoprotein lIb-IIIa receptor antagonists.

Advances in antithrombotic therapy of acute myocardial infarction

The aim of the acute treatment of myocardial infarction is to restore, as promptly as possible, blood flow in the culprit vessel. Thrombolysis is a cornerstone of treatment, and direct coronary angioplasty (PTCA) is emerging as a valuable or even better alternative reperfusion strategy. The activation of hemostasis after plaque disruption, thrombolysis, or PTCA represents a strong rationale for the use of antithrombotic drugs. The results of the ISIS-2 trial and the data from the Antiplatelet Trialists’ Collaboration indicated that aspirin is mandatory in patients with acute myocardial infarction and for secondary prevention. Recently, the efficacy of abciximab and other glycoprotein IIb/IIIa inhibitors was proven in the treatment of acute coronary syndromes and after PTCA, and their early use in patients with acute myocardial infarction is presently under evaluation. Anticoagulation with heparin appears to be only slightly effective in acute myocardial infarction not treated with thrombolysis; however, a rationale exists for its use in patients undergoing percutaneous and/or surgical revascularization and in conjunction with fibrin-specific thrombolytic agents. Further studies are under way on the possible usefulness of low-molecular-weight heparin. Direct antithrombin agents (hirudin, hirulog, and others) have been recently studied as an adjunct to thrombolysis. The data from these studies indicate the presence of a narrow therapeutic window, with only marginal advantage over heparin; studies with newer compounds are ongoing. Aspirin is still a mandatory drug in patients with acute myocardial infarction; the most promising agents in this setting seem to be glycoprotein IIb/IIIa inhibitors. Heparin and low-molecular-weight heparins are indicated in selected cases, and further studies are needed to assess the value of newer direct thrombin inhibitors. (Am Heart J 1999;138:S171-S176.)

Effect of reteplase on hemostasis variables: analysis of fibrin specifity, relation to bleeding complications and coronary patency

The first aim of the present study was to characterize the systemic and fibrin-specific lytic effect of reteplase in the treatment of patients with acute myocardial infarction. The second aim was to investigate the relation of hemostasis variables to risk of bleeding complications and to coronary patency. The present study is a hemostatic substudy of the German Recombinant Activator Study. Forty two patients have been treated with 10 MU of reteplase (Group A) and 100 patients with 15 MU of reteplase (Group B), given as a single bolus. Blood samples for assessment of fibrinogen, plasminogen, alpha-2-antiplasmin, fibrinogen degradation products (FDP) and D-dimers were obtained before and at 2, 4, 8, and 24 h after thrombolytic therapy. The median fibrinogen concentration was decreased from 279 to 169 mg/dl in Group A and from 254 to 92 mg/dl in Group B four hours after administration of reteplase. The decrease in fibrinogen was significantly more pronounced in Group B ( P=0.0004). The median plasminogen concentration was decreased to 53% in Group A and to 33% in Group B two hours after administration of reteplase ( P=0.0001). Alpha-2-antiplasmin was reduced to 27% and 17,5%, respectively ( P=0.0007). D-Dimer levels were increased to 5.2 μg/ml in Group A and 11,6 μg/ml in Group B ( P=0.02) and FDP levels to 3.0 μg/ml in Group A and 12,6 μg/ml in Group B ( P=0.04). Patients with bleeding complications revealed significant lower nadir levels of fibrinogen than patients without bleeding complications (54 mg/dl versus 125.5 mg/dl, P=0.02). There was no significant difference in any hemostatic parameter between patients with patent and nonpatent infarct related arteries. Conclusions: Reteplase causes a moderate systemic lytic effect comparable with other relative fibrin specific thrombolytic agents. An increase in the dose from 10 to 15 MU is associated with a marked increase in both fibrin specific and systemic lytic effect. Patients with bleeding complications reveal significant lower nadir levels of fibrinogen than patients without bleeding complications. Determination of any hemostatic parameter seems to be no useful method to predict efficacy of thrombolysis in terms of coronary patency in the individual patient.

Intravenous thrombolysis with recombinant staphylokinase versus tissue-type plasminogen activator in a rabbit embolic stroke model.

Timely intravenous administration of recombinant tissue-type plasminogen activator (alteplase, rTPA) to patients with evolving ischemic stroke improves neurological outcome. The present study was designed to compare the effects of rTPA and recombinant staphylokinase (Sak), a highly fibrin-specific thrombolytic agent, in an experimental model of rabbit embolic stroke. Groups of 5 to 12 rabbits were given intravenous saline or heparin and aspirin with, in addition, either Sak (1 or 2 mg/kg infused over 30 minutes or 2 mg/kg injected over 1 minute) or rTPA (3 or 6 mg/kg infused over 30 minutes or 6 mg/kg injected over 1 minute). Infusions were started 15 minutes after selective injection of standardized 125I-fibrin labeled rabbit plasma clots into the internal carotid artery. Mean clot lysis over 60 minutes increased from 3.8% after saline to between 27% and 44% after Sak regimens (P = .0001 versus control) and to between 15% and 34% after rTPA regimens (P = .0001). Median volume of the ischemic lesion at 5 hours decreased from 190 mm3 after saline to between 11 and 17 mm3 after Sak (P = .02) and to between 0.5 to 54 mm3 after rTPA (P = .04). Mean neurological impairment at 5 hours (on a scale of 0 to 3) decreased from 2.3 after saline to between 1.3 to 1.6 after Sak (P = .003) and to between 1.1 to 1.9 after rTPA (P = .02). At the highest doses used, fibrinogen depletion was marginal with Sak but total with rTPA. Marked prolongation of car puncture and cuticle bleeding times was only observed after bolus administration of rTPA. In the present rabbit model of embolic stroke, Sak was significantly more fibrin-specific than rTPA and at least as effective in lysing arterial emboli and limiting ischemia and neurological impairment.