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Background: The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods., Methods and Results: Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke., Conclusions: This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis.

Because of the relatively low incidence of TEs in children, the diagnostic and therapeutic approaches used are largely extrapolated from guidelines for adults. Features that differ in children compared with adults include underlying disorders, high incidence of CVL-related DVT in the upper venous system, and response to SH, warfarin, and thrombolytic agents. There is a paucity of information on the risk/benefit ratio of the therapeutic interventions and long-term outcome. Clinical trials are urgently needed to clarify optimal management for pediatric patients with TEs.

Objectives: We sought to assess the effects of antithrombotic therapy after thrombolysis for acute myocardial infarction on markers of thrombin generation and activity and to determine the relation of these markers with clinical outcomes., Background: Thrombin activation and generation often occur with thrombolysis for acute myocardial infarction. Antithrombotic regimens have been developed to reduce the resulting thrombotic complications., Methods: We sampled plasma markers of thrombin generation and activity after thrombolysis in 292 patients. We assessed the relations of these markers with clinical outcomes at 30 days., Results: Fibrinopeptide A (FPA), a marker of thrombin activity toward fibrinogen, was elevated at baseline (12.3 ng/ml) and increased to 18.4 ng/ml by 90 min after streptokinase and subcutaneous heparin treatment. With intravenous heparin, this increase was attenuated, but intravenous heparin did not prevent thrombin generation, as measured by prothrombin fragment 1.2 (F1.2). Heparin level, measured by anti-Xa activity, correlated with activated partial thromboplastin time (aPTT, r = 0.62 to 0.67). Thrombin activity, measured by FPA, was as closely related to aPTT as to the heparin level. Baseline levels of F1.2 were significantly related to the risk of death or reinfarction at 30 days (p = 0.008); values 12 h after enrollment also were related to 30-day mortality (p = 0.05)., Conclusions: Although intravenous heparin partly suppresses the increased thrombin activity associated with thrombolysis, it does not inhibit thrombin generation. The aPTT was as good a measure of suppression of thrombin activity as the heparin level itself. Hematologic markers of thrombin generation were found to be related to the subsequent risk of thrombotic events.

Objectives: We sought to determine the extent of Factor V proteolysis during thrombolytic therapy., Background: Thrombin- or Factor Xa-activated Factor V is an essential cofactor in the prothrombinase complex. In purified systems, plasmin, the major product of thrombolytic therapy, is known to first activate then inactivate Factor V., Methods: We used quantitative gel electrophoresis and Western blotting to analyze the cleavages in plasma Factor V after thrombolytic therapy., Results: The addition of streptokinase to plasma resulted in the activation then inactivation of Factor V, confirming previous results using purified reagents. We also identified the Factor V fragments resulting from the action of thrombin and plasmin. After thrombolytic therapy, there was considerable Factor V cleavage. The cleavage patterns were consistent with the action of plasmin, with little evidence for the action of thrombin. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (n = 17), we observed an average 58% loss of intact Factor V at 6 h (range 1% to 91%). Samples from the Thrombolysis in Myocardial Infarction trial, Phase II (n = 12), collected on a shorter time scale, showed a loss of up to 99% at 50 min, with the loss of intact Factor V associated with the plasma concentration of plasminogen activator. Samples from patients with bleeding (n = 12) showed extensive Factor V cleavage., Conclusions: Factor V cleavage in thrombolytic therapy is primarily plasmin mediated, rapid and often extensive. It is likely that transient increases, as well as longer term losses, of Factor V cofactor activity play a role in both ischemic and hemorrhagic events subsequent to thrombolytic therapy. The extensive loss of Factor V in some patients may affect the estimation of heparinization.

Percutaneous coronary revascularization in patients with unstable angina and coronary thrombus carries a high complication rate. A new strategy to reduce thrombus burden before revascularization was tested in a multicenter prospective trial. Patients with unstable angina and coronary thrombus (n = 45) received alteplase through an infusion catheter at the proximal aspect of the target lesion and concomitant intracoronary heparin via a standard guiding catheter. Angiography was performed before and alter lesion-directed therapy and post-intervention. Systemic fibrinogen depletion and thrombin activation were not observed, while fibrinolysis was evident for > or = 4 hr after treatment. Target lesion stenosis did not change significantly after lesion-directed therapy, but thrombus score was reduced, particularly among patients who had large thrombi (mean 2.2 vs. 1.6, P = 0.02). Revascularization was successful in 89% of patients. Median final stenosis was 30% and mean final thrombus score was 0.4. Complications included recurrent ischemia (11%), MI (7%), abrupt closure (7%), severe bleeding (4%), and repeat emergency angioplasty (2%). Patients with overt thrombus appeared to derive the most angiographic benefit from lesion-directed alteplase plus intracoronary heparin. Later revascularization was highly successful. This strategy may be a useful adjunct to percutaneous revascularization for patients with unstable angina and frank intracoronary thrombus.

Background: Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29,656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes., Methods and Results: Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (P < .00001) as well as older age, female sex, and lack of cigarette smoking (all PT< .0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin., Conclusions: Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.

Although coronary thrombosis is thought to play a pivotal role in the pathogenesis of unstable angina and non-Q wave myocardial infarction and antithrombotic therapy is a mainstay in the early management of these patients, the relation between measures of systemic anticoagulation and clinical events has not been defined clearly. In the Thrombolysis in Myocardial Ischemia III trial, 1473 patients with ischemic chest pain at rest evaluated within 24 hours of symptom onset were randomized to (1) tissue plasminogen activator (TPA) or placebo and (2) an early invasive or an early conservative strategy. All patients received a full complement of anti-ischemic medication, aspirin, and continuous intravenous heparin titrated to an activated partial thromboplastin time (aPTT) of 1.5 to 2.0 times control for 72 to 96 hours. The median aPTT in all study groups exceeded the minimum threshold (45 seconds) by 24 hours and remained within the designated range during the protocol-directed heparin infusion. No differences in median aPTT values for the 72- to 96-hour study period were observed between groups (p=not significant). Median 12-hour heparin concentrations were >0.2 U/ml in all groups; however, values <0.2 U/ml were common thereafter, particularly in TPA-treated patients. Time-dependent covariate analyses failed to identify statistically significant differences in either aPTT or heparin levels between patients with in-hospital clinical events (spontaneous ischemia, myocardial infarction, or death) and those without events (p=0.27). Furthermore, early clinical events occurred in a similar percentage of patients with optimal anticoagulation (all aPTTs >60 seconds, all heparin levels>0.2 U/ml), and those with aPTTs or heparin levels below these thresholds. Aggressive (high-intensity) anticoagulation with heparin to achieve aPTTs >2.0 times control does not appear to offer additional clinical benefit to lower levels (1.5 to 2.0 times control) among patients with unstable angina and non-Q wave myocardial infarction receiving intravenous heparin and oral aspirin. Therefore, the optimal level of anticoagulation in this common clinical setting is between 45 and 60 seconds when heparin is included in the treatment strategy. Direct plasma heparin measurement does not offer an advantage to routine aPTT monitoring. The occurrence of spontaneous ischemia, myocardial infarction, and death in spite of antischemic therapy and optimal anticoagulation (as it is currently defined) with heparin supports ongoing efforts to develop more effective antithrombotic agents.

Background: To better understand the role of race/ethnicity in survival after acute myocardial infarction, we compared clinical and laboratory data, response to thrombolytic therapy, and clinical outcome in 2885 patients participating in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) Trial among three groups of patients (2564 whites, 174 blacks, and 147 Hispanics)., Methods and Results: Differences were found in baseline characteristics among the three groups including (1) age (mean age for whites, 57.2 years; blacks, 54.8 years; Hispanics, 52.8 years; P < .001), (2) sex (percentage of women for whites, 17.6; blacks, 28.7; Hispanics, 14.3; P < .001), and (3) risk factor prevalence: current smoking (percent for whites, 49.4; blacks, 62.1; Hispanics, 55.1; P < .003), history of hypertension (percent for whites, 36.6; blacks, 55.7; Hispanics, 39.5; P < .001), and diabetes mellitus (percent for whites, 11.9; blacks, 22.4; Hispanics, 19.7; P < .001). Changes in hemostatic factors 5 hours after infusion of recombinant tissue plasminogen activator (rt-PA) revealed a more profound fall in fibrinogen levels in black patients compared with the response seen in Hispanic or white patients (mean change in fibrinogen +/- SD, mg/dL: 151.3 +/- 107.4, 112.2 +/- 97.0, 109.4 +/- 98.6; P < .001, respectively) without more frequent infarct-related artery patency or hemorrhagic complications. Mortality was similar in the white, black, and Hispanic patients through the first year after adjustment for baseline variables., Conclusions: TIMI II data yield evidence that (1) corroborates published reports of a high prevalence of classic cardiovascular risk factors among minority patients with acute myocardial infarction, (2) there is a greater decrease in fibrinogen levels 5 hours after the start of rt-PA infusion among black patients than in white and Hispanic patients without evidence of more frequent infarct-related artery patency or hemorrhagic complications, and (3) thrombolytic therapy with appropriate supplemental measures is associated with comparable 1-year mortality in white, black, and Hispanic patients.

Monitoring coagulation parameters during thrombolytic therapy could be useful for prediction and treatment of haemorrhagic episodes. Technology based on dry reagent chemistry has been developed that allows rapid (less than 10 min) assays on small samples of whole blood. The assay principle is based on the restriction of motion of paramagnetic particles during fibrin polymerization, and subsequent liberation of particle motion during fibrinolysis. This technology was used to monitor prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels and fibrinolysis profiles during thrombolytic therapy with tissue plasminogen activator for acute myocardial infarction. The PT and aPTT obtained with the COAG-1 correlated well with conventional assays (r = 0.93 and 0.92 for PT and aPTT, respectively; p = 0.0001). Fibrinogen estimates, obtained by COAG-2 also correlated well with modified Clauss assays (r = 0.86, p = 0.0001). The rapid determination of the aPTT may improve management of adjunctive anticoagulant therapy following thrombolysis. The fibrinolysis profile may be useful during thrombolytic therapy to verify that a lytic state has been achieved, to monitor the lytic state throughout therapy, and to verify that the lytic state normalizes once therapy has been completed.

The use of thrombolytic therapy has dramatically altered the treatment of acute myocardial infarction and is rapidly spreading from large medical centers to community hospitals throughout the country. The widespread use of thrombolytic therapy will benefit a wide range of people, but the potential risks of this form of therapy must be understood. Hemorrhage is one of the major risks of thrombolytic therapy. This review will focus on the data available from a number of recent, large trials of thrombolytic therapy for acute myocardial infarction with respect to laboratory parameters that may predict hemorrhagic complications and/or help with their management. We will discuss both conclusions drawn from currently available data and address future research directions.

Objectives: To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events., Design: A multicenter, randomized, controlled trial., Setting: Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II)., Interventions: Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy., Measurements: Patients were monitored for hemorrhagic events during hospitalization., Main Results: In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose., Conclusions: Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

In the Thrombolysis in Myocardial Infarction, Phase II pilot and clinical trial, 908 patients [326 (35.9%) in the pilot study and 582 (64.0%) in the randomized study] were treated with 150 mg recombinant tissue-type plasminogen (rt-PA) activator in combination with heparin and aspirin, and 3,016 patients [64 (2.1%) in the pilot study and 2,952 (97.9%) in the randomized study] were treated with 100 mg rt-PA in combination with heparin and aspirin. Adverse neurological events occurred in 23 patients treated with 150 mg rt-PA (2.5%) [nine cerebral infarctions (1.0%), 12 intracerebral hemorrhages (1.3%), and two subdural hematomas (0.2%)] and in 33 patients treated with 100 mg rt-PA (1.1%) [20 cerebral infarctions (0.7%), 11 intracerebral hemorrhages (0.4%), and two subdural hematomas (0.1%)]. The difference in adverse neurological events observed comparing the two rt-PA regimens was primarily due to a higher frequency of intracerebral bleeding among patients treated with 150 mg rt-PA (1.3% versus 0.4%, p less than 0.01). Patients with recent (within 6 months) histories of stroke were not eligible for the study, and patients with any history of cerebrovascular disease were declared ineligible early in the study. The small number of patients (89, or 2.3%) with any history of neurological disease, intermittent cerebral ischemic attacks, or stroke who were enrolled before the stricter eligibility criteria were imposed or on the basis of incomplete baseline information experienced an increased frequency of intracerebral hemorrhage compared with patients without such histories (3.4% versus 0.5%). Mortality at 6 weeks after presentation among 23 patients who had intracerebral hemorrhage was 47.8%. Intracerebral hemorrhage is a severe but infrequent complication of rt-PA therapy for acute myocardial infarction. The combined frequency of intracerebral hemorrhage, subdural hematoma, and cerebral infarction after treatment with 100 mg rt-PA is comparable to that observed in other trials with thrombolytic agents in acute myocardial infarction.

The validity of markers in plasma of in vitro thrombolysis was investigated in 12 patients with extensive fibrinogen breakdown (greater than 80%, group 1) and in 12 patients with minimal breakdown (less than 20%, group 2). The patients were treated with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) in the "Thrombolysis in Myocardial Infarction II" (TIMI II) trial. Cross-linked fibrin degradation product levels were measured with two variant enzyme-linked immunosorbent assays (ELISAs), both using a fibrin fragment D-dimer specific capture antibody. In one instance, a tag antibody was used that cross-reacts with fibrinogen (pan-specific tag ELISA); in the other, the tag antibody was specific for fibrin fragment D (fibrin-specific tag ELISA). Apparent concentrations of cross-linked fibrin degradation products at baseline were within normal limits with both assays in most patients. At 8 hours after rt-PA infusion, the measured cross-linked fibrin degradation products were increased about twofold to fourfold in group 2 with both assays. However, in group 1, levels were significantly higher with the pan-specific tag ELISA (5.8 +/- 4.2 micrograms/mL) compared with the fibrin-specific tag ELISA (1.5 +/- 1.3 micrograms/mL). This observation was most likely a result of detection of fibrinogen degradation products in the pan-specific ELISA. Apparent levels of fibrinopeptide B beta 1-42, a marker of fragment X formation, increased during thrombolysis from 4.2 +/- 2.8 pmol/mL to 2,000 +/- 230 pmol/mL in group 1 and from 4.1 +/- 2.1 pmol/mL to 300 +/- 43 pmol/mL in group 2, and were correlated significantly with the extent of fibrinogen breakdown (r = -0.8). Fibrinopeptide beta 15-42 levels increased from 4.3 +/- 3 pmol/mL to 70 +/- 19 pmol/mL in group 1, but did not increase in group 2. The apparent increase in group 1 could be explained by cross-reactivity of fibrinopeptide B beta 1-42 in the fibrinopeptide beta 15-42 assay. We conclude that cross-linked fibrin degradation product levels as measured with a pan-specific tag ELISA and fibrinopeptide beta 15-42 levels as measured with certain monoclonal antibody-based ELISA are influenced by the extent of fibrinogen degradation. Fibrinopeptide B beta 1-42 is a marker specific for fibrinogen breakdown. Cross-linked fibrin degradation product levels, measured with a fibrin-specific tag ELISA, appear to be markers specific for thrombolysis. Consequently, assays similar to the fibrin-specific tag ELISA may provide more accurate information when correlated with clinical endpoints.