Br Heart J 1990;64:355-8 355 Br Heart J: first published as 10.1136/hrt.64.6.355 on 1 December 1990. Downloaded from ORIGINAL ARTICLES A systemic non-lytic state and local thrombolytic failure of anistreplase (anisoylated plasminogen streptokinase activator complex, APSAC) in acute myocardial infarction Johan Brugemann, Jan van der Meer, Bert H Takens, Hans Hillege, Kong I Lie Abstract changes in haematological variables such as The relation between coronary throm- fibrinogen, plasminogen, and a2 antiplasmin bolysis and coagulation variables after during the first 24 hours after they were administration of anistreplase (anisoy- given.' These changes were ascribed to lated plasminogen streptokinase activator systemic effects. Some patients, however, complex, APSAC) was studied in showed no substantial decrease in plasma patients with an acute myocardial in- fibrinogen after anistreplase or streptokinase farction. Fifty eight consecutive patients administration.7 This suggests resistance to with acute myocardial infarction were these drugs. It has been suggested that a given 30 U of anistreplase intravenously systemic lytic state, defined as a low plasma within 4 hours of the onset of symptoms. concentration of fibrinogen after thrombolytic A fall in the plasma concentration fib- treatment, is a prerequisite for local thrombo- rinogen to < 10 g/l 90 minutes after lytic efficacy.8 was con- To investigate the possibility of drug administration of anistreplase copyright. sidered to reflect a systemic lytic state. resistance as an explanation for failure of Coronary angiography was performed 48 thrombolytic treatment, we performed a hours after thrombolytic treatment. The retrospective study to assess the relation overall patency rate was 74% (43/58). between the systemic fibrinolytic effects and Patency rates were significantly dif- the local efficacy of anistreplase in patients ferent in patients with a systemic lytic with acute myocardial infarction. (83% (43/52)) and a systemic non-lytic state (0% (0/6)). The absence of a sys- http://heart.bmj.com/ temic lytic state after anistreplase Patients and methods administration seemed to be highly PATIENTS predictive of the failure of coronary We studied 58 consecutive patients (47 men, 11 thrombolysis. Coagulation studies women), mean age 57 years (range 34-71), who showed evidence of inhibition of anistre- presented within 4 hours of the onset of chest plase induced fibrinolytic activity which pain. Selection criteria for thrombolytic treat- may explain the failure of thrombolytic ment included the presence of characteristic treatment in patients with evidence of a symptoms of myocardial infarction and ST state. segment elevation of at least 0 1 mV in one or systemic non-lytic on September 27, 2021 by guest. Protected more of the standard leads or at least 0-2 mV in Department of precordial leads in a 12 Cardiology, two or more of the University of Thrombolytic drugs reduced mortality in lead electrocardiogram and the presence of Groningen, The patients with acute myocardial infarction symptoms unresponsive to sublingual glyceryl Netherlands treated within 6, 12, or even 24 hours of the trinitrate. We excluded patients with contra- J Brugemann L H Takens onset of symptoms.1 When treatment was indications for thrombolytic treatment and H Hillege started within the first 4-6 hours after the those who had been treated with streptokinase K I Lie onset of chest pain, reperfusion was shown in or anistreplase within the previous 6 months. Department of most the infarct related coronary arteries. Hematology, of University of However, in up to 30-40% of the patients no STUDY PROTOCOL Groningen, The reperfusion could be achieved.4 Failure of Patients were treated with 30 U of anistreplase Netherlands thrombolytic treatment has been reported (Eminase, SmithKline Beecham) administered J van der Meer irrespective of the drug used.4 The con- intravenously in 4-5 minutes. Infusion with Correspondence to an heparin (30 000 U in 24 hours) was started 4-6 Dr Johan Brugemann, figuration of coronary obstruction may be Department of Cardiology, important determinant of the success of treat- hours after thrombolytic treatment and was Thoraxcentre University continued until an adequate level of anti- Hospital Groningen, ment,5 but inhibition of drug activity has Oostersingel 59, 9713 EZ never been ruled out. coagulation had been achieved with oral acen- Groningen, The In general, streptokinase and anistreplase ocoumarol, which was started after 48-72 Netherlands. hours. To assess patency of the infarct related Accepted for publication (anisoylated plasminogen streptokinase acti- 31 July 1990 vator complex, APSAC) caused comparable artery, coronary angiography was performed 356 Brugemann, van der Meer, Takens, Hillege, Lie Br Heart J: first published as 10.1136/hrt.64.6.355 on 1 December 1990. Downloaded from 48 hours (range 36-60) after the administration patients showing a systemic lytic state and a of anistreplase in all patients. In the first 30 systemic non-lytic state were performed by consecutive patients patency was also assessed means of Student's t test for independent after 90 minutes (range 1 to 3 hours). Patency samples. Comparisons within the groups were was documented according to the score used in made with the paired Student's t test. the thrombolysis in myocardial infarction Measurements of reptilase time, euglobulin (TIMI) trial.9 Scores of grade 0 or 1 indicated clot lysis time, and fibrinogen/fibrin degrada- occlusion of the infarct related vessel and tion products were expressed as median grades 2 and 3 patency. (range). Patient groups were compared by the Mann-Whitney U/Wilcoxon rank sum test. COAGULATION ANALYSES Differences within the groups were tested by Coagulation and fibrinolytic variables were the Wilcoxon matched paired signed ranks test. studied immediately before and 90 minutes and We used Fisher's exact test to compare the 48 hours after anistreplase administration. result of treatment in terms of patency and the Venous blood samples were collected on ice in a presence of a systemic lytic state. A two tailed p 1/10 volume 3 05% trisodium citrate for value of <0-05 was regarded as statistically measurements of fibrinogen, plasminogen, a2 significant. antiplasmin, reptilase time, and euglobulin clot lysis time. Assays were performed immediately or plasma was stored at - 80°C for analysis Results later. Fibrinogen was measured according to COAGULATION DATA the method of Clauss. " Plasminogen and a2 Fifty eight patients were retrospectively antiplasmin assays were performed with a syn- classified into two groups. Fifty two showed a thetic chromogenic substrate (Kabi) according systemic fibrinolytic state and in six patients to the method of Friberger et al.'1 Reptilase plasma fibrinogen concentrations did not time was determined by the method of Soria et decrease below 1 0 g/l. Initial values of fibrin- al 12 and euglobulin clot lysis times by the ogen, plasminogen, a2 antiplasmin, reptilase method of Buckell.'3 The assay for fibrinogen/ time, euglobulin clot lysis time, and fibrinogen/ fibrin degradation products was carried out on fibrin degradation products were similar in the serum collected at the times mentioned above two groups (table 1). with a latex agglutination kit (Wellcome) After 90 minutes, fibrinogen, plasminogen, according to the method of Pitcher.'4 and a2 antiplasmin concentrations were A systemic lytic state was defined as a significantly reduced in both the lytic and non- decrease of the plasma concentration of lytic groups. Mean plasma concentrations ofcopyright. fibrinogen to below 1 0 g/l, measured 1-5 hours fibrinogen in the lytic and the non-lytic groups after the administration of anistreplase. were 0-0 g/l and 2-3 g/l (normal range 1-7-3-5); of plasminogen 11% and 57% (normal range STATISTICAL ANALYSIS 70-130); and of a2 antiplasmin 4% and 35% Plasma concentrations of fibrinogen, plas- (normal range 90-130) respectively. These minogen, and a2 antiplasmin were expressed as differences were statistically significant. mean (SD). Statistical comparisons between Individual values for fibrinogen in the six non- http://heart.bmj.com/ lytic patients before and 90 minutes after treatment with anistreplase were: 3-3 v 2-7; 2 7 Table 1 Coagulation variables of all patients stratified according tofibrinolytic state v 23; 24v 1 1; 3v 22; 24 v 1-8, and 37v 3-6 g/l respectively. The reptilase time was Variable Lytic Non-lytic p value$ considerably prolonged in the lytic group from Fibrinogen (g/l): 19 to 109 seconds but did not change in the Before 3-1 (0-96) 2-9 (0-48) NS non-lytic group (19 v 24 seconds). Euglobulin 90 minutes after 0.0 (0-15)* 2-3 (0-78)t <0-01 48 h after 2-5 (0-68)* 4-2 (0-84) <0-01 clot lysis time was shortened from > 120 before to < 10 minutes after the administration of Plasminogen (%): on September 27, 2021 by guest. Protected Before 97 (18) 104 (6) NS anistreplase in both groups (normal value 90 min after 11(13)* 57 (9)* <0-01 > 120 minutes). Serum concentrations of 48 h after 55 (13)* 78 (12)t < 0-01 fibrinogen/fibrin degradation products a, antiplasmin () remained within normal ranges (< 8 in Before 93 (14) 90 (12) NS Mg/ml) 90 min after 4 (5)* 35 (2)t < 0-01 the non-lytic group, whereas they were con- 48 h after 80 (16)* 99 (8) <0-01 siderably increased in the lytic group (median Reptilase time (s): value >256 Mg/ml). Before 19 (10-27) 19 (18-20) NS These changes declined after 48 hours. At 90 min after 109 (44-201)* 24 (18-31) <0-01 48 h after 19 (15-23) 20 (19-21) NS that time mean plasma concentrations offibrin- ogen, plasminogen, and a2 antiplasmin were Euglobulin clot lysis time (min): still significantly lower in the lytic group, and, Before > 120 (> 120) > 120 (> 120) NS with the exception of fibrinogen, below the 90minafter <10(<10)* <10(<10-15)t NS 48 h after > 120 (95->120) > 120 (> 120) NS normal ranges.