Dietrich C. Gulba

Increased thrombin levels during thrombolytic therapy in acute myocardial infarction : relevance for the success of therapy

BackgroundIt has been suggested that thrombolysis in a feedback reaction may generate pro-coagulant activities. Methods and ResultsFifty-five patients were treated with urokinase-preactivated pro-urokinase (n = 35) or tissue-type plasminogen activator (n =20) for acute myocardial infarction and underwent coronary angiography at 90 minutes and at 24-36 hours into thrombolysis, and fibrinogen (Ratnoff-Menzie), D-dimer (ELISA) and thrombin-antithrombin III complex levels (ELISA) were measured. Primary patency was achieved in 39 patients (70.9%), 13 of whom (33.3%) suffered early reocclusion. Nonsignificant decreases in fibrinogen levels were observed while D-dimer levels increased +3,008±4,047 gg/l (p<0.01), differences not being significant in respect to the thrombolytic agents or to the clinical course. In contrast, while thrombin-antithrombin III complex levels decreased −4.4 ± 13.0, ug/l in patients with persistent patency, they increased +7.5±13.6 pg/l in case of nonsuccessful thrombolysis (p<0.02) and + 11.9±23.8, g/l in case of early reocclusion (p <0.001). For patients with thrombin-antithrombin III complex levels greater than 6 ng/l 120 minutes into thrombolysis, the unfavorable clinical course was predicted with 96.2% sensitivity and 93.1% specificity. ConclusionGeneration of thrombin, occurring during thrombolysis, is a major determinant for the success of therapy and thrombin-antithrombin III levels may serve as predictors for the short-term prognosis. (Circulation 1991;83:937–944)

Role of thrombolysis and thrombin in patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty

In a series of 447 patients with single vessel angioplasty, 27 (6.0%) had acute thrombotic occlusion early after the procedure. They were treated with combined intracoronary (20 mg)/intravenous (50 mg) thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and repeat mild balloon inflations. Reopening of the vessel was achieved in 22 patients (81.5%). Follow-up coronary angiography 24 to 36 h later revealed reocclusion in 12 patients (54.5%). Thrombin levels measured as thrombin-antithrombin-III complex in patients with successful thrombolysis and persistent patency decreased from 8.5 +/- 11.4 micrograms/liter at baseline to 3.5 +/- 1.4 micrograms/liter 120 min after the start of thrombolysis; these levels increased from 9.4 +/- 15.0 micrograms/liter at baseline to 15.7 +/- 13.5 micrograms/liter 120 min after the start of thrombolysis in the patients with unsuccessful thrombolysis or early reocclusion (p less than 0.05). When a borderline value for thrombin-antithrombin-III complex level of 6 micrograms/liter was selected to separate the two groups of patients, patients with an unfavorable clinical course were identified 120 min after the start of thrombolysis by levels greater than 6 micrograms/liter (sensitivity 100%, specificity 92.8%). Thus, after abrupt thrombotic vessel closure during coronary angioplasty, the short-term results of thrombolysis seem to be governed by the release of thrombin. In two thirds of patients, however, the thrombin release cannot be suppressed by concomitant aspirin and heparin therapy. Even after successful reopening of the vessel these patients should therefore undergo immediate aortocoronary bypass grafting.

Low dose urokinase preactivated natural prourokinase for thrombolysis in acute myocardial infarction.

By inducing minimal free-fibrinolytic activity with low dose urokinase, the lag phase of prourokinase can be overcome, and the rate of thrombolysis with this substance can be strongly enhanced. The thrombolytic potency of a combination of 250,000 IU of urokinase and 2 doses of prourokinase (4.5 or 6.5 megaunits) was evaluated in an open-label, nonrandomized dose-finding study. Thirty-one patients participated. With 4.5 megaunits of prourokinase (group 1, 15 patients) patency was demonstrated angiographically at 60 minutes in 33% while with 6.5 megaunits (group II, 16 patients) 75% patency was achieved (p less than 0.01). A second angiogram recorded 24 to 36 hours after thrombolysis revealed reocclusion in 60 versus 8% of primarily patent coronary arteries (p less than 0.05). Hemostatic monitoring in both groups revealed only slight to moderate consumption of fibrinogen (-9 vs -13%), plasminogen (-29 vs -34%) and alpha 2-antiplasmin (-59 vs -63%), and an increase in D-dimers, the split products of cross-linked fibrin, to a maximum of 1.008 +/- 1.211 vs 0.547 +/- 0.684 micrograms/liter. None of these differences was significant. Bleeding complications were more frequently observed in group II (13 vs 37%) (difference not significant), but were mild and related to puncture sites, except in 1 patient with mild oozing from the gum. No major hemorrhage was observed. These results suggest that low dose urokinase preactivation enhances the thrombolytic potency of prourokinase, without affecting its high fibrin specificity. Compared to previous studies using only prourokinase, low dose urokinase preactivation reduces by 50% the prourokinase dose as required for effective thrombolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty of subacute and chronic total coronary occlusions: Success, recurrence rate, and clinical follow-up

Angioplasty of single total, subacute, or chronic coronary occlusions was performed in 90 patients. It was successful in 54 occlusions (60%), in 77% of those less than 6 weeks old, and in 44% of those of greater than 6 weeks duration (p less than 0.005). All procedures were uneventful. Control angiography was performed in 53 (98%) patients with successful angioplasty after an average interval of 97 +/- 53 days. Stenosis had recurred in 16 patients (30%). During a follow-up period of 36 +/- 13 months, three patients died, five patients underwent coronary bypass operation, and 10 had reangioplasty. Despite an additional late angiographic recurrence of stenosis in seven patients, 36 patients revealed angiographic long-term success. In the 46 nonoperated patients, angina pectoris and exercise stress tests were substantially improved. Thus angioplasty of subacute and chronic total coronary occlusions is an uneventful procedure, the success rate depending on the duration of the occlusions. Despite a high angiographic recurrence rate, the angiographic and clinical long-term results are favorable.

Percutaneous transluminal angioplasty of aortocoronary venous bypass grafts and effect of the caliber of the grafted coronary artery on graft stenosis

The influence of morphologic parameters on the recurrence of stenosis after percutaneous transluminal coronary angioplasty of 49 stenoses in aortocoronary venous bypass grafts of 41 patients was investigated. Vessel dimensions were measured quantitatively. Angioplasty was successful in 46 stenoses (94%) of 38 patients (93%). In 35 patients (92% of successfully treated patients) with 42 stenoses, control angiography was performed after a mean interval of 189 +/- 186 days. In 9 patients (26%), 9 stenoses (21%) had recurred. The diameter of the grafted coronary artery distal to the anastomosis was significantly smaller in grafted arteries with than without recurrent stenoses (1.92 +/- 0.52 vs 2.45 +/- 0.50 mm; p less than 0.01). Recurrence also correlated with the ratio between graft diameter and coronary artery diameter greater than 1.35 (p less than 0.02) and with the stenosis length greater than 10 mm before angioplasty (p less than 0.01). Graft age, graft diameter and stenosis location in the graft had no significant influence on recurrence. Thus, the diameter of the grafted coronary artery and the length of the critical stenosis are parameters for recurrence after angioplasty of graft stenoses and should be considered in the selection of patients for this intervention.

Potentiative effect of heparin in thrombolytic therapy of evolving myocardial infarction with natural pro-urokinase

Abstract In order to find out if concomitant heparin therapy is really necessary when using pro-urokinase as a thrombolytic agent, we have treated 18 patients with evolving myocardial infarction with a combined therapy consisting of 250 000 iu urokinase as a i.v. bolus and 4.5 or 6.5 Mio latent Urokinase U of pro-urokinase infused i.v. within 40 min. Nine patients were treated without simultaneous heparinisation (group 1), while in 9 additional patients (group II) thrombolytic therapy was started with a 5000 heparin bolus followed by continuous i.v. heparin infusion of 1250 iu/h. In only 1 of the patients not heparinised (group 1) primary patency of the infarct-related vessel could be demonstrated angiographically within 90 min into thrombolysis, while in 7 out of 9 patients heparinised prior to thrombolysis (group II) an open infarct-related coronary artery was documented with the first coronary angiogram performed (p

Vasodilatory effects of nisoldipine on coronary arteries—Correlation with plasma levels

SummaryVasomotion of angiographically normal and stenotic epicardial coronary arteries was analyzed up to 15 minutes after the onset of an intravenous infusion (4 minutes) of 0.5 mg (13 patients, group A) or 1 mg nisoldipine (13 patients, group B). After both doses the maximal increase of the mean diameters of normal coronary segments was achieved not before the 15th minute, averaging 11±6% in group A (p<0.001) and 18±9% in group B (p<0.001). Eleven of 15 and 8 of 9 coronary stenoses in groups A and B dilated to 5–80% and 15–70%, respectively.The nisoldipine concentration reached maximal levels at the end of the infusion (fourth minute) with an average of 8 ±4 ng/ml and 17±7 ng/ml in groups A and B, respectively. A significant correlation between nisoldipine plasma levels and dilation of normal coronary segments was obtained only with the individual maxima of these parameters and only in group A (p<0.01). The hysteresis of the coronary dilation in relation to the drug plasma levels may be due to the high receptor affinity of nisoldipine.In either group nisoldipine provoked a persistent increase in coronary sinus oxygen sáturation (p<0.01) and a substantial and prolonged drop in systolic and diastolic aortic pressure (p<0.001). Both doses of nisoldipine induced a rise in heart rate (p<0.01) and a slight drop in the rate-pressure product (p<0.05).