Pharmacokinetics and haemostatic status during consecutive infusions of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction.

Pharmacokinetics and systemic effects of recombinant tissue-type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean +/- SD) of 3310 +/- 950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of 2210 +/- 470 ng/ml and 930 +/- 200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380 +/- 74 ml/min, t1/2 alpha was 3.6 +/- 0.9 min and t1/2 beta was 16 +/- 5.4 min. After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, alpha 2-antiplasmin to 25%, alpha 2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 micrograms/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

Loco-regional thrombolysis for deep vein thrombosis: fact or fiction? A study of hemostatic parameters.

Loco-regional thrombolysis for deep-vein thrombosis (DVT) has been claimed to be equally effective and safe compared with systemic thrombolysis. It is not known whether a loco-regional thrombolytic effect exists and of what it might consist. To investigate this issue, we studied eight patients with DVT undergoing loco-regional thrombolysis with 20 mg alteplase infused over 4 h in a dorsal foot-vein of the affected leg, while the leg was kept tightly bandaged; alteplase infusions were repeated every 24 h, the number of therapy cycles (TC) was seven, and full-dose heparin was given. For coagulation analyses, 'loco-regional' blood samples were taken from a vein of the affected leg and 'systemic' samples were taken from an antecubital vein. After a median number of six TC, good partial reperfusion was achieved in 4/8 patients, moderate partial reperfusion in 2/8, major bleedings occurred in 2/8, and minor bleedings in 1/8 patients. During the first TC, recombinant tissue-type plasminogen activator (rtPA) activity and antigen, as well as FgDPs and d-dimers, were elevated significantly loco-regionally over systemic values, and a complete breakdown of plasmin-inhibitor activity occurred with only a slight systemic reduction; no other differences were found. During successive TC, differences in rtPA-activity and -antigen levels decreased, and no significant differences were found for all other parameters. Thus, a local fibrinolytic effect was demonstrable during loco-regional thrombolysis for DVT; the magnitude of this effect diminished during successive TC, giving rise to the hypothesis that the fibrinolytic efficacy may be decreased due to growing, antifibrinolytic activity. The preserved, loco-regional plasmin-inhibitor activities during the later TC, in contrast to the complete breakdown during the first TC, suggest that part of the enhanced antifibrinolytic activity is due to loco-regionally increased plasmin-inhibitor activity. The ultimate goal of loco-regional thrombolysis, the induction of local fibrinolysis without systemic effects, has not, however, been achieved.

[The clinical course of coumarin-induced necrosis]. / Klinischer Verlauf bei Cumarin-Nekrose.

In three patients painful reddening of a well-circumscribed area of the skin occurred within five days of starting anticoagulant treatment with phenprocoumon (Marcumar), and within a short time it developed into a full-blown picture of coumarin necrosis. The indication for phenprocoumon was, in the first patient (a 29-year-old mother lying-in after her second child had been born) an increased platelet count and the presence of high risk factors for thromboembolism. In the second patient (25-year-old man) and the third one (45-year-old woman) it was secondary prophylaxis after pulmonary embolus and deep-vein thrombosis, respectively. All three patients were very obese and had a drug allergy, as well as other allergies (bronchial asthma in Cases 1 and 2; allergic rhinitis in Case 3). Phenprocoumon was at once discontinued in all three patients and low-dose heparin administration (Cases 1 and 3) or dextran infusion (Case 2: heparin intolerance) started. All three needed excision of the necrotic tissue with grafting to the skin defect. The coexistence of obesity and allergic diathesis may thus present an especially high risk for coumarin necrosis.

[Prevention of thrombosis with low molecular weight heparin and hydroxyethyl starch in general surgery]. / Thromboseprophylaxe mit niedermolekularem Heparin (LMWH) und Hydroxyaethylstärke (HES) in der Allgemeinchirurgie.

In an open, randomized, controlled and prospective study we compared the efficacy of LMWH with unfractionated heparin (UFH) and the effects of both heparin preparations on haemostatic and fibrinolytic parameters. We also stratified subgroups which received HES intra- and postoperatively. The study groups were well matched with regard to baseline characteristics. With LMWH 4 patients (4.1%) displayed a positive fibrinogen uptake test (1 patient with HES). With UFH 5 patients (5%) demonstrated a positive uptake (3 patients with HES). Antifactor Xa levels were significant higher in the LMWH groups; all other fibrinolytic and haemostatic factors, bleeding and local wound complications did not differ. These data suggest that LMWH in equally effective and safe as UFH in general surgery. HES may have and additive effect.

[Thrombolytic therapy of pulmonary artery embolism in early pregnancy with recombinant tissue-type plasminogen activator]. / Thrombolytische Therapie einer Lungenarterienembolie in der Frühschwangerschaft mit rekombinantem Gewebe-Plasminogen-Aktivator.

We report on successful thrombolytic treatment of massive pulmonary embolism in a patient in early pregnancy with recombinant tissue-type plasminogen activator (rt-PA). Therapy was started with 20 mg rt-PA intravenously over 20 minutes, followed by two further infusions of 20 mg rt-PA within the next 8 hours. Clinical symptoms and haemodynamic parameters improved 24 hours after initiation of therapy. No bleeding complications were observed and the foetus was not affected. Further thromboembolic episodes could be prevented by anticoagulation with low molecular weight heparin up to full term normal delivery.

Investigating the presence of HIV sequences and the distribution of virological markers in hemophiliacs and their sexual partners.

In this study, we report the investigation of a hemophiliac cohort, in which the last HIV-1 seroconversion occurred in 1985. We wanted to evaluate whether 5 years later the results of serological screening and polymerase chain reaction (PCR) technology would match. We examined 61 German patients with congenital deficiencies of factors VII, VIII-c, and IX, and 16 sexual partners (15 partners of anti-HIV-1-negative hemophiliacs). Patients' and partners' anti-HIV-1 status was determined by ELISA and Western blot. Further, we applied the PCR to investigate the possible presence of HIV sequences in anti-HIV-1-negative individuals. Four sets of primers were used in four separated reactions to avoid false-negative results due to genetic variation, as well as false-positive results due to DNA carryover. The data by PCR were not different from the data attained by conventional serological methods. The prevalence of serological markers for HBV and HCV was determined.

Prospective randomized clinical study in general surgery comparing a new low molecular weight heparin with unfractionated heparin in the prevention of thrombosis.

A prospective, randomized, controlled clinical trial was performed comparing the antithrombotic efficacy of the low molecular weight heparin LMWH 21-23, (Braun) with an unfractionated heparin in elective general surgical patients over an observation period of 7 postoperative days. A total of 230 patients were admitted: 103 (group I) received low molecular weight heparin and 100 (group II) low-dose unfractionated heparin treatment given subcutaneously. In group I 41 patients (46%) were operated on for malignant disease and in group II 54 patients (54%). Due to the large amount of great abdominal procedures the intra- and perioperative application of hydroxyethyl starch was allowed for volume substitution. None of the patients died due to fatal pulmonary embolism. In group I four patients revealed positive 125I-labeled fibrinogen uptake (3.9%); two patients belonged to the hydroxyethyl starch subgroup. In group II five patients displayed a positive fibrinogen uptake (5%); two belonged to the hydroxyethyl starch subgroup. The results of the hemostaseological investigations (e.g., prothrombin time, activated partial thromboplastin time, thrombin clotting time, fibrinogen, antithrombin III, protein C, plasminogen, alpha 2-antiplasmin, tissue-type plasminogen activator, plasminogen activator inhibitor) revealed no statistically significant differences between groups I and II or their subgroups, although a tendency to prolonged clotting times was observed. The antifactor Xa activity values, however, displayed a statistically significant difference between the two groups (P < 0.05). The antifactor Xa activity measured up to 0.16 U/ml for the low molecular weight heparin (group I) and 0.05 U/ml for the unfractionated heparin (group II) in the postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)