Lys-plasminogen as an adjunct to local intra-arterial fibrinolysis for carotid territory stroke: laboratory and clinical findings.

To improve the efficacy of local intraarterial fibrinolysis (LIF), we compared different fibrinolytic drugs in a cerebral circulation model in the laboratory. The technical efficacy of fibrinolysis, defined as the clot volume lysed per unit time, was found to be optimal with r-tissue plasminogen activator (TPA) activated lys-plasminogen (= plasmin). Subsequently, 20 patients with stroke due to carotid artery territory occlusion were treated by local intraarterial fibrinolysis using the plasmin regimen. The angiographic data and clinical outcome of these patients were compared with those of 40 patients who received plasminogen activators (urokinase or r-TPA) only. Laboratory and clinical data confirmed that plasmin lysis is superior to treatment using only plasminogen activators.

Thrombolytic therapy in fulminant pulmonary thromboembolism.

For the treatment of massive pulmonary embolism thrombolytic therapy is efficient in reducing late mortality and complications from chronic pulmonary hypertension. Best results are achieved if treatment is started as soon as possible. Even after days or weeks after pulmonary thromboembolism, however, thrombolytic therapy is beneficial. In life threatening conditions due to right heart failure an initial bolus of 2,000,000 U urokinase should be administered. The number of contraindications can be markedly reduced due to the well controlled thrombolysis with urokinase.

The effects of aprotinin on hemostatic function during cardiac surgery.

The mechanism of action by which large doses of aprotinin decrease blood loss during cardiac surgery is not completely understood. In a prospective, controlled study, 30 patients undergoing cardiac surgery were given high-dose aprotinin in accordance with a commonly used regimen. Twenty untreated but otherwise comparable patients served as the control group. The effects of aprotinin therapy during cardiopulmonary bypass on coagulation parameters, the kallikrein-kinin system, fibrinolysis, platelet stimulation, and the release of elastase from neutrophils were studied. The fibrinolysis parameters were the only measurements that showed clear and significant differences between the two groups. Aprotinin almost completely inhibited the formation of fibrin and fibrinogen degradation products. It is assumed that inhibition of systemic fibrinolysis and suppression of local fibrinolysis contribute to the hemostatic action of aprotinin. The study did not demonstrate a significant protective effect of aprotinin on platelets. In addition, the dose of aprotinin administered did not affect the kallikrein-kinin system of elastase. Therefore, these data suggest that the previously demonstrated hemostatic effects of aprotinin derive primarily from its antifibrinolytic action.

[Color-coded Doppler sonography for phlebothrombosis]. / Farbkodierte Duplexsonographie bei Phlebothrombosen.

Between November 1988 and February 1990, a total of 180 patients (76 men and 104 women; mean age 59 [17-79] years), suspected of having sustained a deep-vein or pelvic thrombosis were examined by colour Doppler ultrasound, the results being compared with those obtained by conventional phlebography. For 154 phlebographically confirmed acute venous thromboses (demonstrated by colour Doppler ultrasound in 153), four older thromboses (colour Doppler ultrasound: 7), and 22 without significant venous disease (colour Doppler ultrasound: 20), the specificity for colour Doppler ultrasound was 99%, its sensitivity 94%. In 49 patients with confirmed venous thrombosis thrombolytic treatment was started with 250,000 IU urokinase, followed by 62,500 IU hourly, the results being assessed by colour Doppler ultrasound and phlebography. This gave a specificity, compared with phlebography, of 99%, and a sensitivity of 97%. These data indicate that, in the diagnosis of venous thrombosis of the legs, colour Doppler ultrasound noninvasively provides information at least as reliable as phlebography. It may even be superior to phlebography in the demonstration of residual flow in partly thrombosed veins.

[Noncardiac risk factors in heart surgery--the blood coagulation system]. / Nichtkardiale Risikofaktoren in der Herzchirurgie--Gerinnungssystem.

Diagnostics and therapy in coagulation disorders are presented. A special emphasis is given to alterations of blood coagulation in cardiac surgery. No major rule can be defined for this particular field. All disturbances of blood coagulation may become clinically overt in highly variable combinations, thus representing no or high risk to patients conditions. This implies that the actual risk has to be estimated individually for every patient and that the risk of the cardiac disorder has to be considered in view of the risk of the operation plus potential disturbances in coagulation. The latter in order to be assessed appropriately, clearly requires a laboratory specialised in diagnostics of coagulation, as well as a highly experienced coagulation physiologist for decision making. Following this policy, we have not been forced to disagree about extracorporeal circulation for cardiac surgery in most instances. Problems have been confined to patients suffering from various hepatic disorders or from impaired platelet functions.

[Intraoperative coagulation activity--a defined group of trauma surgery patients]. / Intraoperative Gerinnungsaktivierung--Untersuchungen an einem definierten Patientengut der Unfallchirurgie.

Analyses of blood coagulation in a defined group of patients before, during, and after trauma-surgery confirms an intraoperative trigger-mechanism, that causes postoperative thromboembolic complications. They also proof the correlation between extent of tissue-lesion and extent of triggering, this was previously presumed from the postoperative incidence of thromboembolic complications. Apart from the usual blood coagulation tests the following parameters where analysed: Factor VIII: C, Ristocetin-Co-factor, Factor Xa, AT III, TAT, Reptilase-time, tPA, D-dimers, and FPA. Simultaneously, it was shown, that a preoperative prophylaxis of thrombosis can prevent an intraoperative increase of Factor Xa, that plays a key role in postoperative thromboembolic complication. The increased intraoperative turnover of coagulation factors, which is necessary for physiologic blood coagulation, is not prevented.

[Lysis treatment of left ventricular thrombi. Acute and long-term results]. / Lysebehandlung linksventrikulärer Thromben. Akut- und Langzeitergebnisse.

Intravenous thrombolysis with urokinase (60,000 U/h) was undertaken in 15 patients with large thrombi in the left ventricle (demonstrated by echocardiography) after myocardial infarction. Complete lysis was achieved in ten, partial in four. None had post-thrombolysis signs of arterial emboli, two patients developed haematuria and one had partial separation of the thrombus which required operative removal. Four patients who had a mean ejection fraction of 37 +/- 12% had died a sudden cardiac death within six months of the thrombolysis. Nine patients survived for up to four years without recurrence of thrombi: seven of them had been treated with aspirin (acetylsalicylic acid), two with coumarin derivatives. Two patients could not be followed-up. These preliminary results suggest that large left-ventricular thrombi can be successfully lysed by intravenous thrombolysis without significant complications, probably without recurrent thrombi.

[Fibrinolytic activity, thrombocyte function and pharmacokinetics during intra-arterial or intravenous prostaglandin E1 infusion in patients with chronic arterial occlusive disease]. / Untersuchungen zur fibrinolytischen Aktivität, Thrombozytenfunktion und Pharmakokinetik während intraarterieller oder intravenöser Prostaglandin-E 1-Infusion bei Patienten mit chronisch arterieller Verschlusskrankheit.

Monitoring various parameters of fibrinolytic activity in 6 patients with arterial occlusive disease during intra-arterial (i.a.) or intravenous (i.v.) prostaglandin (PG) E1 infusions indicated activation of the endogenous fibrinolytic system. However, due to the small number of patients not all test parameters revealed significant changes. None of the PGE1 infusion regimens used (1.25 or 2.5 ng/kg/min i.a. or 5 or 10 ng/kg/min i.v. for 120 min in each case) led to any significant change in various parameters checked for ex-vivo platelet function. In agreement with these data the radioimmunological determination of PGE1 in venous plasma did not reveal any significant rise. On the other hand, the circulating metabolite of PGE1, 15-keto-13, 14-dihydro-PGE1, reached plasma levels which correlated well with expected theoretical values taking the infusion rate into consideration. A potential mechanism by which even low plasma concentrations of PGE1 might affect platelet function in vivo is discussed.

Antithrombin III in surgery.

Monitoring of AT III values and, if necessary, replacement therapy, are particularly important during the peri- and postoperative phase, or after multiple trauma, in order to prevent thromboembolic complications especially in operations on the liver, or when using heart-lung machines and in shock and pronounced DIC. AT III deficiency is partly dependent on the type and severity of the disorder with the resultant increased in turnover and partly on the synthesis capacity of the liver. Life-threatening complications can be prevented by AT III replacement.

Effectiveness of intraarterial plasminogen application in combination with percutaneous transluminal angioplasty (PTA) or catheter assisted lysis (CL) in patients with chronic peripheral occlusive disease of the lower limbs (POL).

The accepted correct procedure for treating occlusive arterial diseases includes surgical disobstruction, CL as well as PTA. Combined non-surgical strategies are effective in about 60% of these patients. However, a high risk of rethrombosis despite from the prophylaxis with anticoagulants like heparin or antiplatelet drugs like ASA is proven, especially in patients with multi-segmental stenosis as well as in patients with extensive narrowing of the arteries. In these cases primary lesions (endangitis obliterans) or secondary lesions of the endothelium cause local depletion of plasminogen in the endothelium. Independent of the method used for reopening the vessel in these patients, a significant progression of the vessel disease and a high rethrombosis rate during longterm follow-up is observed. These results lead us to apply plasminogen locally to decrease the rate of rethrombosis. In patients suffering from stage III-IV (La Fontaine) including patients with multi-segmental stenosis as well as extended narrowing of the artery, PTA in combination with CL was performed. The catheter was placed as near as possible to the thrombus. In some cases the 'fibrinolyticum' could be injected directly into the thrombus. In these cases a bolus of 4,000 U/ml was locally infused, otherwise 1.0-1.5 million U urokinase per 24 hrs. were locally infused with heparin. In 28% (22 patients) no sufficient clinical response occurred using this combined therapy and plasminogen was applied locally. The following criteria supported our decision to include the patients in this study: 1. Insufficient response occurring after 12-24 hrs. of local infusion. 2. Following 6 bolus injections no reopening of the vessel occured within 60 minutes or the clinical response was insufficient due to rethrombosis. 3. Insufficient effects of lysis therapy after 2 hours and contraindication for a systemic fibrinolytic therapy (e.g. hypertension, age, etc.). 1,000 U plasminogen per ml were infused locally or 2,000 U up to 5,000 U plasminogen (in 5 to 10 ml 0.9% saline) were infused slowly (2-4 minutes infusion time) into the catheter in these patients 10 minutes after unsuccessful treatment with local urokinase therapy. Five minutes after administering plasminogen local intraarterial fibrinolytic therapy with urokinase was continued. No severe side effects due to this therapy were observed, although some patients suffered from acute pains in the peripheral segments of the arteries occurring immediately after infusion of plasminogen. In 16 of 22 patients a complete recanalization occurred and in 3 patients a satisfying clinical improvement was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Fibrinolytic therapy of pulmonary embolism.

Fibrinolytic therapy of pulmonary emboli is indicated in persistent pulmonary hypertension or acute shock. If possible, diagnosis should be confirmed by pulmonary angiography - in our hands digital subtraction angiography has proved of value. Emboli of such size that spontaneous lysis is unlikely can be actively removed by lysis therapy so as to minimize late damage. Small or insignificant emboli do not require such therapy. As lysis therapy does not reduce early mortality it follows that mortality is not a suitable parameter for evaluating the results of treatment. Rapid clinical improvement and fall in pulmonary arterial pressure and oxygen tension some 24 to 48 hours later should not lead to erroneous conclusion that the thrombus mass has been lysed. Pulmonary angiography demonstrates that lysis takes 48 hours to 13 days. Large thrombi require a mean duration of treatment of 6 days. Only complete elimination of the vascular occlusion leads to permanent improvement. Obviously, the duration of therapy in cases of demonstrable phlebothrombosis will also depend upon the results of phlebography. In the case of contraindications lytic therapy should only be initiated where the risk from the emboli is greater than the possible haemorrhagic risk from the contraindication. Under such circumstances urokinase therapy with 40,000 to maximal 60,000 units/hour is preferable.

[Monitoring drug therapy in venous thrombosis]. / Uberwachung der medikamentösen Therapie der Venenthrombose.

Minimal prerequisites for the follow-up of thrombolytic therapies are determinations of partial thromboplastin time, thrombin time and fibrinogen concentration. With help of these tests it is possible to lower the risk of rethromboses and haemorrhages. By including additional tests some patients may benefit in respect of safety and better knowledge of the underlying mechanisms. However, until now there exists no laboratory tests that is able to give information about success or failure of the therapy independent of phlebography. For the gentechnological products like tPA and prourokinase final conclusions can be drawn only after having established dose-response curves for patients suffering from thromboses.