Monika Barthels

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)

Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters

Abstract We prospectively evaluated the clinical relevance of genetic risk factors of thrombosis in 137 paediatric patients with solid tumours or leukaemia/lymphoma. The factor V G1691A (FV-L), the prothrombin G20210A (FII-L) and the homozygous MTHFR variant were examined. In addition, protein C, protein S and antithrombin (AT) deficiency were evaluated in patients with ALL or thrombosis. The inter-group incidence of risk factors and thrombotic events was compared. 73 of the 137 patients had ALL and 64 another form of leukaemia, lymphoma or a solid tumour. They were treated according to the established paediatric tumour protocols ALL-BFM, NHL-BFM, COSS, CWS and others. All patients had central venous lines. No patient received heparin or any other anticoagulant. Endpoints of the study were thrombosis, regular completion of chemotherapy or death. Incidence of mutations in the whole group: FV-L (7.3% heterozygous, 0.7% homozygous); FII-L (2.9% heterozygous, no homozygotes); MTHFR (51.8% heterozygous, 10.9% homozygous). Ten patients (7.3%), 6 with ALL and 4 with solid tumours, developed thrombosis. 4 of the 6 patients with ALL and thrombosis (67%) but only 21% of ALL patients without thrombosis had a genetic risk factor (P < 0.013, χ2). No genetic defect was found in the 4 patients with other malignancies and thrombosis,. However, besides a tumour, these patients had additional exogenous risk factors including diabetes insipidus and hemiparesis. Conclusion Genetic mutations appear to be additional risk factors for the development of thrombosis in patients with ALL. In contrast, these mutations do not appear to be relevant risk factors for thrombosis in the small number of children with other malignant diseases reported here. This difference may be due to asparaginase and corticosteroids being used in ALL but not in solid tumour protocols.

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.

Quantification and Facilitated Comparison of von Willebrand Factor Multimer Patterns by Densitometry

The analysis of von Willebrand factor (vWF) multimers is an important laboratory tool for distinguishing among the numerous subtypes of von Willebrand disease (vWD). Comparability and reproducibility of this method are insufficient; standardization and external references are pending. Interlaboratory comparison of results therefore may be difficult. We applied densitometry to obtain a reproducible quantification of vWF multimer patterns in healthy donors, patients with vWD variants, and factor VIII/vWF concentrates to improve the reproducibility and comparability of vWF multimer analysis. Multimers were separated and visualized luminographically on x-ray films. Films were scanned and evaluated by densitometry. The variation inherent in vWF multimer analysis and the range of the normal could be quantified. In vWD variants and factor VIII/vWF concentrates, densitometry could quantify and visualize alterations of vWF multimer patterns and facilitate their comparison. Densitometry permits a precise quantitative comparison of sample patterns to a reference plasma. It could be a valuable tool offering reproducible quantification and additional visualization of normal and pathologic vWF multimer patterns, facilitating their comparison and contributing to a standardization of vWF multimer analysis.

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)

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

Anticoagulant prophylaxis and therapy in patients with cancer.

Due to the various reported mechanisms by which tumours may alter haemostasis directly or indirectly, a close relationship between tumour and thrombosis is convincing. As patients with cancer represent a diverse group, the establishment of general treatment guidelines concerning antithrombotic prophylaxis and therapy requires more data than are present to date. However, in cancer patients who are candidates for surgery, chemotherapy, indwelling central venous line, or prolonged immobility, primary prophylaxis is recommended. Patients with manifest thromboembolism should receive immediate treatment and a secondary prophylaxis for more than 3 months or at least as long as the cancer is active. In patients inappropriate for oral anticoagulation, the administration of LMWH is a suitable alternative. More prospective, randomized and larger studies are required to determine the optimally tailored primary prophylaxis, the best time to start and to stop treatment, to determine the best route, dosage and pharmacological antithrombotic, and to define the role of newer anticoagulants as hirudins in the anticoagulative prophylaxis and treatment of patients with cancer.

Peri- und postoperative kontinuierliche Infusion rekombinanter Faktor-VIII-Konzentrate bei Hämophilie A

Patienten mit Hamophilie A oder B bzw. schwerem von-Willebrand-Syndrom werden ublicherweise durch intravenose Applikation von Bolusinjektionen von Faktorenkonzentrat behandelt. Diese Form der Therapie ergibt typischerweise starke Schwankungen der minimalen und maximalen Plasmalevel (Levine 1987). Kritisch sind dabei die Phasen niedriger Spiegel vor der nachsten Substitution, in denen es zu Nachblutung aufgrund insuffizienter Substitution kommen kann. Um dies zu verhindern, werden haufig hohere Dosen verabreicht, als die Situation es erfordert. Dies belastet den Patienten und erhoht die Kosten.

Stellenwert und Prävalenz der Prothrombin-G20210A-Mutation bei Patienten mit hereditärer Thrombophilie

Kurzlich wurde eine neue Mutation im Gen des Prothrombins beschrieben (Poort 1996), die gehauft bei Patienten mit Thrombosen vorkommt und mit einer erhohten Thromboseneigung einher gehen soll (Brown 1997; Poort 1996; Cumming 1997; Hillarp 1997; von Depka Prondzinski 1997). Bei dieser Mutation handelt es sich um einen Austausch von Guanin gegen Arginin an der Position 20210 innerhalb eines nicht translatierten Bereichs des Prothrombingens. Diese kam bei 18% aller Patienten mit familiarer Thrombophilie vor, dagegen nur bei ca. 1% gesunder Kontrollen, und ist mit einem ca. 3fach erhohten Thromboserisiko gegenuber der gesunden Bevolkerung assoziiert. Inzwischen liegen auch Daten uber die Pravalenz der Prothrombinmutation bei Kindern mit thromboembolischen Komplikationen und malignen Erkrankungen vor (Wermes 1998).

Keine Dosisreduktion des vWF-Konzentrates trotz kontinuierlicher Infusionstherapie bei erworbenem von-Willebrand-Syndrom

Die Entwicklung eines erworbenen von-Willebrand-Syndroms mit Verlust der grosen Multimere ist bei Herzvitien ein bekanntes Phanomen [2–4]. Die Ursache fur diese Storung ist bisher ungeklart. Die Behandlung dieser Patienten im Rahmen von Blutungskomplikationen oder Operationen besteht in der Substitution von vonWillebrand-Faktor-haltigen Faktor-VIII-Konzentraten, ublicherweise als Bolusapplikation alle 8–12 h. Durch kontinuierliche Infusionstherapie konnte der Verbrauch von Faktor-Konzentraten bei Patienten mit kongenitalem von-WillebrandSyndrom um bis zu 50% reduziert werden [1].