Dabigatran in patients with atrial fibrillation: perioperative and periinterventional management.

In any type of invasive surgery, the patient's individual risk of thromboembolism has to be weighed against the risk of bleeding. Based on various everyday situations in clinical routine, the purpose of the present expert recommendations is to provide appropriate perioperative and periinterventional management for patients with atrial fibrillation undergoing long-term treatment with the thrombin inhibitor dabigatran. As we currently have no routine laboratory test to measure therapeutic levels of the substance or the risk of bleeding, general measures such as a standardized documentation of the patient's history, a sufficient time interval between the last preoperative dose and the procedure, and careful control of local hemostasis should be given special attention.

Prediction of recurrent venous thromboembolism by the activated partial thromboplastin time.

BACKGROUND: Venous thromboembolism (VTE) is a multi-factorial disease. Extensive thrombophilia screening is costly and often inconclusive. Simple laboratory methods are required to predict the risk of recurrence. OBJECTIVE: To assess if measurement of activated partial thromboplastin time (APTT) allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence. PATIENTS AND METHODS: We prospectively followed 918 patients with a first unprovoked VTE and studied the relationship between recurrence and an APTT after discontinuation of anticoagulation. APTT was expressed as a ratio of test to reference coagulation times. Study endpoint was symptomatic recurrent VTE. RESULTS: Venous thromboembolism recurred in 101 (11%) patients. Patients without recurrence had a greater APTT ratio than those with recurrence (0.97 +/- 0.09 vs. 0.93 +/- 0.09, P = 0.001). After 4 years, probability of recurrent VTE was 8.5% (95% CI: 5.5-11.5%) among patients with a ratio equal to or > 0.95 and 15.6% (95% CI: 11.4-19.9%) among patients with a lower ratio (P = 0.005). Compared with patients with an APTT ratio < 0.95, the relative risk (RR) of recurrence among patients with a ratio equal to or > 0.95 was 0.56 (95% CI: 0.38-0.84, P = 0.005) before and 0.58 (95% CI: 0.39-0.87, P = 0.009) after adjustment for sex, age, factor V Leiden, and factor II G20210A. CONCLUSIONS: Measurement of APTT allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence.

[Recurrent miscarriage or failed in-vitro fertilization: antibodies against annexin V, cardiolipin, beta-2-glycoprotein-1 and APC-resistance]. / Rezidivierende Aborte und frustrane In-vitro-Fertilisation. Antikörper gegen Annexin-V, Cardiolipin und beta-2-Glykoprotein-1, oder APC-Resistenz.

UNLABELLED: Antibodies against annexin-V, a potent anticoagulant abundant in placental tissues, were recently controversially reported to be associated with recurrent miscarriages or failures of in-vitro-fertilization (IVF) attempts. PATIENTS, MATERIAL, METHODS: We screened 56 women (34.7 +/- 4.3 years of age: mean +/- 1 SD) with recurrent IVF failures and/or early pregnancy losses for resistance against activated protein C, lupus anticoagulant and antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. Among them the prevalence of APC-R (8/56, 14%) and elevated levels of IgG- or IgM-anti-cardiolipin antibodies (7/56, 12%) were more common than elevated levels of (IgG or IgM) antibodies against beta(2)-glycoprotein-1 (3/56, 5%) or annexin-V (1/56, 2%). 42 (75%) of the women had another IVF-attempt after this haemostaseological evaluation and received low molecular weight heparin and/ or acetylsalicylic acid in the case of positivity for APC-resistance, lupus anticoagulant or antibodies against annexin V, cardiolipin or beta(2)-glycoprotein-1. RESULTS: The outcome of these IVF-attempts were 19 pregnancies (34%): 4 early miscarriages (7%) and 15 so far uncomplicated pregnancies (27%). The only woman with an elevated anti-annexin V (IgG) level had had 7 IVF before and received 40 mg Enoxaparin (Lovenox) subcutaneously once daily during the 8(th) IVF, which resulted in a healthy pregnancy. DISCUSSION, CONCLUSION: Our findings suggest that among women with recurrent IVF failures anti-annexin V antibody positivity is less prevalent than APC-resistance, lupus anticoagulant (LA) or elevated levels of antibodies against cardiolipin, beta(2)-glycoprotein-1 and that the IVF-result of women with APC-R, LA or with elevated levels of antibodies against annexin V, cardiolipin or beta(2)-glycoprotein might be positively influenced by low molecular weight heparin.

[Monitoring of tienopyridines or glycoprotein IIb/IIIa-receptor antagonists: simple platelet function tests]. / Monitoring von Tienopyridinen und GPIIb/IIIa-Antagonisten: Einfache, praktikable Plättchenfunktionstests.

Platelet function analyses were known as mystified, complicated, and time consuming laboratory investigations with a high coefficient of variation. Only in rare cases they led to precise interpretations under routine clinical laboratory conditions. In the first line they were focussed on bleeding tendencies. Only few were suited to evaluate the state of hyperaggregability of platelets. This short presentation of the GTH-Symposium 2004 gives a survey on the most simple and practicable tests for checking platelet function which may be used for the monitoring of therapy with tienopyridines and glycoprotein IIb/IIIa-receptor antagonists.

HCV genotypes and age distribution in patients of Vienna and surrounding areas.

BACKGROUND: Chronic hepatitis C (CHC) can result in liver cirrhosis and hepatocellular carcinoma. Determination of the hepatitis C virus (HCV) genotype/subtype may be of prognostic value to estimate the risk of development of liver cirrhosis. OBJECTIVE: The HCV genotype/subtype was determined in patients with CHC and possible associations with age, source of HCV transmission, duration of HCV infection, and development of liver cirrhosis were investigated. STUDY DESIGN: A total of 250 consecutive patients with CHC were studied. HCV genotypes/subtypes were determined with a commercially available assay based on the reverse-hybridization principle. Source of HCV transmission and duration of HCV infection were taken from the patient documentation and liver cirrhosis was diagnosed by clinical, biochemical, and sonographic data. RESULTS: HCV genotypes 1, 2, 3, 4, and 5 were found in 74.8, 2.8, 16, 5.2, and 0.4% of the patients. Most frequent subtypes were 1b (54%), 1a (15.6%), and 3a (15.6%). Patients with genotype 1 (mean, 52.8 years) or 2 (mean, 51.0 years) were significantly older than patients with genotype 3 (mean, 37.2 years) or genotype 4 (mean, 37.2 years). Patients with subtype 1b (mean, 58.1 years) were significantly older than patients with subtype 1a (mean, 40.8 years) or 3a (mean, 37.5 years). The main sources of HCV infection were intravenous drug abuse in 30.0% of all patients (genotype 1 in 53.3%; genotype 3 in 40%) or transfusion of blood and blood products in 21.6% of all patients (genotype 1 in 83.4%). The source of transmission, however, remained unknown in 44.8% of all patients. The prevalence of genotype 1 was significantly higher in patients with long duration (more than 20 years) of CHC. In none of the patients with genotype 2 or 3, duration of CHC for more than 20 years was observed. The prevalence of genotype 4 was significantly higher in patients with short duration (less than 10 years) of CHC. Liver cirrhosis was diagnosed in 13.6% of all patients (97.1% of patients with genotype 1). Patients with liver cirrhosis were significantly older compared to asymptomatic patients (mean, 63.8 vs. 51.3 years). CONCLUSION: HCV subtype 1b was found to be the main subtype in the investigated population and is currently the major contributor to liver cirrhosis. Patients infected with subtype 1a, however, are at comparable risk for development of liver cirrhosis. In future, subtype 3a and genotype 4 may also become an increasing problem.

Rational, high quality laboratory monitoring before, during, and after infusion of prothrombin complex concentrates.

Prothrombin complex concentrates (PCCs) have been used for over thirty years to treat or prevent bleeding due to hemophilia B, vitamin K deficiency, warfarin overdose, liver disease, or deficiency of one of the prothrombin complex factors. This article tries to answer the questions of which profile of laboratory assays is required for the establishment of the diagnosis; what are indications of replacement therapy with PCCs; how to monitor the therapeutic effect; and how to monitor a possible prethrombotic state after PCC infusion. After proposing basic, standard, and optimal profiles of hemostaseological assays, the basic principal characteristics of a quality management satisfying the requirements of good laboratory practice are discussed.

Venous thromboembolism at a young age in a brother and sister with coinheritance of homozygous 20210A/A prothrombin mutation and heterozygous 1691G/A factor V Leiden mutation.

We report on members of a Turkish thrombophilic family with coinheritance of the prothrombin mutation PT20210A and the factor V Leiden mutation. The 23-year-old propositus and his elder sister both had episodes of venous theomboembolism at a young age (23 years and 26 years, respectively) and are homozygous for the PT20210A mutation and heterozygous for the factor V Leiden mutation. The 51-year-old father is suffering from coronary heart disease and is heterozygous for both thrombophilic mutations. The asymptomatic 43-year-old mother is heterozygous for the PT20210A mutation, but without activated protein C resistance. Two other children, a 20-year-old girl who is homozygous for the PT20210A mutation and a 13-year-old boy who is heterozygous for the PT20210A mutation, are both free from activated protein C resistance and thrombosis. This report provides further evidence for an early onset of thromboembolic disorders in individuals with an homozygous state of the prothrombin variant 20210A/A and coinheritance of another thrombophilic mutation. Consensus guidelines are required for the treatment and prophylaxis of patients and subjects who remain asymptomatic with homozygous or more than one heterozygous genetic defect associated with thrombophilia.

A hitherto unknown splice site defect in the protein S gene (PROS1): the mutation results in allelic exclusion and causes type I and type III protein S deficiency.

A hitherto unknown splice site mutation, in the splice acceptor of intron B (tctag to tctgg), was identified in a symptomatic patient with type III protein S deficiency. The mutation co-segregated with type I/III protein S deficiency in the patient's family. RNA analysis showed allelic exclusion of the mutant transcript in affected individuals. The apparent type III deficiency in the propositus was not associated with the protein S Heerlen variant.

Mutations in the human factor XII gene.

The factor XII gene from 31 unrelated factor XII-deficient patients from Germany, Switzerland, and Austria was screened for mutations at the genomic level. Several novel mutations were detected and their absence in a control group of 74 healthy unrelated individuals was checked. Most changes are in the serine protease domain affecting the catalytic triad His-393-Asp-442-Ser-544; two missense mutations, R398Q (arginine 398 to glutamine; gene bank accession no. U71276) and L395M (leucine 395 to methionine; gene bank accession no. U71277), are close to the active site histidine at position 393. Another mutation detected in a cross-reacting material (CRM)-positive female with a history of three abortions affects the active site aspartic acid by changing it to asparagine (D442N; gene bank accession no. U71275). The novel mutation G570R (glycine 570 to arginine; gene bank accession no. U71274) giving rise to a CRM-positive phenotype is located next to Cys571, which forms a vital disulfide bridge. Two mutations are causing reading frame shifts: one single basepair deletion in exon 12 [exon 12: 10590(DelC); gene bank accession no. U71278] and one acceptor splice site mutation [exon 14: 11397(G --> A); gene bank accession no. L43615]. The putative regulatory mutation exon 1:-8 (g --> c) in the upstream region of the gene is associated with an aberrant Taq I restriction site allele in intron B of the gene (gene bank accession no. X80393).

Anti-GM1 antibodies in polyneuropathies of unknown origin.

This study was undertaken to determine whether anti-GM1 titres are raised in polyneuropathies of unknown origin and whether determination of these titres is useful for diagnosing these conditions. The study population comprised 20 controls (aged 36-88 years), 12 patients with polyneuropathies of known origin (aged 31-81 years) and 15 patients with polyneuropathies of unknown origin (aged 40-77 years). Antibody levels were measured using a commercial GM1 enzyme linked immunosorbent assay kit (Buehlmann Laboratories). Mean anti-GM1 IgG and IgM antibody titres were not raised in patients with polyneuropathies of unknown origin. Anti-GM1 IgG antibody titres were raised in one and GM1 IgM antibody titres in none of the patients with polyneuropathies of unknown origin. In conclusion, GM1 antibody levels are rarely raised in polyneuropathies of unknown origin and probably play a minor role in the pathogenesis of these conditions.

Comparison of a new automated kinetically determined fibrinogen assay with the 3 most used fibrinogen assays (functional, derived and nephelometric) in Austrian laboratories in several clinical populations and healthy controls.

A new automated kinetically determined fibrinogen assay was measured in plasmas of healthy subjects and three clinical cohorts (acute-phase reaction, liver cirrhosis and fibrinolytic therapy) that were expected to show normal, high and low levels of fibrinogen. The results were compared with the results of fibrinogen measurement using the derived method, the method according to Clauss and an immunological-nephelometric method. Altogether, the best correlation was achieved between the kinetic and the derived method. However, results from the derived method were generally higher than values obtained through the kinetic method. This was particularly true for high concentration levels above 400 mg/dl (patients with acute phase reaction) as well as for plasmas containing fibrin(ogen) degradation products and low concentrations of fibrinogen (below 150 mg/dl). Fibrinogen determinations in several commercial plasma pools with declared fibrinogen levels show remarkable heterogeneity when different methods were applied. To improve the discernment of fibrinogen determinations we suggest adjustment of standard preparations to international reference materials and the specification of the method used. Furthermore the attending physician is asked to cast a critical eye on fibrinogen values with regard to the used method of determination.

Platelet size, fibrinogen and lipoprotein(a) in coronary heart disease.

BACKGROUND: An increase in mean platelet volume has been reported to be associated with arterial thrombosis and myocardial infarction. A larger mean platelet volume has been regarded as an independent risk factor for recurrent myocardial infarction. We therefore investigated whether it is also increased in patients with coronary heart disease examined a few days before cardiac surgery. METHODS: Four hundred and twenty-six patients with coronary heart disease who were waiting for cardiac surgery and 125 healthy individuals were included in the study. Mean platelet volume and other platelet parameters were obtained from a routine blood count procedure using a flow cytometric haematology analyser. RESULTS: Mean platelet volume did not differ significantly between patients and controls; however, as expected from the literature, patients had significantly elevated levels of fibrinogen, cholesterol, triglyceride, apolipoprotein B and apolipoprotein(a). Furthermore, we observed no significant difference in mean platelet volume between patients without myocardial infarction and those who had survived at least one myocardial infarction. CONCLUSION: Our findings suggest that, using a routine laboratory procedure, mean platelet volume cannot be used as a predictive marker for coronary heart disease or myocardial infarction.

Quality assurance of high-dose i.v. heparin treatment exemplified by patients implanted with coronary Palmaz-Schatz stents.

The need to standardize treatment with high-dose IV standard heparin by using activated partial thromboplastin time (APTT) reagents tested for their heparin sensitivity and by establishing a standard treatment schedule led to the development of the "Lainz concept" of heparin management. The determination of heparin sensitivity of the 2 APTT reagents used (APTT Micronized Silica and APTT Actin FSL), their good agreement (r = .9977; P = .000), and their therapeutic APTT ratio of 1.5-2.5 fold of baseline APTT (therapeutic range, forty-five to seventy-five seconds) equivalent to 0.3-0.7 antifactor Xa units are presented. The "Lainz concept" was tested in 29 patients receiving high-dose heparin after coronary artery stenting. A mean dose of 1,273 U of standard heparin/hour (15.7 U/kg body weight/hour) was shown to produce APTTs in the therapeutic range. From the introduction of the "Lainz concept" 81% of the APTTs were kept within the therapeutic range by using a defined heparin-monitoring schedule based on a guideline protocol for controlling heparin treatment. Only 19% of the APTTs were below the therapeutic range. Factors underlying subtherapeutic APTTs are discussed. The reduction in the rate of subtherapeutic APTTs to less than 3% seen after the introduction of the "Lainz concept" constitutes an important contribution toward quality assurance in high-dose heparin treatment.

[Changes in antithrombin III, prothrombin fragment 1 + 2 and thrombin-antithrombin III complex following implantation of a coronary Palmaz-Schatz stent]. / Veränderungen von Antithrombin III, Prothrombinfragment 1 + 2 und Thrombin-Antithrombin-III-Komplex nach Implantation von koronaren Palmaz-Schatz-Stents.

To detect changes in the clotting parameters antithrombin III (AT III), prothrombin-fragment 1 + 2 (F 1 + 2) and thrombin-antithrombin-III-complex (TAT) after implantation of Palmaz Schatz stents, coagulation was monitored at standardized time points in 35 patients for 10 days. All patients were anticoagulated using a combination of heparin, phenprocoumon, and acetyl salicylic acid. Heparin therapy was guided by APTT levels (normal range 25-35 s), which were still within the therapeutic range (median 49.6 s (25%/75% percentiles 41.6/54.4) on day 10. Simultaneous oral anticoagulation was found to be effective on day 8 on average (INR median 2.24 (1.93/2.50)). The AT III activity dropped significantly (p < 0.0001) after a heparin loading dose of 15,000 IU during stenting. As the heparin dose was reduced on the following days, AT III levels increased significantly (p < 0.0001) during the observation time. There was a highly significant (p < 0.001) negative correlation between AT III and heparin levels. On days 4 and 5 F 1 + 2 values were significantly (p < 0.001 and p < 0.05) higher than on the day of stenting (median 1.07 (0.90/1.31) 1.13 nmol/l and 1.06 (0.85/1.23) nmol/l vs. 0.97 (0.69/1.15) nmol/l) and dropped during anticoagulation. F 1 + 2 levels showed a significant negative correlation (p < 0.0005) with APTT values. TAT values showed no significant changes during the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)