[Prehospital management of acute coronary syndrome in patients on long-term direct oral anticoagulant treatment]. / Prähospitale Behandlung des akuten Koronarsyndroms unter DOAK-Dauertherapie.

BACKGROUND: Despite an increasing incidence of patients suffering from acute coronary syndrome (ACS) under simultaneous treatment with direct oral anticoagulants (DOAC), neither sufficient scientific data nor uniform guidelines for the anticoagulation treatment of these patients are currently available. OBJECTIVE: The aim of this study was to determine the current practice of preclinical treatment of ACS in patients under DOAC treatment. MATERIAL AND METHODS: An internet and paper-based survey of emergency physicians, specialists of internal medicine, anesthesiologists, emergency and intensive care physicians was performed concerning the prehospital treatment of ACS in patients under long-term DOAC treatment. RESULTS: Overall, 284 questionnaires were answered. Substantial differences in the current treatment of ACS under long-term DOAC therapy were identified. While 39% of the respondents stated that they administer a combination treatment of heparin and acetylsalicylic acid (ASA), 36% renounced the administration of heparin. If a dose reduction was performed, 71% answered that they reduce the heparin dosage. Also, in cases of ST-segment elevation myocardial infarction 48% of the physicians renounced the administration of heparin. CONCLUSION: In Germany there is currently a heterogeneous practice of emergency treatment of ACS patients under DOAC therapy with respect to the administration of heparin and ASA. Therefore, guidelines of the specialist medical societies should address the prehospital emergency anticoagulation management of ACS in patients under therapy with DOAC, which correspond to the needs of patients and emergency physicians.

[Anticoagulation-direct oral anticoagulants]. / Antikoagulation ­ direkte orale Antikoagulanzien.

Since direct oral anticoagulants (DOAC) have become available, use of anticoagulant treatment has become easier and safer-for patients suffering from thromboembolic diseases as well as for patients with atrial fibrillation: Because of constant bioavailability, fixed dose regimen treatment is possible, monitoring not necessary and severe bleeding complications-particularly intracranial hemorrhages-rare in comparison to vitamin K anticoagulants. To gain all these advantages, it is essential to give DOAC in the correct dosage. Dose reduction of single DOAC has to be considered depending on underlying disease, body weight and renal function. DOAC are not allowed in patients with artificial heart valves, in pregnancy and in children. In case of severe bleeding complications under DOAC treatment, prothrombin complex concentrates is one treatment option. For dabigatran an antidote is available.

Reduced platelet aggregation in a boy with scurvy.

Pediatric scurvy is a rare condition characterized by perifollicular petechiae and bruising, hemorrhagic gingivitis and musculoskeletal symptoms, all assumed to be predominantly related to abnormal collagen structure. We report on a 9-year-old autistic boy with vitamin C deficiency due to a highly limited food range presenting with multiple petechiae, gum bleeding and debilitating bone pain, in whom platelet aggregometry revealed a distinctly reduced thrombocyte aggregation, normalizing after vitamin C supplementation. This observation indicates that platelet dysfunction may additionally contribute to the hemorrhagic diathesis in scurvy, and demonstrates that ascorbic acid deficiency should be considered in children with an otherwise unexplained acquired thrombocytopathy.

[Hemorrhagic disorders]. / Blutungsneigung.

Patients suffering from hemorrhagic disorders often present with only minimal bleeding during surgery or injuries. However, some patients have life-threatening bleeding. Simple screening tests can be used to find the cause of the bleeding: patient and family histories provide information on whether the bleeding tendency is hereditary or acquired. Clinical examination can reveal the bleeding type. Measurement of platelet count can be used to exclude thrombocytopenia. Coagulation tests, such as prothrombin time (PT, Quick) and activated partial thromboplastin time (aPTT) can supply initial information concerning deficiency states of coagulation factors. Bleeding time is often prolonged in patients suffering from von Willebrand disease, thrombocytopenia or thrombocytopathy. If--due to the results of these screening tests-further testing of particular coagulation factors or platelet function is needed, then patients should be referred to a centre specialized in blood coagulation.

Inhibitor-immunology-study. Evaluation of inhibitor development in haemophilia B.

UNLABELLED: The development of inhibitors in haemophilia B is one of the most important complications of replacement therapy, affecting mortality and morbidity. Inhibitor development is based on complex immunological factors, and to date, only little is known about its underlying mechanisms. Here, we present first results of the haemophilia B group of our Inhibitor-Immunology study. PATIENTS, METHODS: So far we have analysed 15 patients with haemophilia B. Four of them developed a high titre inhibitor; the remaining 11 had no inhibitor. We evaluated 9 SNPs in 8 genes (CD40, CTLA-4 , IL-1ß, IL-10, TLR2 , TLR4, TLR9, TNF-α). We compared the distribution of these alleles between inhibitor and non-inhibitor haemophilia B patients and between haemophilia B patients and a normal male control population. HLA typing was performed in all patients. Results, discussion: There appears to be a trend towards a skewed distribution of TLR 9, IL-10 and CTLA4 alleles in haemophilia B patients. Due to the limited number these differences are, however, not statistically significant. The t-test of all patients with inhibitor versus without inhibitor was significant for HLA-A*03 and DPB1*0401 and borderline for DRB1*0201.

[New anticoagulants. Characteristics, monitoring and management of bleeding]. / Neue Antithrombotika. Wirkprinzip, Monitoring und Blutungsmanagement.

Vitamin K antagonists and heparins have been standard anticoagulation drugs over the past decades. They are effective and safe but they have several drawbacks which has led to the development of new oral anticoagulants. Dabigatran etexilate is a specific oral thrombin inhibitor and rivaroxaban and apixaban are oral inhibitors of factor Xa. These agents produce a predictable anticoagulant response after fixed-dose administration so that routine coagulation monitoring is unnecessary. Currently, dabigatran etexilate, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective total hip or knee replacement surgery. Since august 2011, dabigatran etexilate is licensed for patients with atrial fibrillation, rivaroxaban will follow. However, indications will be expanded e.g. for therapy of venous thromboembolism. It is important to be aware of the pharmacokinetic and pharmacodynamic profiles of these new agents. The drugs considerably influence the global test of coagulation thus making an interpretation of test results difficult. Currently, there is a lack of suitable coagulation tests to monitor anticoagulation in emergency cases, such as bleeding. Specific antidotes are not yet available.

Clinical multicenter evaluation of a new FXa-based Antithrombin assay.

INTRODUCTION: The determination of functional Antithrombin is a central part of thrombophilia screening. In this multicenter study, a new FXa-based method (INNOVANCE® Antithrombin) was evaluated on four different analyzers. METHODS: The INNOVANCE Antithrombin method was evaluated by precision and reference interval studies and by comparing the new method with established methods through parallel measurement of samples from 249 patients and 151 apparently healthy individuals. RESULTS: The INNOVANCE Antithrombin assay demonstrated on all analyzers repeatability coefficients of variation (CVs) ≤ 3.2% and within-device and between-run CVs ≤ 6.9%. The reference intervals of all analyzers are comparable with 2.5th percentiles between 80% and 85% of normal. The INNOVANCE Antithrombin and the FIIa-based Berichrom® AT III (A) methods demonstrated good concordance with correlation coefficients of r = 0.908 or higher. The INNOVANCE Antithrombin method demonstrated furthermore an excellent comparability with the STA® Antithrombin III assay and an acceptable comparability with the Coamatic® LR Antithrombin assay. The patients with congenital deficiency (n = 31) were identified with all assays except for the patients carrying the P41L heparin-binding site mutation, which was only identified with the INNOVANCE Antithrombin and the STA Antithrombin III methods. CONCLUSION: The INNOVANCE Antithrombin assay has high sensitivity for Antithrombin deficiencies and is reliable, precise and suitable for routine clinical use.

Postoperative bleeding after AB0-incompatible living donor kidney transplantation.

BACKGROUND: Since 2007, we have performed 14 AB0-incompatible (AB0i) living kidney transplantations to increase the number of living kidney transplantations. METHODS: To prevent clotting, donor kidneys were perfused with an HTK/heparin solution with heparin washed out immediately pretransplantation. However, in 4/14 recipients, significant postoperative diffuse hemorrhage occurred with the need for surgical intervention in 3 patients. To analyze the cause of postoperative diffuse bleeding, sequentially before and after opening the graft anastomosis, we prospectively performed coagulation studies: partial thromboplastin time (PTT), thrombin time, thromboplastin time, fibrinogen, antithrombin, D-dimers, plasminogen, and thrombelastography. RESULTS: We found no clotting disturbances owing to blood group-specific immunoadsorption. However, 3/4 patients with bleeding complications showed elevated PTT values even 2 hours after opening the anastomosis, which was proven to be a heparin effect by in vitro application of heparinase. Hyperfibrinolysis and disturbances of platelet aggregation were not detected. Because of these results, we lowered the heparin dose administered after donor nephrectomy from initially 10,000-20,000 to 4000 IU resulting in significantly lower PTT values at 2 hours (34.6 ± 4.5 s among patients 6-14 vs 69.0 ± 16.3 s among patients 1-5; P = .012). There were no further bleeding complications. Lowering the heparin dosage had no impact on graft function: serum creatinine at discharge of 1.5 ± 0.1 versus 1.6 ± 0.2 mg/dL. CONCLUSION: Our data indicated that postoperative hemorrhage after AB0i kidney transplantation was associated with the amount of heparin used for graft perfusion after donor nephrectomy. The use of antifibrinolytic agents may be harmful; no hyperfibrinolysis takes place in the AB0i transplant setting.

Long- and short-term in vitro D-dimer stability measured with INNOVANCE D-Dimer.

In vitro D-dimer stability in plasma is widely assumed, but has not yet been documented by systematic studies using samples covering a wide range of D-dimer. We investigated the short- and long-term stability of D-dimer in clinical citrated plasma samples with normal and pathological levels. The short-term stability was analysed by measuring D-dimer fresh, after storage of plasma for 4 hours at room temperature (RT) and after an additional 24 h storage at +2 to +8 degrees C (n=40). Long-term stability samples (n=40) were measured fresh and after storage for 19, 25 and 36 months at < or =-60 degrees C. The effect of repeated freezing was analysed by measuring samples (n=50) fresh and after four consecutive freeze-thaw cycles. D-dimer was measured on the BCS System using the INNOVANCE D-Dimer assay (Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany). D-dimer values at baseline ranged from 0.23-22.2 mg/l FEU. The mean percentage change after storage for 4 hours at RT and additional 24 hours at +2 to +8 degrees C was +3.8% and +2.7%, respectively. The mean percentage change after frozen storage for 19, 25 and 36 months at < or =-60 degrees C was -11.7%, -4.8% and -9.3%, respectively. The small decrease of D-dimer values after frozen storage was not time-dependent. Repeated freezing did not significantly alter D-dimer values (mean change < or =5%). The data demonstrate stability of D-dimer in plasma prior to freezing for up to 4 hours at RT and for up to 24 hours at +2 to +8 degrees C as well as in plasma stored for up to three years at < or =-60 degrees C.

Distinct C-terminus of the B subunit of factor XIII in a population-associated major phenotype: the first case of complete allele-specific alternative splicing products in the coagulation and fibrinolytic systems.

OBJECTIVES: The purpose of this study was to elucidate the molecular bases of the heterogeneity of the B subunit of coagulation factor XIII (FXIII-B), classified by isoelectric focusing into its three population-associated major phenotypes. METHODS AND RESULTS: By genetic sequencing and polymerase chain reaction (PCR)-restriction fragment length polymorphism analyses, a C-to-G change was identified in intron K for the Asian-associated major phenotype FXIII-B*3. A transcript containing the novel exon XII' was detected by reverse transcription PCR using hepatocyte cell lines with this allele. The exclusive existence of a novel C-terminal peptide in a homozygote of FXIII-B*3 was also detected by matrix-assisted laser-desorption ionization time of flight mass spectrometry. The FXIII-B*3 isoform had a C-terminus 15 residues longer than the other isoforms, containing two additional basic amino acids and one extra acidic amino acid. Accordingly, the C-to-G nucleotide substitution created an efficient splice acceptor AG dinucleotide, which resulted in allele-specific alternative splicing in intron K. When compared with FXIII-B*1, the third major phenotype, FXIII-B*2, had an A-to-G change in exon III, converting His95 to Arg, and a rare phenotype, FXIII-B*4, had an A-to-T change in exon VII, converting Glu368 to Val. CONCLUSIONS: We found an extremely rare event of complete allele-specific alternative splicing for FXIII-B. The FXIII-B*3 isoform had a distinct C-terminal peptide, while the FXIII-B*2 and FXIII-B*4 isoforms had His95 to Arg and Glu368 to Val substitutions, respectively, which led to differential isoelectric points of these isoforms. Such variations in the amino acid sequence of FXIII-B may have profound effects on its structure-function relationship, plasma FXIII levels, and disease susceptibility.

[Relevance of a single dose of 270 microg/kg recombinant factor VIIa for the treatment of patients with haemophilia and inhibitors - Recommendations from the GTH experts]. / Stellenwert der Einzelgabe von 270 microg/kg rekombinantem Faktor VIIa in der Behandlung von Hämophilie-Patienten mit Hemmkörpern - Empfehlungen der Experten.

Recombinant factor VIIa (rFVIIa; NovoSeven) is, besides other indications, authorised for the treatment of bleeding episodes in patients with hereditary haemophilia A or B and inhibitors. Based on the results of three clinical studies, marketing authorisation was granted for the single dose of 270 microg/kg body weight rFVIIa for the treatment of mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors in March 2007. Thereupon, an expert group analysed the relevance of this additional treatment option for clinical routine. Compared with the repeated application of 90 microg/kg body weight rFVIIa, quality of life may be improved if the single dose of 270 microg/kg body weight rFVIIa reduces the number of injections. The single dose has a benefit for those patients who require several rFVIIa applications or who do not respond adequately to low doses. Moreover, patients with poor venous access or patients who fear injections or reject them (especially children) may benefit from the single dose. The prescription of 270 microg/kg body weight rFVIIa as a single dose instead of multiple dosing of 90 microg/kg body weight is basically an individual and indication-related decision.

[Anticoagulation by oral treatment with vitamin K antagonists]. / Orale Antikoagulanzien vom Cumarintyp.

A survey is given on pharmacology and indications for the treatment with vitamin K antagonists. The therapeutic handling and self control by the patient is described.

Elevated Lipoprotein(a) does not promote early atherosclerotic changes of the carotid arteries in young, healthy adults.

BACKGROUND: Elevated levels of Lipoprotein(a) [Lp(a)] have been linked to an increased risk of ischemic cardiovascular events. Yet the mechanism by which Lp(a) might contribute to this increased risk is not clear. METHODS: To elucidate whether high plasma levels of Lp(a) contribute to the development of early atherosclerotic vessel wall changes, the intima-media thickness of the common carotid arteries [CCA-IMT] of 151 healthy young volunteers without additional relevant cardiovascular risk factors was measured by high-resolution ultrasound. Plasma concentrations of Lp(a) were quantified and other established risk factors, such as body mass index [BMI], plasma levels of cholesterol, triglycerides and homocysteine, were determined. Furthermore, the carotid arteries were examined for the presence of plaques and stenoses. RESULTS: Univariate analysis showed a significantly negative correlation of CCA-IMT with HDL cholesterol and positive correlations with age, BMI, total and LDL cholesterol, triglycerides and even with homocysteine, but not with Lp(a). When the study population was dichotomized according to Lp(a) levels, no statistically significant differences in CCA-IMT could be detected between persons with plasma Lp(a)<300mg/l or >or=300mg/l, respectively. CONCLUSION: Our data suggest that elevated Lp(a) levels alone do not contribute to increased cardiovascular risk by promoting early atherogenesis in vivo.

[Osteoporosis in patients under oral anticoagulant treatment]. / Osteoporose bei Patienten unter oraler Antikoagulantien-Therapie.

BACKGROUND AND OBJECTIVE: Osteoporosis is thought to be one possible side-effect of oral anticoagulant therapy, especially after long-term treatment. Nevertheless, data concerning this problem only exist from earlier years. Therefore, we decided to look for the incidence of osteoporosis in patients under long-term oral anticoagulant treatment. PATIENTS AND METHODS: 30 patients (15 female, 15 male) - age between 38 and 77 years (average age 65,1+/-11,2 years) were examined. Group A: 10 patients with a capture time between 0,5 - 5 years, Group B: 10 patients with a capture time between 6 - 11 years, Group C: 10 patients with a capture time more than 11 years. The control group consisted 30 healthy persons - age between 39 and 81 years (18 female, 12 male, average age 61,5 +/- 12 years). RESULTS: In 21 out of 30 patients (9 female, 12 male) osteoporosis was found due to results of x-ray and bone-density-measurements. In 9 patients (6 female, 3 male) no osteoporosis was detected. No correlation between appearance of osteoporosis and duration of oral anticoagulant treatment was detected. Nevertheless, the number of patients presenting with osteoporosis in comparison with the control group was highly unexpected and astonishing. CONCLUSION: While treating patients with oral anticoagulants the possibility of appearing osteoporosis should be kept in view. In those circumstances the therapy should be supported by calcium and vitamin D.

[Oral anticoagulants and coumarin classes]. / Orale Antikoagulanzien vom Cumarintyp.

A survey is given on pharmacology and indications for the treatment with vitamin K antagonists. The therapeutic handling and self control by the patient is described.

Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways.

BACKGROUND: Activation of coagulation and fibrinolysis play a role in the pathophysiology of experimental arthritis. OBJECTIVE: To determine the extent of activation of the coagulation and fibrinolytic pathways in different joint diseases in humans and to ascertain the factors that may influence fibrin deposition within the joint. METHODS: Plasma from normal subjects (controls, n= 21) and plasma and synovial fluid samples from patients with rheumatoid arthritis (RA; n = 64), osteoarthritis (OA; n = 29), spondyloarthropathy (SpA; n = 22) and crystal arthritis (CA; n = 25) were analyzed for the levels of TF (tissue factor) and tissue factor pathway inhibitor (TFPI) activities, thrombin-antithrombin III (TAT) complexes, and F1 + 2 (thrombin fragment), fibrin d-dimer and thrombin-activated fibrinolysis inhibitor (TAFI) antigenic levels. The measurements were analyzed by pairwise correlation with each other as well as with standard parameters of inflammation [C-reactive protein (CRP), joint leukocyte count]. Inter-group comparisons were performed to look for disease-specific differences. RESULTS: Compared with healthy controls, patients with joint diseases had higher levels of TAT, F1 + 2 and d-dimers in their plasma. In the synovial fluid, TF activity, TAT, d-dimers, and TAFI were significantly higher in inflammatory arthritides than in OA. The levels were highest in RA patients. In the plasma, TF activity was correlated with TAT and d-dimer levels with CRP, TFPI, and TAT. In the synovial fluid, TF activity correlated with plasma CRP levels, synovial fluid leukocyte count, and synovial TAT and TAFI levels. In addition, synovial d-dimers correlated with CRP, and synovial TAFI levels were correlated with synovial F1 + 2 and TAT. CONCLUSIONS: Activation of the coagulation and fibrinolytic cascades in the joint and in the circulation is evident in both inflammatory and degenerative joint diseases. Within the joint, inflammatory mechanisms leading to TF-mediated activation of the coagulation pathway and subsequent fibrin deposition is the most likely explanation for the observed findings. In the plasma, the link between inflammation (CRP increase) and TF activation is weak, and a non-TF-mediated mechanism of coagulation activation could explain these findings. RA is characterized by significantly higher levels of TAT in the synovial fluid and plasma than other arthritides. Although fibrinolytic activity is linked to inflammation, the increased amounts of TAFI in the joint, particularly in RA, may explain why fibrin formation is so prominent in this condition compared with other joint diseases.

[Initiation of oral anticoagulant treatment: comparison between different dosage regimens of warfarin and phenprocoumon]. / Initialphase der oralen Antikoagulanzientherapie: Vergleich verschiedener Dosierungen von Warfarin und Phenprocoumon.

A high "loading dosage" is often given during initiation of oral anticoagulant treatment in order to reach sufficient anticoagulation within short time. Increased bleeding risk as well as a transient prothrombotic tendency are complications of this treatment schedule. The aim of our study was to find proper dosage regimens of phenprocoumon and warfarin allowing initiation of oral anticoagulant treatment in a short time. For 50% of the patients 7.5 mg warfarin daily resulted in stable INR values within 4 days. Patients receiving higher (10 mg) or lower (5 mg) daily dosages of warfarin or 6 or 9 mg phenprocoumon daily during the first days of therapy reached the therapeutic range significantly later. Furthermore, no significant differences of prothrombin fragment F 1+2 were observed, indicating that no enhanced thrombin formation occurred. Thus, initiation of oral anticoagulant treatment using 7.5 mg warfarin daily is a simple and safe dosage regimen.