Hämostaseologie Hämostaseologie haemo de-de http://www.schattauer.de/rss.html Sat, 23 Sep 17 04:02:56 +0200 http://www.schattauer.de/uploads/pics/rss.jpg Ahead of print: Characterization and diagnostic work-up of a patient with functionally impaired... http://haemo.schattauer.de/t3page/1214.html?manuscript=27828 V. Klümpers (1), I. Müller (2), P. Hellstern (3), T. J. Schulze (1), C. Mannhalter (4), P. Bugert (1), H. Eichler (2) 27828 2017-08-16 16:41:35 May-Thurner syndrome: missed diagnosis and missed early treatment? http://haemo.schattauer.de/t3page/1214.html?manuscript=27808 A. Trinchero (1), S. Schotten (2), B. Lämmle (1), M. B. Pitton (2) 27808 2017-08-07 17:15:11 Ahead of print: Diagnostic single gene analyses beyond Sanger http://haemo.schattauer.de/t3page/1214.html?manuscript=27730 Molecular testing of congenital coagulation and platelet disorders offers confirmation of clinical diagnoses, supports genetic counselling, and enables predictive and prenatal diagnosis. In some cases, genotype-phenotype correlations are important for predicting the clinical course of the disease and adaptation of individualized therapy. Until recently, genotyping has been mainly performed by Sanger sequencing. While next generation sequencing (NGS) enables the parallel analysis of multiple genes, the cost-value ratio of custom-made panels can be unfavorable for analyses of specific small genes. The aim of this study was to transfer genotyping of small genes involved in congenital coagulation and platelet disorders from Sanger sequencing to an NGS-based method. A LR-PCR approach for target enrichment of the entire genomic regions of the genes F7, F10, F11, F12, GATA1, MYH9, TUBB1 and WAS was combined with high-throughput sequencing on a MiSeq platform. NGS detected all variants that had previously been identified by Sanger sequencing. Our results demonstrate that this approach is an accurate and flexible tool for molecular genetic diagnostics of single small genes.... J. Najm (1), M. Rath (1), W. Schröder (1), U. Felbor (1) 27730 2017-07-17 14:50:29 Ahead of print: The impact of bleeding disorders on the socioeconomic status of adult patients http://haemo.schattauer.de/t3page/1214.html?manuscript=27716 The impact of inherited bleeding disorders on the socioeconomic status (SES) of affected individuals is not clear. The SES of adult patients with congenital bleeding disorders (PWBD) from a centre in Germany (age 42.3 ± 15.0 years) was compared to that of a gender- and age-matched control group of patients with thrombophilia or a thrombotic event (PWT). Patients completed a questionnaire including aspects of SES, impact of the disease on their lives, and health-related quality of life (HRQoL). Forty-five patients were enrolled in each group; 71 % of PBWD had a severe form of the bleeding disorder (FVIII/IX activity < 1 % or VWD type 3), and 60 % of all PWBD were treated on-demand. PWBD had a lower monthly income (p = 0.029) and a worse occupational status (p = 0.047) than PWT, but there was no difference regarding the project-specific SES index. PWBD also reported a worse HRQoL in the physical summary component score of the SF-36 (p < 0.001). More PWBD (69.8 %) reported a high impact of the disease on their lives than PWT (33.3 %, p < 0.001). In summary, PWBD had a worse occupational status, monthly income, health behaviour, HRQoL, and impact of the disease on their lives compared to PWT, but not a significantly different SES in general.... K. Holstein (1), S. von Mackensen (2), C. Bokemeyer (1), F. Langer (1) 27716 2017-07-10 16:05:27 Ahead of print: Acute transmural myocardial infarction by coronary embolism in a patient with JAK2... http://haemo.schattauer.de/t3page/1214.html?manuscript=27715 J. Rotta detto Loria (1), J. Rawluk (2), T. Krauss (3), C. Bode (1), M. Moser (1), T. Helbing (1) 27715 2017-07-10 16:00:47 Ahead of print: Clinical pearls: Laboratory assessments of direct oral anticoagulants (DOACS) http://haemo.schattauer.de/t3page/1214.html?manuscript=27705 Direct oral anticoagulants (DOACS) are being used for stroke prevention in patients with atrial fibrillation as well as for prophylaxis and treatment of venous thromboembolism. Clinicians who treat, or may encounter, patients with DOAC exposure, should be aware of the limitations of coagulation testing in this setting, and seek counsel from their laboratory to understand the effects of DOACS on coagulation results. Generally, assays that employ clot based principles, or methods that require thrombin or Factor Xa activation or substrates may be affected by the presence of DOACS. The clinical laboratory should have an algorithmic testing plan for adequately assessing the presence of all DOACS and readily provide this information to clinicians. We describe Clinical Pearls for DOAC assessment using common and esoteric coagulation testing. R. C. Gosselin (1), J. Douxfils (2), D. Adcock (3) 27705 2017-07-05 17:32:21 Ahead of print: Direct oral anticoagulants for the treatment of cancer-associated venous... http://haemo.schattauer.de/t3page/1214.html?manuscript=27539 Cancer patients with venous thromboembolism (VTE) are at increased risk for both bleeding and VTE recurrence. Anticoagulation with low-molecular-weight heparin (LMWH) is the standard of care during the initial and long-term treatment phase (i.e. during the first 3 – 6 months of therapy) based on its overall beneficial safety and efficacy profile compared to vitamin K antagonists (VKAs). The direct oral anticoagulants (DOACs) rivaroxaban, apixaban, edoxaban, and dabigatran are approved for the treatment of acute VTE, and the combined six phase-3 trials have included > 1500 patients with active cancer, as defined by variable selection criteria. Subgroup analyses of these patients, either pooled or separately reported, suggest that DOACs could be a safe and efficacious alternative to VKA therapy for the treatment of cancer-associated VTE. However, the populations of cancer patients included in the DOAC and LMWH trials are not comparable with regard to mortality and VTE risk, and no specific data from direct head-to-head comparisons of DOACs with LMWHs are currently available. The use of DOACs for the management of VTE in cancer is thus not recommended by clinical practice guidelines.... M. Voigtlaender (1), F. Langer (1) 27539 2017-05-16 11:32:59 Hemophilia in focus http://haemo.schattauer.de/t3page/1214.html?manuscript=27517 Rüdiger E. Scharf (1, 2, 3) 27517 2017-05-10 14:21:53 Fragen zum Thema "Molekularbiologische Diagnostik" http://haemo.schattauer.de/t3page/1214.html?manuscript=27516 27516 2017-05-10 14:07:33 Neue Entwicklungen in der molekularbiologischen Diagnostik http://haemo.schattauer.de/t3page/1214.html?manuscript=27436 Die uns heute zur Verfügung stehenden molekularbiologischen Analysemethoden sind technisch weitgehend ausgereift und werden bereits breit eingesetzt. Daraus ergibt sich die Notwendigkeit der Einführung von Regeln zur Überprüfung der Qualität der Tests sowie der Testlabors, was im Artikel im Detail besprochen wird. Nachdem Nukleinsäuren isoliert und amplifiziert wurden, werden sie zur Genotypisierung herangezogen, wobei zahlreiche Fragen adressiert werden können wie z.B. die Diagnose erblich bedingter Krankheiten oder erblicher Prädispositionen, forensische Aspekte, die Identifizierung und Typisierung von Krankheitserregern, aber auch die Aufklärung evolutionärer Zusammenhänge. Die Wahl des Verfahrens zur Mutationssuche ist eng mit der Art und Heterogenität der für einen Phänotyp verantwortlichen Mutationen verbunden. Derzeit werden in vielen Labors für die Diagnostik PCR-Analysen neben der klassischen Sequenzierung nach Frederick Sanger eingesetzt. Zunehmend kommt jedoch die relativ neue „next generation sequencing“ (NGS) Analyse zur Anwendung. Obwohl der Einsatz der NGS-Technologie in der klinischen Diagnostik mit zahlreichen Herausforderungen verbunden ist, wird die Umstellung auf diese Methode aufgrund der Vorteile in naher Zukunft vollzogen werden. Die deutliche Preisreduktion des NGS auf ca. 1000,- USD brachte die Genomsequenzierung schon sehr nahe an klinische Anwendungen heran. Bis zum routinemäßigen Einsatz müssen jedoch noch die Daten-Prozessierung, die Speicherung der riesigen Datenmengen und die Interpretation der Ergebnisse vereinfacht werden. Es gibt dafür unterschiedliche Datenbanken, von denen einige angeführt werden. Das Verständnis verschiedener Polymorphismen in Genen von Gerinnungsfaktoren und die Bedeutung der personalisierten Medizin, die ein wichtiges Werkzeug zur Risikostratifizierung der Patienten darstellt, wurden sehr vertieft. Beide Aspekte haben heute große Bedeutung und werden im vorliegenden Beitrag diskutiert.... C. Mannhalter (1) 27436 2017-04-13 09:39:52 Wishes and worries of haemophilia patients http://haemo.schattauer.de/t3page/1214.html?manuscript=27407 Haemophilia care in Germany has achieved a high level and enables the majority of patients to lead a largely normal life. The Bluter Betreuung Bayern e.V. (BBB) aims to improve health care and support for haemophilia patients. A questionnaire has been developed by BBB representatives to evaluate unmet medical needs from the patient perspective. It was sent to 290 haemophilia patients and/or their parents in Bavaria in November 2015. The response rate was 51.4 %: 66 children aged  44 years (95.8 % severe). Prophylactic therapy in patients with severe haemophilia aged  60 %, respectively. Substitution therapy is mostly uncomplicated. Satisfaction with medical care is high. Chronic pain is a problem with increasing age. Patients aged 25–44 years worry least regarding future health, safety and availability of factor products, patients > 44 years most. Overall, 80–100 % of the patients from all age groups are interested in information on the current state of science. Offers of the BBB for psychosocial support in addition to the medical care seem to be helpful and needed in all age groups.... H. Lechner (1), A. Schleiermacher (1), K. Berger (2), D. Schopohl (2), W. Schramm (3) 27407 2017-04-10 09:29:42 Ahead of print: Direct oral anticoagulants (DOAC) – Management of emergency situations http://haemo.schattauer.de/t3page/1214.html?manuscript=27394 The worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on antiplatelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in „real-life“ conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.... E. Lindhoff-Last (1) 27394 2017-04-06 13:31:26 Myocardial infarction in a neonate http://haemo.schattauer.de/t3page/1214.html?manuscript=27336 Due to the lack of evidence-based guidelines, management strategies for neonatal MI should be individualized and administered largely at the discretion of responsible treating teams. Supportive care with a focus on preserving adequate circulation and antithrombotic therapy with a view to restoring vascular patency are the mainstays of treatment. Thrombolytic therapy of neonatal MI includes a chance to completely restore myocardial function. Understanding the resilience of the neonatal heart and mechanism of cardiac cell repair in neonates may spark novel treatment strategies for severe MI in the large number of affected individuals in an aging population. W. Streif (1) 27336 2017-03-20 11:50:38 Ahead of print: Physiotherapy treatments in musculoskeletal pathologies associated with haemophilia http://haemo.schattauer.de/t3page/1214.html?manuscript=27322 The aim of this study is to offer physiotherapists a synthesis of the main therapeutic tools available for the treatment of musculoskeletal pathologies in patients with haemophilia, according to the scientific literature. Although bleeds are recognised as no longer being a cause of death for people with haemophilia, the accompanying musculoskeletal injuries now represent the main problem associated with this disorder. There is a lack of clear guidelines to date regarding the physiotherapy treatment of these disorders. We performed a keyword searches of Pubmed, Scopus, Sciencedirect, Cochrane and PEDro databases. In total, 555 references were retrieved, of which only 55 fulfilled the inclusion criteria. Publications were grouped by the main symptoms caused by haemophilia and the physiotherapy treatments available. The literature reviewed shows that physiotherapists have a range of therapeutic tools at their disposal for the treatment of the main musculoskeletal disorders suffered by patients with haemophilia. Physiotherapy interventions act upon inflammation and pain, as well as favouring the reabsorption of haematomas, preventing muscle fibrosis and joint ankylosis and recovering the joint range from prior to the lesions. Also, these interventions help prevent muscle atrophy and provide patients with the optimal physical conditions for facing the small and repetitive injuries that, over time, can have a detrimental effect on their quality of life. Conclusion: Haemophilic patients suffer from a series of musculoskeletal disorders, which are associated with important functional disability. Physiotherapy and adapted sports are essential for decreasing disability and improving the quality of life of affected patients.... J. Guodemar-Pérez (1), M. Ruiz-López (2), E. Rodríguez-López (1), P. García-Fernández (3), J. P. Hervás-Pérez (1) 27322 2017-03-14 09:01:51 Ahead of print: Advances in anticoagulation management of patients undergoing cardioversion of... http://haemo.schattauer.de/t3page/1214.html?manuscript=27321 Atrial fibrillation (AF) is a major cause of stroke. The restoration of sinus rhythm through cardioversion, either chemical or electrical is a common practice. Interestingly, there is an incremental increase from the baseline risk for embolisation in the immediate post-cardioversion period, with most events occurring within 10 days from cardioversion. Especially patients with recent onset AF show the lowest rates of antithrombotic therapy, while having a high stroke risk. Despite the increased risk for embolisation, anticoagulation in patients undergoing cardioversion of atrial fibrillation is often inadequate. Moreover, since the implementation of non-vitamin K antagonists oral anticoagulants (DOACs) there are several therapeutic approaches for pericardioversion anticoagulant therapy and not all suits to all patients. In addition, the extensive use of transesophageal echocardiography provides an alternative strategy, especially useful for patients of high haemorrhagic risk. In this review article, we aim to provide an update on the anticoagulation strategies for patients undergoing cardioversion of non-valvular atrial fibrillation in the advent of the use of DOACs.... G. Benetos (1), M. Bonou (1), K. Toutouzas (2), P. Diamantopoulos (3), N. Viniou (3), J. Barbetseas (1) 27321 2017-03-14 08:47:40 Therapeutic genome editing with engineered nucleases http://haemo.schattauer.de/t3page/1214.html?manuscript=27033 Targeted genome editing with designer nucleases, such as zinc finger nucleases, TALE nucleases, and CRISPR-Cas nucleases, has heralded a new era in gene therapy. Genetic disorders, which have not been amenable to conventional gene-addition-type gene therapy approaches, such as disorders with dominant inheritance or diseases caused by mutations in tightly regulated genes, can now be treated by precise genome surgery. Moreover, engineered nucleases enable novel genetic interventions to fight infectious diseases or to improve cancer immunotherapies. Here, we review the development of the different classes of programmable nucleases, discuss the challenges and improvements in translating gene editing into clinical use, and give an outlook on what applications can expect to enter the clinic in the near future. S. A. Haas (1, 2, 3), V. Dettmer (1, 2, 4), T. Cathomen (1, 2, 5) 27033 2017-01-10 09:40:01 Lifecycle of Weibel-Palade bodies http://haemo.schattauer.de/t3page/1214.html?manuscript=27026 Weibel-Palade bodies (WPBs) are rod or cigar-shaped secretory organelles that are formed by the vascular endothelium. They contain a diverse set of proteins that either function in haemostasis, inflammation, or angiogenesis. Biogenesis of the WPB occurs at the Golgi apparatus in a process that is dependent on the main component of the WPB, the haemostatic protein von Willebrand Factor (VWF). During this process the organelle is directed towards the regulated secretion pathway by recruiting the machinery that responds to exocytosis stimulating agonists. Upon maturation in the periphery of the cell the WPB recruits Rab27A which regulates WPB secretion. To date several signaling pathways have been found to stimulate WPB release. These signaling pathways can trigger several secretion modes including single WPB release and multigranular exocytosis. In this review we will give an overview of the WPB lifecycle from biogenesis to secretion and we will discuss several deficiencies that affect the WPB lifecycle.... M. Mourik (1), J. Eikenboom (2) 27026 2016-12-22 11:43:30 Management of cardiovascular disease in aging persons with haemophilia http://haemo.schattauer.de/t3page/1214.html?manuscript=26998 With the aging of the haemophilia population, age related comorbidities become more and more a medical issue. Managing haemophilia patients with cardiovascular disease is a difficult task for many haemophilia-treating physicians. Over the years, insights on prevalence, risk factors and management of cardiovascular disease in haemophilia have improved substantially. It is now recognised that many risk factors, such as hypertension and overweight, occur quite frequently in patients with haemophilia. Several new insights in anticoagulation management of atrial fibrillation and coronary ischaemia in haemophilia have been suggested. This review provides an general overview of the current knowledge of these topics in literature. R. E. G. Schutgens (1), M. Voskuil (2), E. P. Mauser-Bunschoten (1) 26998 2016-12-14 09:49:29 Management of chronic hepatitis C in 2017 http://haemo.schattauer.de/t3page/1214.html?manuscript=26939 Hepatitis C virus (HCV) represents one of the most common aetiologies of chronic liver disease and causes a major global health burden. Globally an estimated 80 million people are chronically infected, but the majority of whom is still undiagnosed. Prior to the discovery of the virus in 1989 a significant number of patients were exposed and consecutively infected with HCV via contaminated transfusions, as it is a blood-borne disease. Chronic HCV infection pursues a progressive course that ultimately results in the development of cirrhosis, liver failure and hepatocellular carcinoma (HCC), if left untreated. The efficiency and tolerability of therapeutical approaches improved considerably with the development of direct-acting antivirals (DAA). The majority of patients treated with the recommended DAA combinations can be cured, which is reflected in achievement of sustained virological response (SVR). This review is intended to provide guidance in the management of patients with chronic hepatitis C, including recommendations for adequate screening, diagnostic procedures, clinical care, treatment and follow-up strategies.... L. von Köckritz (1), J.-F. Dufour (1) 26939 2016-11-29 09:15:45 A new era of treatment for patients with haemophilia A? http://haemo.schattauer.de/t3page/1214.html?manuscript=26923 Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII. Due to the different structure of this antibody it cannot be neutralized by factor VIII inhibitors and has the possibility to achieve haemostasis in patients with severe haemophilia A with and without inhibitors. First studies in healthy volunteers and in patients showed a shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. The half-life of the drug was 4 to 5 weeks. There were no clinical signs of thrombosis and no laboratory abnormalities indicating hypercoagulability. In a first study with 18 patients with severe haemophilia A with and without inhibitors a remarkable reduction in the annualised bleeding rate occurred. Safety of the drug has to be proven in ongoing research. Mimicking the cofactor activity of factor VIII by a bispecific antibody for the treatment of severe haemophilia A is so far safe and seems to be effective and is one highlight in haemostasis 2016.... R. Klamroth (1) 26923 2016-11-25 09:21:25 Plasma-derived versus recombinant factor concentrates in PUPs: a never ending debate? http://haemo.schattauer.de/t3page/1214.html?manuscript=26894 Inhibitor development in haemophilia is a serious complication to treatment with factor concentrates. Since the advent of more pure products, especially developed using recombinant DNA technology, some studies have shown an increased incidence of inhibitors in previously untreated patients (PUPs) receiving recombinant products whereas plasma-derived concentrates sometimes have been claimed to have a protective role, probably due to the content of von Willebrand factor (VWF). In fact, experiments indicate that the VWF may block uptake of factor VIII into macrophages for further processing to the immune system. Also, a competition between VWF and inhibitor binding to the C2 domain of factor VIII has been suggested. Recently, large cohort and surveillance studies have created a vigorous debate about the role of product class for inhibitor development as results have been conflicting. The only randomised prospective study, the SIPPET study, was published in 2016, and substantiated previous reports claiming that plasma derived concentrates give less inhibitors in patients with severe haemophilia A, previously not exposed to factor VIII. The debate will continue.... E. Berntorp (1) 26894 2016-11-23 11:29:43 New findings on venous thrombogenesis http://haemo.schattauer.de/t3page/1214.html?manuscript=26893 Venous thrombosis (VT) is the third most common cause of cardiovascular death worldwide. Complications from VT and pulmonary embolism are the leading cause of lost disability-adjusted life years. Risks include genetic (e.g., non-O blood group, activated protein C resistance, hyperprothrombinemia) and acquired (e.g., age, surgery, cancer, pregnancy, immobilisation, female hormone use) factors. Pathophysiologic mechanisms that promote VT are incompletely understood, but involve abnormalities in blood coagulability, vessel function, and flow (so-called Virchow’s Triad). Epidemiologic studies of humans, animal models, and biochemical and biophysical investigations have revealed contributions from extrinsic, intrinsic, and common pathways of coagulation, endothelial cells, leukocytes, red blood cells, platelets, cell-derived microvesicles, stasis-induced changes in vascular cells, and blood rheology. Knowledge of these mechanisms may yield new therapeutic targets. Characterisation of mechanisms that mediate VT formation and stability, particularly in aging, are needed to advance understanding of VT.... J. R. Byrnes (1), A. S. Wolberg (1) 26893 2016-11-23 11:28:37 Von Willebrand factor processing http://haemo.schattauer.de/t3page/1214.html?manuscript=26879 Von Willebrand factor (VWF) is a multimeric glycoprotein essential for primary haemostasis that is produced only in endothelial cells and megakaryocytes. Key to VWF’s function in recruitment of platelets to the site of vascular injury is its multimeric structure. The individual steps of VWF multimer biosynthesis rely on distinct posttranslational modifications at specific pH conditions, which are realized by spatial separation of the involved processes to different cell organelles. Production of multimers starts with translocation and modification of the VWF prepropolypeptide in the endoplasmic reticulum to produce dimers primed for glycosylation. In the Golgi apparatus they are further processed to multimers that carry more than 300 complex glycan structures functionalized by sialylation, sulfation and blood group determinants. Of special importance is the sequential formation of disulfide bonds with different functions in structural support of VWF multimers, which are packaged, stored and further processed after secretion. Here, all these processes are being reviewed in detail including background information on the occurring biochemical reactions.... M. A. Brehm (1) 26879 2016-11-21 13:22:19 New treatment options for thrombotic thrombocytopenic purpura http://haemo.schattauer.de/t3page/1214.html?manuscript=26878 The thrombotic-thrombocytopenic purpura (TTP) is an acute, life-threatening disease, characterised by enhanced platelet aggregation, disturbed microcirculation and organ dysfunction. With the currently available treatment (plasma exchange, infusions, corticosteroids) mortality ist still as high as 10–15 %. Recent, pathophysiology-based developments may improve the outcome. The most promising candidates for future treatment of TTP are: rituximab for termination of the autoimmune process, caplacizumab for prevention of platelet-VWF-interaction, and recombinant ADAMTS13 for replacement of the inhibited or missing enzyme. P. Knöbl (1) 26878 2016-11-21 13:20:47 Abstracts http://haemo.schattauer.de/t3page/1214.html?manuscript=26786 26786 2016-11-08 10:47:13