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Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour-normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families.We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data.We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases.Tumour-normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour-normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families.

Bei Tumorpatienten sind tiefe Venenthrombosen und Lungenembolien – trotz angewandter primarpraventiver Masnahmen – haufige, die Lebensqualitat und Prognose beeintrachtigende Komplikationen. Aufgrund der oft oligo- bis asymptomatischen Entstehung ist ihre Diagnostik erschwert. Die Therapie unterscheidet sich wesentlich vom Vorgehen bei Nichttumorpatienten. Die Leitlinien empfehlen eine prolongierte, regelhaft uber 3 Monate hinausgehende Antikoagulation unter Berucksichtigung des Malignomverlaufs. Alternativ zur parenteralen Gabe niedermolekularer Heparine stehen nun auch evidenzbasiert orale Faktor-Xa-Inhibitoren fur die Initialtherapie und Sekundarprophylaxe zur Verfugung. Bei der patientenspezifischen Entscheidung uber Art, Dauer und Intensitat der Antikoagulation bedarf die therapiebedingte Zunahme eines bei Malignompatienten vorbestehend erhohten Blutungsrisikos besonderer Berucksichtigung.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02397-7.

Unter einer oralen Antikoagulation mit Vitamin-K-Antagonisten (VKA) mussen sich etwa 30 % der Patienten innerhalb von 2 Jahren einem chirurgischen Eingriff unterziehen. Dabei stellt sich die Frage nach der Notwendigkeit und Art einer periinterventionellen Uberbruckungstherapie mit Heparin. Wahrend fruher fast regelhaft von der Notwendigkeit dieses sogenannten Bridgings ausgegangen wurde, wird heute auf der Grundlage neuer Studienergebnisse eher diskutiert, wer uberhaupt noch ein Bridging benotigt. Die Sichtung und wissenschaftliche Einordnung der aktuell verfugbaren Empfehlungen und Studienergebnisse lassen die Schlussfolgerung zu, dass die Indikation zum Bridging mit Heparin heute eng gefasst werden muss, unter genauer Berucksichtigung und patientenindividueller Abwagung des Blutungs- und Thromboembolierisikos. Ein Bridging mit Heparin bleibt vor allem Patienten mit sehr hohem Risiko vorbehalten. Diese Ubersicht mochte daher Orientierung fur ein risikoadaptiertes periinterventionelles Vorgehen beim Management von Patienten bieten, die einer dauerhaften Antikoagulation mit VKA bedurfen.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

Tumorpatienten haben ein erhohtes Risiko fur venose Thromboembolien (VTE). Niedermolekulare Heparine (NMH) werden aufgrund ihrer raschen und zuverlassigen Wirksamkeit zur Prophylaxe und Therapie von VTE bei Tumorpatienten bevorzugt eingesetzt. Wahrend die Prophylaxe perioperativ sowie bei stationaren Tumorpatienten unter Berucksichtigung bestehender Kontraindikationen etabliert ist, wird sie bei ambulanten Tumorpatienten nicht generell empfohlen. In der Initialtherapie und Sekundarpravention von akuten VTE sind NMH effektiver als unfraktionierte Heparine und Vitamin-K-Antagonisten. Die Sekundarprophylaxe mit NMH sollte zunachst fur 3–6 Monate durchgefuhrt und bei fortbestehendem Tumorleiden und niedrigem Blutungsrisiko weitergefuhrt werden. Der Einsatz der neuen direkten oralen Antikoagulanzien (DOAC) kann bei Tumorpatienten aufgrund fehlender Studiendaten gegenwartig nicht empfohlen werden.

Wir berichten uber eine 65-jahrige Patientin mit erworbener Hemmkorperhamophilie. Die erworbene Hemmkorperhamophilie ist durch die Ausbildung von Antikorpern (Inhibitoren) gegen Gerinnungsfaktoren charakterisiert. Durch eine Beeintrachtigung der plasmatischen Gerinnung kommt es bei primar Gerinnungsgesunden zu einer schweren erworbenen Blutungsneigung mit potenziell todlichem Verlauf. In der Diskussion wird auf die Pathophysiologie, Diagnostik und Therapie der Hemmkorperhamophilie eingegangen.

PURPOSE: Radiological-morphological response evaluation plays a major role in oncological therapy and studies for approval. Specific criteria have been developed for some tumor entities and chemotherapeutics. Application, limitations and definitions of the most frequently used criteria for tumor response evaluation will be presented. MATERIALS AND METHODS: Review based on a selective literature research. RESULTS: In clinical oncological therapy studies, WHO and RECIST are the most frequently used criteria to evaluate morphological therapy response. RECIST criteria have been modified recently, especially with respect to the evaluation of lymph nodes, and were published as RECIST 1.1 in 2009. All criteria were originally developed and defined to review clinical multicenter trials for approval. Using these criteria in a clinical situation, certain limitations have to be considered. To evaluate response, a baseline scan before therapy start is mandatory. Special tumor response criteria have been defined for some certain tumor entities. Oncologists and radiologists should define in advance which criteria are used before starting therapy. CONCLUSION: The use of defined criteria is very important in oncology response evaluation. In-depth knowledge of the criteria and their limits is required for correct usage.

SummaryVenous thrombembolism (VTE) is one of the most frequent complication in cancer patients. The current options in prophylaxis and therapy have to be balanced against the risks of major bleeding and the burden for the patients. The Gesellschaft für Thrombose- und Hämostaseforschung, the Deutsche Gesellschaft für Palliativmedizin and the German speaking Societies of Hematology and Oncology have recently published guidelines on VTE in cancer patients. Recommendations include diagnostics, individual prophylaxis and treatment.

The decision how to handle an antithrombotic treatment when an intervention during GI endoscopy is planned is influenced both by the risk of bleeding and by the thromboembolic risk when treatment is suspended. The risk of bleeding is negligible even when on oral anticoagulants in diagnostic procedures with standard forceps biopsies. Oral anticoagulation has to be stopped, however, when planning invasive procedures such as polypectomy or EPT. In the case of patients with a high risk of thromboembolic complications such as artificial valves in mitral position or atrial fibrillation with risk factors, one has to temporarily switch to anticoagulants with shorter action ("bridging"). Treatment with inhibitors of platelet function does not preclude procedures with a low risk of bleeding including forceps biopsy. Urgent procedures with a high risk of bleeding should be performed after stopping clopidogrel one week previously but only after consultation with the treating cardiologist. In the case of colonoscopy, in particular as a screening procedure, there are two options: 1) stopping oral anticoagulation (with or without bridging) or clopidogrel, respectively, or 2) continuing antithrombotic treatment and performing a second elective endoscopy for polypectomy with tapered antithrombotic medication if polyps are found which are not amenable to resection by biopsy forceps. The choice between these two options has to be made individually.

Haufig werden Tumorerkrankungen primar oder in ihrem Verlauf durch venose Thrombosen und/oder Lungenembolien kompliziert. Dies bedeutet fur die betroffenen Patienten ein erhohtes Mortalitatsrisiko: Venose Thromboembolien wurden in Untersuchungen als zweithaufigste zum Tode der Patienten fuhrende Komplikation identifiziert. Der Beitrag gibt einen Uberblick zur Prophylaxe und Behandlung von venosen Thromboembolien bei Tumorpatienten.

A 49-year-old man had for 30 years suffered from severe recurrent thromboembolism with leg-vein thrombosis, pulmonary emboli, mesenteric infarction, cerebrovascular accident, cerebral vein thrombosis, portal vein thrombosis and femoral artery occlusion requiring leg amputation. In addition to moderately increased clotting activation with single-fold positive demonstration of fibrin monomers and a D-dimer concentration of 1 mg/l platelet aggregation was increased and could not be influenced by aspirin, 300 mg daily. Despite aspirin there were recurrent transitory attacks of cerebral ischaemia. Fibrin monomers were threefold positive and D-dimer concentration was increased to 4 mg/l (elevated clotting activation). Ticlopidine administration (250 mg daily) reduced adenosine diphosphate-induced platelet aggregation by 30% without effect on collagen-induced platelet aggregation. In parallel to these changes the patient's general condition clearly improved: fibrin monomers were no longer demonstrated and the D-dimer level fell to 0.5 mg/l.

ZusammenfassungAusgehend von dem zunehmenden Verständnis der bei Patienten mit Sepsis beobachteten Gerinnungsstörung sowie den bisher erfolglosen Versuchen durch Modulation der Zytokinantwort die Prognose von Sepsispatienten zu verbessern, wurden in den vergangenen Jahren gerinnungstherapeutische Ansätze der Sepsisbehandlung intensiver untersucht. Während die Phase-III-Studien mit den Gerinnungsinhibitoren, Antithrombin und TFPI (tissue factor pathway inhibitor) für das Gesamtkollektiv der Patienten mit schwerer Sepsis keine Prognoseverbesserung zeigten, fand sich für rekombinantes humanes aktiviertes Protein C (rhAPC) eine signifikante, 19%ige relative Reduktion der Sterblichkeit. Weitere Analysen verdeutlichten, dass die Therapie mit rhAPC insbesondere bei Patientengruppen mit hoher Sterblichkeit im Plazeboarm zu klinisch relevanten Ergebnisverbesserungen führt.Die durch natürliche Gerinnungsinhibitoren bewirkte Hemmung der Gerinnselbildung, spiegelt sich in allen drei Studien in einer, z.T. signifikanten Zunahme der Sepsis-immanenten Blutungsneigung wider, wobei im Falle von Antithrombin die gleichzeitige Heparingabe das Blutungsrisiko deutlich erhöht und möglicherweise dem erhofften Antithrombineffekt auf die Patientenprognose entgegenwirkt. Hinweise auf einen möglicherweise positiven Effekt von Heparin in den Plazeboarmen einerseits, andererseits auf nachteilige Effekte von Heparin in den Therapiearmen (v. a. mit Antithrombin bzw. TFPI) führen zur kontroversen Diskussion des Nutzen/Risiko-Verhältnisses von Heparin in prophylaktischer Dosis bei Patienten mit schwerer Sepsis. Während die Bedeutung und optimale Applikation von Heparin bei schwerer Sepsis der weiteren Klärung bedarf, haben die Studiendaten zu rhAPC zur Zulassung dieses Therapieprinzips und seiner Verankerung in den Empfehlungen zur Behandlung von Patienten mit schwerer Sepsis geführt.

ZusammenfassungPräklinische und klinische Untersuchungen der vergangenen Jahre erweiterten das pathophysiologische Verständnis der bei Patienten mit schwerer Sepsis ablaufenden Störungen deutlich . Dabei wurde deutlich, dass die den septischen Krankheitsbildern zugrunde liegende Infektion im engeren Sinne für die Schwere und ungünstige Prognose der Sepsis weniger verantwortlich ist. Vielmehr ist es die außer Kontrolle geratene Reaktion des Organismus auf diese Infektion, die sich bei nicht (mehr) lokalisierter Infektion in Form einer im Wesentlichen Zytokin-vermittelten Entzündungsreaktion dem systemischen inflammatorischen Response-Syndrom mit seinen Folgen widerspiegelt.Die im Rahmen dieses Syndroms freigesetzten Mediatoren, z.T. in Zusammenwirkung mit Produkten aus infektiösen Mikroorganismen, führen auch zu einer systemischen Aktivierung der Hämostase. Die Aktivierung von Monozyten/Makrophagen sowie die des Endothels stehen dabei im Zentrum des pathophysiologischen Modells. Die davon ausgehende Aktivierung von plasmatischen Kaskadensystemen betreffen auch Gerinnungs-und Fibrinolysesystem, wobei die bei Sepsis beobachtete Gerinnungsaktivierung und Fibrinolysehemmung ihrerseits mit Leukozyten und Endothel interagiert und zur zunehmenden Schädigung der Mikrozirkulation beiträgt. Als deren klinisches Korrelat können Organdysfunktionszustände aufgefasst werden. Es kommt zu einem individuell unterschiedlichen Nebeneinander von überschießender Fibrinbildung, Faktoren-, Inhibitoren-und Thrombozytenverbrauch sowie Störungen des Fibrinolysesystems. Klinisch kann dies neben Organdysfunktionen zu einer disseminierten intravasalen Gerinnung, z.T. mit Blutungskomplikationen, führen.

A resurgence of sexual risk taking, STDs, and HIV incidence has been reported among men who have sex with men (MSM) in several countries. We asked 113 MSM in 12 focus groups conducted in five California cities to identify factors leading to increased risk taking and assess prevention messages to reduce risk in this population. Participants perceived that HIV risk taking has increased because (1) HIV is not the threat it once was due to more effective therapies, (2) MSM communicate less about HIV, and social support for being safe has decreased, and (3) community norms have shifted such that unsafe sex is more acceptable. The prevention messages ranked most likely to motivate risk reduction encouraged individuals to seek social support from friends. Themes ranked least likely to succeed were those that described the negative consequences of HIV or reinforced existing safer sex messages.

Background: For monitoring of arterial blood pressure (ABP) during whole body hyperthermia (WBH) different methods have been recommended. This investigation was performed to evaluate the agreement of invasive measurements at various sites, and to compare invasive and non-invasive methods of ABP monitoring under conditions of a heat-induced extreme vasodilation. Methods: In 19 patients, 48 treatments with WBH were performed. Measurements of ABP in the radial and femoral artery by oscillometry and by sphygmomanometry were taken at four temperature levels during WBH (37, 40, 41.8 and 39°C). Results: Significant differences were observed between invasive and non-invasive methods for systolic ABP, with higher values for non-invasive measurements. When compared with both invasive measurements for diastolic blood pressures, sphygmomanometry gave higher values and oscillometry gave lower values. Sphygmomanometry also showed higher values for mean ABP compared with all other techniques, while measurements in radial and femoral artery and by oscillometry only differed by approximately 5 mmHg. Conclusion: The mean arterial pressure and not the systolic and/or diastolic pressure should guide hemodynamic management during WBH. The sphygmomanometric technique is not recommended for use during hyperthermia.

SUMMARY In developed countries there is an age dependent increasing incidence of deep vein thrombosis. Hereditary thrombophilia is usually suspected by the clinical constellation and anamnestic informations. For economical reasons usually laboratory testing should be avoided if the results will not change directly the therapeutic process. But for hereditary defects consequences for the patient in future and for relatives should be taken into account especially as more selective strategies for prophylaxis and treatment have to be expected by increasing information in that field of research. As deficiencies of anticoagulant proteins (PC, PS, AT) have an impact on anticoagulant treatment, the indication for testing should not be held too strict. Time point for diagnostic procedures should be early after a thromboembolic event as negative results exclude hereditary defects definitely which allows the planning of the aimed treatment duration. After first onset of deep vein thrombosis, even in presence of hereditary coagulation defects the duration of anticoagulation usually depends on the clinical and anamnestic signs for a thrombophilic tendency of the individual patient. First publications suggest the need for prolonged anticoagulation of carriers with combined defects, showing an elevated rate of re-thrombosis after the first thromboembolic event, when anticoagulation is stopped. Every ongoing anticoagulation should be checked repeatedly in the sense of a risk -benefit evaluation even for patients with a thrombophilic tendency and should be adapted to actual publications.

Occlusion of the aorta and the iliac arteries leads to an insufficient perfusion of the legs and the genital and gluteal region. The occurring symptoms may be variable, mainly depending on the collateralization network of the internal iliac artery (IIA) circulation. Various differential diagnoses need to be excluded. Invasive therapy is almost always inevitable if an aortoiliac stenosis is established. With good patency rates and low mortality rates the indications for reconstructive procedures are liberally interpreted; therefore, invasive therapy can be performed in the early stages of claudication in certain situations. Due to lower invasiveness and therefore lower risk of complications while showing comparable long-term patency rates, endovascular treatment is the preferred first line therapy for the majority of occlusions. Because aortoiliac occlusion processes also affect patients who are actively involved in a professional career, the indications for invasive therapy can be attained even in Fontaine stage IIa.

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3-6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.

We report a 58-year-old female patient with the suspected diagnosis of ovarian cancer. Upon surgical exploration, examination of the appendix revealed the histological diagnosis of primary mucinous adenocarcinoma. This is an unusual consideration in the differential diagnosis of the ovarian cancer. We discuss the diagnosis, classification and treatment of the cancer of the appendix in relation to ovarian cancer.

ZusammenfassungVon den verschiedenen, zur Behandlung der tiefen Venenthrombose zur Verfügung stehenden Optionen, stellt die akute Antikoagulanzientherapie mit Heparinen, insbesondere niedermolekularen Heparinen, gefolgt von der frühzeitig überlappend eingeleiteten oralen Antikoagulation, das Standardvorgehen dar. Thrombolyse, Thrombektomie und Implantation von Kavaschirmfiltern kommen nur bei wenigen Patienten sinnvoll in Betracht. Während somit die medikamentöse Therapie mit Heparinen und Cumarinen die medikamentöse Standardbehandlung darstellt, sind begleitende Therapiemaßnahmen, wie die Notwendigkeit zur initialen Immobilisation der Patienten sowie zur Kompressionsbehandlung bei tiefen Venenthrombosen in ihrer Wertigkeit ungesichert und Gegenstand kontroverser Diskussionen. Darüber hinaus werden die optimale Dauer der oralen Antikoagulation, der Stellenwert einer prolongierten Therapie mit niedermolekularen Heparinen sowie der Stellenwert neuerer Antithrombotika wie Antithrombine, Faktor-Xa-Hemmstoffe und »Tissue factor pathway inhibitor« diskutiert.

ZusammenfassungBis zur Entdeckung und Beschreibung der Resistenz gegenüber aktiviertem Protein C (»APC-Resistenz«) durch Dahlbeck et al. 1993 (1) blieb die Ursache einer familiären thrombophilen Diathese bei einem Großteil der Patienten ungeklärt. Bei weniger als einem Viertel der Patienten mit Häufung thrombembolischer Ereignisse konnten bis dahin vererbare Defekte in den bekannten Inhibitoren der plasmatischen Gerinnung nachgewiesen werden. Heute ist die familiäre APCResistenz aufgrund einer Faktor-V-Mutation mit verminderter Inaktivierbarkeit von Faktor V durch APC mit einer Inzidenz von etwa 5% der Bevölkerung als der wichtigste thrombophile Risikofaktor in der nord- und mitteleuropäischen Bevölkerung anzusehen. Bei familiärer thrombophiler Diathese zeigen bis zu 40% der Patienten diese Störung. Im Gegensatz zur initial von Dahlbeck beschriebenen funktionellen Methodik lassen sich mit modernen, einfach und schnell durchführbaren Gerinnungstesten zuverlässige Aussagen über das Vorliegen der Faktor-V-Punktmutation sowie den heterozygoten oder homozygoten Merkmalträgerstatus machen. Die Erkennung zusätzlicher hereditärer oder erworbener Risikofaktoren und ihrer Gewichtung tragen dazu bei, die Strategie einer primären oder sekundären Thromboseprophylaxe festzulegen.

Aufgrund der zentralen Bedeutung der Leber als Syntheseort wesentlicher Hamostasekomponenten und ihrer funktionellen Rolle im retikoendothelialen System fuhren Lebererkrankungen laboranalytisch zu verminderten Werten der hepatisch synthetisierten Hamostasefaktoren und Zeichen eines vermehrten Umsatzes der plasmatischen Gerinnung und Fibrinolyse. Meist resultiert ein labiles Hamostasegleichgewicht auf niedrigem Niveau. Bei kompensierten Hamostasestorungen ergibt sich in der Regel keine Notwendigkeit zur symptomatischen Therapie der Hamostasestorung. Wird dieser labile Zustand durch verschiedene Noxen weiter gestort, treten klinisch meist Blutungen mit mehr oder weniger Verbrauchskoagulpathie- oder Hyperfibrinolyse-ahnlicher Befundkonstellation und nur ausnahmsweise Thromboembolien auf.

Adenocarcinoma of the exocrine pancreas is one of the most aggressive types of solid tumor and stands at fourth position in the tumor death frequency scale due to a high mortality rate. Effective screening methods are not available and only radical surgery offers a curative option. With adjuvant chemotherapy the median survival time can be prolonged up to 23 months and approximately 25 % of patients are still alive after 5 years. Of these patients approximately 75-80 % are already in a palliative therapy situation at the time of diagnosis. In the last 5 years treatment options have been increased by the introduction of new chemotherapeutic drugs. For patients with metastasized disease median survival times of 6-12 months can currently be achieved depending on the general performance status at diagnosis but less than 5 % of these patients are still alive after 5 years. Neoadjuvant treatment strategies, radiation and immunotherapy do not play a role in evidence-based clinical practice. Despite progress in the understanding of cancer biology and new treatment options, non-resectable adenocarcinoma of the pancreas remains a disease with a very poor prognosis.

Das Lymphgefassystem stellt ein dem Venensystem paralleles Drainagesystem dar. Die Lymphgefase leiten die Lymphe in das Venensystem ab, wahrend die lymphatischen Organe wie Milz, Tonsillen, Thymus, Lymphknoten als Abwehrorgane dienen [8].

ZusammensetzungAufgrund der zentralen Bedeutung der Leber als Syntheseort wesentlicher Hämostasekomponenten und ihrer funktionellen Rolle im retikoendothelialen System führen fortgeschrittene Lebererkrankungen laboranalytisch zu verminderten Werten der hepatisch synthetisierten Hämostasefaktoren und Zeichen eines vermehrten Umsatzes der plasmatischen Gerinnung und Fibrinolyse. Bei der orthotopen Lebertransplantation (OLT) wird die vorbestehend gestörte Hämostase durch den langdauernden operativen Eingriff, die Entfernung der hä-mostaseologisch noch bedeutsamen, erkrankten Leber und der komplexen Transplantat-Wirt-Auseinandersetzung stark beeinträchtigt. Schwere Blutungskomplikationen, die fast ausschließlich nach Perfusion der Transplantatleber bei einem relevanten Anteil der Patienten auftraten, bestimmen die Prognose der Patienten. Während der präanhepatischen Phase finden sich nur geringe Abweichungen der Hämostase von der Ausgangssituation. Regelhaft treten zunehmende Zeichen der Hyperfibrinolyse während der anhepatischen Phase auf, die bei Reperfusion des Spenderorgans, in der postanhepatischen Phase, rasch in eine der disseminierten intravasalen Gerinnung vergleichbare Laborkonstellation übergehen. In dieser letzten Operationsphase werden auch Aktivierungen anderer Kaskadensysteme im Sinne der leukozytären Freisetzung von Proteasen und der Zytokinbildung beobachtert. Von den verschiedenen Versuchen der medikamentösen Hämostaseoptimierung führt die antifibrinolytische Therapie insbesondere mit Aprotinin bei prophylaktischer Applikation zur Reduktion der Blutungskomplikationen und zur Verminderung des Transfusionsbedarfes.

Zur Bewertung der Sedimentbelastung von Oberflachengewassern mit schwerfluchtigen chlorierten Kohlenwasserstoffen, Trialkylphosphaten, organischen Phosphorpestiziden und Polyaromatischen Kohlenwasserstoffen wurden dem Konzept des Bund-/Landerarbeitskreises “Zielvorgaben” folgend okound umwelttoxikologisch begrundete Orientierungswerte fur 16 Stoffe abgeleitet. Vorhandene Zielvorgaben fur die Wasserphase (8 Stoffe) und von den Autoren abgeleitete Orientierungswerte fur weitere 8 Stoffe wurden unter Berucksichtigung stoffspezifischer Verteilungsgleichgewichte (Gleichgewichtsverteilungsansatz) auf Sedimentkonzentrationen umgerechnet. Unabhangig von der Frage einer angemessenen Beschreibung der Bioverfugbarkeit sedimentgebundener Schadstoffe liegen damit okotoxikologisch begrundete Orientierungswerte fur Sedimentschadstoffe vor, die im chemischen Gleichgewicht mit der Wasserphase stehen. Darauf aufbauend wurde ein Konzept zur handlungsorientierten Klassifizierung entwickelt, das zwischen der Bewertung der Sedimente in situ und einer Bewertung bei Aushub von Sedimenten unterscheidet. In situ werden drei okotoxikologische Belastungsklassen gebildet: Sedimentaushub wurde unter Berucksichtigung von Bodenschutzaspekten bewertet und ein “Ausschluswert Verbringung” vorgeschlagen, der mogliche, sich durch Ausbringung von Sedimentaushub ergebende Gefahrdungspotentiale im Hinblick auf den Menschen berucksichtigt. Die schutzgut- und nutzungsbezogene Klassifizierung erlaubt eine okotoxikologische Charakterisierung der Sedimentbelastung von Oberflachengewassern und die Identifizierung von Belastungsschwerpunkten, so das sich ein stoff- und ortspezifisches Kataster der okotoxikologischen Gefahrdung der aquatischen Lebensgemeinschaften durch Sedimentschadstoffe ergibt. Gleichermasen lassen sich nutzungsbeschrankende Bodenkontaminationen durch ausgebrachten Sedimentaushub vermeiden.

Heparin-coated systems for extracorporeal lung-assist (ECLA) were developed to reduce hemorrhagic risk by lowering the systemic heparinization, monitored by global tests, e.g. activated coagulation time (ACT) and activated partial thromboplastin time (APTT). Since this strategy gives no insight into procoagulant states, five ARDS patients receiving ECLA with heparin-coated systems were investivated for changes in coagulation using both global and extended tests. During ECLA onset the APTT and ACT were within or near normal ranges, platelets decreased 76.5% within 48h, fibrinogen decreased 28.7%, thrombin-antithrombin-III complexes were elevated before ECLA (53 μg/L), but demonstrated an additional peak (238 μg/L), plasminogen-activator-inhibitor-1 increased 12-fold, and the C1-inhibitor dropped 14.1%. In conclusion, after the onset of ECLA from a previous prethrombotic state, the precoagulant, anticoagulant, fibrinolytic and complement systems were activated in a similar way to that reported for non-heparinized systems with high-dose heparin. This was however only monitored by an extended test panel which was unable to predict thromboembolic events during ECLA.

The indication for medical venous thrombosis prophylaxis in ambulatory cancer patients is still under discussion. To provide more data on this topic we conducted an analysis in ambulatory patients with advanced pancreatic adenocarcinoma, reflecting a patient cohort at high risk of symptomatic venous thromboembolism (sVTE).Data from 312 consecutively recruited patients of the CONKO-004 trial were analysed according to predefined parameters and additionally with respect to established scores. To focus on patients with highest risk of sVTE unvaried and multivariate analyses were conducted.The global analyses had educed a number needed to treat (NNT) by medical thrombosis prophylaxis of 12 patients to prevent one sVTE. The modified score model did not provide further clinical benefit. However, the regression model can identify single parameters with a trend to higher risk of sVTE or higher risk of severe bleeding. Most of the parameters do not have enough power to be significant, but they can support clinical decisions.These data suggest that medical thrombosis prophylaxis should be performed in patients with advanced pancreatic cancer at least for the initial 3 months of first line chemotherapy.

To assess the technical feasibility, safety and clinical outcome of CT-guided high-dose-rate brachytherapy (CT-HDRBT) for achieving local tumour control (LTC) in isolated lymph node metastases.From January 2008 to December 2011, 10 patients (six males and four females) with isolated nodal metastases were treated with CT-HDRBT. Five lymph node metastases were para-aortic, three were at the liver hilum, one at the coeliac trunk and one was a left iliac nodal metastasis. The mean lesion diameter was 36.5 mm (range 12.0-67.0 mm). Patients were followed up by either contrast-enhanced CT or MRI 6 weeks and then every 3 months after the end of treatment. The primary end point was LTC. Secondary end points included primary technical effectiveness rate, adverse events and progression-free survival.The first follow-up examination after 6 weeks revealed complete coverage of all nodal metastases treated. There was no peri-interventional mortality or major complications. The mean follow-up period was 13.2 months (range 4-20 months). 2 out of 10 patients (20%) showed local tumour progression 9 and 10 months after ablation. 5 out of 10 patients (50%) showed systemic tumour progression. The mean progression-free interval was 9.2 months (range 2-20 months).CT-HDRBT is a safe and effective technique for minimally invasive ablation of nodal metastases.CT-HDRBT of lymph node metastases is feasible and safe. CT-HDRBT might be a viable therapeutic alternative to obtain LTC in selected patients with isolated lymph node metastases.

Dabigatran, an oral, reversible direct factor IIa inhibitor, is approved in Europe for stroke prevention in atrial fibrillation and for the prevention of venous thromboembolism after elective hip and knee replacement. In contrast to vitamin K antagonists, a routine coagulation monitoring during the treatment with dabigatran etexilate is not necessary. However, in specific clinical situations such as invasive emergency procedures or serious haemorrhage, the actual anticoagulant status of dabigatran may be of importance for the treating clinician and can be assessed by clotting tests (aPTT, TT, ECT). The diluted thrombin time test (Hemoclot®), which is specifically calibrated for dabigatran, is useful for quantitative determination of the dabigatran serum concentration. In general, discontinuation of dabigatran etexilate 24 hours before standard elective surgery is sufficient to normalise the bleeding risk in patients with normal renal function. In patients with renal impairment and/or in the case of a high bleeding risk procedure the recommended duration of discontinuation is prolonged. If a bleeding episode occurs in a patient on dabigatran, further treatment should be based on the severity and localisation of the bleeding. A distinct feature of dabigatran is the possibility of effectively removing dabigatran from the circulation by haemodialysis.In the case of clinically minor bleedings, a delay in the administration of the next dabigatran etexilate dose is recommended. The length of the delay is based on the patient's individual thromboembolic risk. In minor bleedings the use of prothrombin complex concentrates is not indicated. In the case of moderate or major bleedings the main focus should be on stabilising the circulation by using fluids and blood products and, if a lesion can be identified, the local treatment thereof. If time and infrastructure is available, dialysis offers an effective and fast option to remove dabigatran out of the circulation. In the incidence of severe and life threatening bleedings, an additional, more complex haemostasis management is required. Besides haemodynamic stabilisation of the circulation, administration of prothrombin complex concentrates should not be delayed. It has to be kept in mind that standard laboratory coagulation parameters may not accurately reflect the effect of prothrombin complex concentrates in patients on dabigatran. Hence the effect of the prothrombin complex concentrate should be monitored clinically and adjusted by means of onset of coagulation in vivo.

The case of a 65-year-old woman with acquired hemophilia is reported. Acquired hemophilia is characterized by the development of inhibitors directed against coagulation factors. Impairment of plasmatic hemostasis leads to a severe bleeding tendency in individuals without a preexisting coagulation defect with considerable mortality. Pathophysiology, diagnostic work-up, and treatment are summarized and discussed.

Thrombomodulin is a surface protein of vascular endothelial cells. A smaller form of thrombomodulin in blood and urine, the soluble (s)thrombomodulin, appears to be derived from injured endothelial cells or to be proteolytically cleaved from thrombomodulin by proteases. Several in vitro and in vivo studies have suggested (s)thrombomodulin as a marker of endothelial damage. In orthotopic liver transplantation, platelet and leukocyte activation as well as prothrombin activation are suspected of being caused by damaged endothelial cells in the graft liver. We determined (s)thrombomodulin antigen as well as thrombin-antithrombin III complexes, protein C, and antithrombin III activities in the course of 23 orthotopic liver transplantations. Samples were taken at 7 different time-points intraoperatively, as well as out of the perfusate released from the graft liver vein during the flushing procedure with arterial blood prior to the opening of the hepatocaval anastomosis. Levels of (s)thrombomodulin antigen and thrombin-antithrombin III complexes showed a significant increase with reperfusion of the graft liver and levels in the perfusate were higher (both: P = 0.0001) than the corresponding systemic levels. In parallel, antithrombin III decreased significantly with reperfusion and perfusate levels of antithrombin III and protein C activities were lower in the systemic circulation (both: P = 0.0001). In conclusion, high levels of (s)thrombomodulin antigen in the early reperfusion phase and in the perfusate strongly indicate endothelial damage to the graft liver vascular bed, paralleled and followed by signs of prothrombin activation.

BACKGROUND: Photodynamic virus inactivation of fresh-frozen plasma (FFP) may result in its impaired coagulation capability. STUDY DESIGN AND METHODS: Double-volume plasmapheresis samples from 11 donors were divided in pairs of 250 mL. One group underwent methylene blue (MB) phototreatment (MB-FFP). The other group was treated according to the standards of the American Association of Blood Banks for preparation and storage of FFP. Parameters of hemostasis and clinically important plasma proteins were tested in native plasma, thawed MB-FFP, thawed FFP, and twice-frozen and thawed FFP (FFP-II). RESULTS: Mean activities of factor V (73.4 vs. 94.5%; p < 0.01), factor VIII (58.1 vs. 86.7%; p < 0.001), and fibrinogen (1.8 vs. 2.8 g/L; p < 0.001) were reduced in MB-FFP as compared to those in FFP. The comparison of MB-FFP to FFP-II revealed reduced activities of factor VIII (58.1 vs. 85.2%; p < 0.001) and fibrinogen (1.8 vs. 2.8 g/L; p < 0.001) but no changes in factor V. Activated partial thromboplastin time in MB-FFP was prolonged beyond the upper normal range (+5.3 sec; p < 0.001) and prothrombin time increased in MB-FFP versus FFP (+0.96 sec; p < 0.001). CONCLUSION: MB phototreatment reduces the in vitro coagulation capacity of FFP, most likely as a result of the effects of an additional freezing and thawing procedure and photooxidation-induced protein damage.

Venous thrombembolism (VTE) is one of the most frequent complication in cancer patients. The current options in prophylaxis and therapy have to be balanced against the risks of major bleeding and the burden for the patients. The Gesellschaft für Thrombose- und Hämostaseforschung, the Deutsche Gesellschaft für Palliativmedizin and the German speaking Societies of Hematology and Oncology have recently published guidelines on VTE in cancer patients. Recommendations include diagnostics, individual prophylaxis and treatment.