BACKGROUND:COVID-19 is a novel viral disease. Severe courses may present as ARDS. Several publications report a high incidence of coagulation abnormalities in these patients. We aimed to compare coagulation and inflammation parameters in patients with ARDS due to SARS-CoV-2 infection versus patients with ARDS due to other causes. METHODS:This retrospective study included intubated patients admitted with the diagnosis of ARDS to the ICU at Munich university hospital. 22 patients had confirmed SARS-CoV2-infection (COVID-19 group), 14 patients had bacterial or other viral pneumonia (control group). Demographic, clinical parameters and laboratory tests including coagulation parameters and thromboelastometry were analysed. RESULTS:No differences were found in gender ratios, BMI, Horovitz quotients and haemoglobin values. The median SOFA score, serum lactate levels, renal function parameters (creatinine, urea) and all inflammation markers (IL-6, PCT, CRP) were lower in the COVID-19 group (all: p < 0.05). INR (p < 0.001) and antithrombin (p < 0.001) were higher in COVID-19 patients. D-dimer levels (p = 0.004) and consecutively the DIC score (p = 0.003) were lower in this group. In ExTEM®, Time-to-Twenty (TT20) was shorter in the COVID-19 group (p = 0.047), these patients also had higher FibTEM® MCF (p = 0.005). Further, these patients presented with elevated antigen and activity levels of von-Willebrand-Factor (VWF). CONCLUSION:COVID-19 patients presented with higher coagulatory potential (shortened global clotting tests, increased viscoelastic and VWF parameters), while DIC scores were lower. An intensified anticoagulation regimen based on an individual risk assessment is advisable to avoid thromboembolic complications.

Objectives: Emicizumab (Emi) is a humanised bispecific antibody with a novel mechanism of action (MoA) - it bridges factor X (FX) and activated factor IX (FIXa) to restore haemostatic function; due to its biochemical properties, Emi interferes with various standard coagulation assays. Emi is approved for prophylactic treatment in people with haemophilia A (PwHA) and FVIII inhibitors. The aim herein is to provide a closer view of available data concerning the questions: how does Emi interfere with coagulation assays? Which assays can be applied in clinical routine?

The peri-prosthetic tissue response to wear debris is complex and influenced by various factors including the size, area and number of particles. We hypothesised that the 'biologically active area' of all metal wear particles may predict the type of peri-prosthetic tissue response. Peri-prosthetic tissue was sampled from 21 patients undergoing revision of a small diameter metal-on-metal (MoM) total hip arthroplasty (THA) for aseptic loosening. An enzymatic protocol was used for tissue digestion and scanning electron microscope was used to characterise particles. Equivalent circle diameters and particle areas were calculated. Histomorphometric analyses were performed on all tissue specimens. Aspirates of synovial fluid were collected for analysis of the cytokine profile analysis, and compared with a control group of patients undergoing primary THA (n = 11) and revision of a failed ceramic-on-polyethylene arthroplasty (n = 6). The overall distribution of the size and area of the particles in both lymphocyte and non-lymphocyte-dominated responses were similar; however, the subgroup with lymphocyte-dominated peri-prosthetic tissue responses had a significantly larger total number of particles. 14 cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, interferon (IFN)-γ, and IFN-gamma-inducible protein 10), chemokines (macrophage inflammatory protein (MIP)-1α and MIP-1ß), and growth factors (granulocyte macrophage colony stimulating factor (GM-CSF) and platelet derived growth factor) were detected at significantly higher levels in patients with metal wear debris compared with the control group. Significantly higher levels for IL-1ß, IL-5, IL-10 and GM-CSF were found in the subgroup of tissues from failed MoM THAs with a lymphocyte-dominated peri-prosthetic response compared with those without this response. These results suggest that the 'biologically active area' predicts the type of peri-prosthetic tissue response. The cytokines IL-1ß, IL-5, IL-10, and GM-CSF are associated with lymphocyte-dominated tissue responses from failed small-diameter MoM THA.

10508 Background: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients. Methods: We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA. Results: We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies. Conclusions: Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clinical trial information: NCT01462994.

Background: Impairment of sleep–wake cycles and circadian rhythm are found in human narcolepsy which is characterized by deficiency of hypocretin (hcrt) or its receptors. A disturbed electroencephalography (EEG) based vigilance regulation is also found in affective disorders such as major depressive disorder (MDD) and mania. For the first time, in the present study hcrt levels were investigated in patients with a manic episode and compared with age-matched patients with MDD and controls. Methods: 15 subjects were enrolled in the study after admission to hospital: 5 manic (mean YMRS 15.6 ± 2.9) and 5 age-matched patients with MDD (mean HDRS 11.6 ± 8.0), and 5 age-matched controls without any neurological or psychiatric disorder. Cerebrospinal fluid (CSF) hcrt levels were measured in all three groups using a fluorescence immunoassay (FIA). Results: Mean hcrt-1 level in manic patients (77.3 ± 20.7 pg/ml) did not differ significantly compared to patients with MDD (75.6 ± 15.7 pg/ml MDD) or controls (74.9 ± 19.3 pg/ml). Hcrt levels and severity of disease did not show a significant association. Conclusion: In the present study, for the first time hcrt-1 levels in manic patients were investigated but did not reveal significant differences neither compared to age-matched patients with MDD nor healthy controls without any psychiatric or neurological disorder.

Summary Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII in adults or elderly patients, who do not have a personal or family history of bleeding. Case: A man (age: 76 years) on prednisone and leflunomide for polymyalgia rheumatica developed spontaneous severe haematomas. The patient was diagnosed with acquired factor VIII deficiency (FVIII activity 1.2%, FVIII inhibitor 31.7 BU). Due to the active bleeding diathesis, treatment was administered with activated prothrombin complex concentrates (FEIBA®, Baxter). Immunosuppressive treatment with a combination of oral prednisone (1 mg/kg daily) and cyclophosphamide (1,5 mg/kg daily) was administered to reduce the FVIII inhibitor. However, after two weeks of treatment, FVIII was only 3% and no clinical improvement was observed. Treatment with the anti CD20 monoclonal antibody rituximab intravenously at 375 mg/m2 once weekly for four consecutive weeks was started. The patient showed rapid clinical improvement following rituximab treatment. He achieved a complete remission defined as return to normal FVIII activity and undetectable FVIII inhibitor titer. After a follow-up of six months no relapse occurred. Conclusion: Rituximab appears an effective and well-tolerated treatment for patients with acquired haemophilia.

Caveolin-1 (Cav-1) is the major structural protein essential to the formation of the caveolae in endothelial cells. Genetic ablation of Cav-1 on an apolipoprotein E knockout background inhibits the progression of atherosclerosis, whereas re-expression of Cav-1 in the endothelium promotes lesion expansion. Although Cav-1-null mice are useful to delineate the importance of caveolae in atherosclerosis, there are additional problems that are difficult to dissect because loss of Cav-1 abolishes both the caveolae organelle as well as the Cav-1-mediated signaling pathways. To study how Cav-1 influences the progression of atherosclerosis in mice with caveolae, we generated a transgenic mouse that overexpresses Cav-1 in the endothelial cells in an apolipoprotein E-deficient background. We found that endothelial-specific overexpression of Cav-1 enhanced the progression of atherosclerosis in mice. Mechanistically, overexpression of Cav-1 reduced endothelial cell proliferation, migration, and nitric oxide production in vitro and increased expression of vascular cell adhesion molecule-1 in vivo.

Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII in adults or elderly patients, who do not have a personal or family history of bleeding.A man (age: 76 years) on prednisone and leflunomide for polymyalgia rheumatica developed spontaneous severe haematomas. The patient was diagnosed with acquired factor VIII deficiency (FVIII activity 1.2%, FVIII inhibitor 31.7 BU). Due to the active bleeding diathesis, treatment was administered with activated prothrombin complex concentrates (FEIBA&reg;, Baxter). Immunosuppressive treatment with a combination of oral prednisone (1 mg/kg daily) and cyclophosphamide (1,5 mg/kg daily) was administered to reduce the FVIII inhibitor. However, after two weeks of treatment, FVIII was only 3% and no clinical improvement was observed. Treatment with the anti CD20 monoclonal antibody rituximab intravenously at 375 mg/m2 once weekly for four consecutive weeks was started. The patient showed rapid clinical improvement following rituximab treatment. He achieved a complete remission defined as return to normal FVIII activity and undetectable FVIII inhibitor titer. After a follow-up of six months no relapse occurred.Rituximab appears an effective and well-tolerated treatment for patients with acquired haemophilia.

Ziele: Evaluation der diffusionsgewichteten MRT zur Detektion von Lebermetastasen bei Patienten mit malignen Pankreastumoren im Vergleich zur MS-CT. Methode: Bei 31 Patienten mit malignitätsverdächtigen Raumforderungen des Pankreas wurde eine diffusionsgewichtete MRT (Magnetom Avanto 1.5 Tesla, Siemens) und ein Multi-Slice CT (Somatom Sensation 64, Siemens, art. + ven. Phase, 3mm Schichtdicke, 90ml i.v.-Bolus Imeron 400 mit 3ml/s) der Leber durchgeführt. Für die diffusionsgewichtete MRT wurde eine atemgetriggerte, single-shot echo planare Sequenz (SSEPI, TR=∞, TE=69ms, Matrix 256×256, Schichtdicke 5mm, GRAPPA 2, b-Werte 50, 300 und 600 s/mm2) in Kombination mit Navigator Echo Technik (PACE) verwendet. Die MR-Bilder wurden mit histologischen und intraoperativen Ultraschall-Befunden korreliert. Ergebnis: In der MS-CT wurden bei 31 Patienten insgesamt 31 fokale Leberläsionen (14 benigne, 7 maligne, 10 unklare) detektiert. Bei der diffusionsgewichteten MRT wurden 52 fokale Leberläsionen (39 benigne, 9 maligne, 4 unklare) detektiert. Im Vergleich mit den histologischen Befunden und dem intraoperativen Ultraschall wurden 33,3% der Lebermetastasen durch die MS-CT detektiert, wohingegen die diffusionsgewichtete MRT 88,9% der Lebermetastasen detektierte. Die Spezifität betrug 77,8% für die MS-CT und 97,5% für die diffusionsgewichtete MRT. Durch die diffusionsgewichtete MRT hätte sich das Therapiekonzept in 6 der 31 Patienten geändert. Schlussfolgerung: Bei Patienten mit malignen Pankreastumoren ist die diffusionsgewichtete MRT in der Detektion von Lebermetastasen der MS-CT deutlich überlegen.

BACKGROUND:C-reactive protein (CRP) levels are modulated by endogenous and exogenous factors independently of inflammation. The present study investigated the impact of oral contraceptives, endogenous oestrogens, age, gender, smoking, body mass index (BMI) and lipid levels on CRP concentrations in a healthy collective.METHODS:Highly sensitive CRP, total cholesterol, HDL-cholesterol and LDL-cholesterol levels were measured in 850 blood donors (438 M, 412 F); 227 women in this group used oral contraceptive formulations (OC). Additionally, serum samples from 58 women undergoing in vitro fertilization cycles (IVF) were tested for CRP. Results. The 97.5th percentile of CRP levels of the blood donors was 4.91 mg/L in men, 7.52 mg/L in OC non-users and 11.95 mg/L in OC users. Overweight gives a 2-fold increase of median CRP levels in men and women. The combination of overweight and OC use in women resulted in 6-fold median CRP levels. Age, smoking and lipid levels were influencing factors of lower significance. In IVF patients the elevated oestradiol levels had no influence on CRP concentrations in multivariance analysis.CONCLUSION:The diagnostic and predictive value of CRP levels is most affected by BMI and oral contraceptive use, which suggests the need for further investigations into the role of CRP modulating factors in monitoring infectious diseases.