scholarly journals Preliminary hemocompatibility assessment of an innovative material for blood contacting surfaces

2021 ◽  
Vol 32 (8) ◽  
Author(s):  
Martina Todesco ◽  
Elena Pontara ◽  
Chunyan Cheng ◽  
Gino Gerosa ◽  
Vittorio Pengo ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Blood Compatibility ◽  
Synthetic Polymer ◽  
Hybrid Membrane ◽  
Polycarbonate Urethane ◽  
Innovative Material ◽  
Porcine Pericardium

AbstractOver the years, several devices have been created (and the development of many others is currently in progress) to be in permanent contact with blood: mechanical circulatory supports represent an example thereof. The hemocompatibility of these devices largely depends on the chemical composition of blood-contacting components. In the present work, an innovative material (hybrid membrane) is proposed to fabricate the inner surfaces of a pulsatile ventricular chamber: it has been obtained by coupling a synthetic polymer (e.g., commercial polycarbonate urethane) with decellularized porcine pericardium. The hemocompatibility of the innovative material has been preliminarily assessed by measuring its capacity to promote thrombin generation and induce platelet activation. Our results demonstrated the blood compatibility of the proposed hybrid membrane.

Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

1987 ◽  
Vol 57 (01) ◽  
pp. 062-066 ◽  
Author(s):  
P A Kyrle ◽  
J Westwick ◽  
M F Scully ◽  
V V Kakkar ◽  
G P Lewis
Keyword(s):  
Platelet Activation ◽  
Thrombin Generation ◽  
Low Dose ◽  
Bleeding Time ◽  
Blood Platelets ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Plug Formation ◽  
Granule Release

SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

scholarly journals Prospective Assessment of Biomarkers of Hypercoagulability in Oncological Patients and Healthcare Workers Following Vaccination Against Sars-Cov-2 with the mRNA Vaccine. the Roadmap-COVID-19-Vaccin Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3207-3207
Author(s):  
Patrick Van Dreden ◽  
Joseph Gligorov ◽  
Evangelos Terpos ◽  
Mathieu Jamelot ◽  
Michele Sabbah ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Tissue Factor ◽  
Platelet Activation ◽  
Research Funding ◽  
Thrombin Generation ◽  
Cell Activation ◽  
Control Group ◽  
Clotting Time ◽  
Endothelial Cell Activation ◽  
Active Cancer

Abstract Background: COVID-19 has been associated with hypercoagulability, endothelial cell injury and frequent thrombotic complications resulting both from direct effects of the virus on the endothelium and from the 'cytokine storm' resulting from the host's immune response. Since the COVID-19 vaccines have been shown to effectively prevent symptomatic infection including hospital admissions and severe disease, the risk of COVID-19-related thrombosis should be expected to (almost) disappear in vaccinated individuals. However, some rare cases of venous thrombosis have been reported in individuals vaccinated with mRNA vaccines. Thus, there is a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and on the rare thrombotic events observed after the vaccination with these vaccines. This phenomenon raised some scepticism of even some fear about the safety of these vaccines which could compromise the adhesion of the citizens in the vaccination program. Aims: We conducted a prospective observational study, to explore the impact of vaccination with the BNT162b2 (Pfizer/BioNTech) on blood hypercoagulability and endothelial cell activation and to investigate if this is modified by the presence of active cancer. Methods: In total 229 subjects were prospectively included in the study from April to June 2021. Subjects were stratified in three predefined groups: 127 vaccinated patients with active cancer (VOnco group), 72 vaccinated health care workers (VHcw group) and 30 non vaccinated health individuals (Control group). Blood samples were obtained 2 days after the administration of the first dose of BNT162b2 vaccine and collected in Vacutainer® tubes (0.109 mol/L trisodium citrate). Platelet poor plasma (PPP) was prepared by double centrifugation at 2000 g for 20 minutes at room temperature and plasma aliquots were stored at -80°C until assayed. Samples of PPP were assessed for thrombin generation (TG) with PPP-Reagent® (Thrombogram-Thrombinoscope assay with PPP-Reagent®TF 5pM), E-selectin, D-dimers, (D-Di), Tissue Factor (TFa), procoagulant phospholipid-dependent clotting time (Procag-PPL) and von Willebrand factor (vWF), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and platelet factor 4 (PF4). All assays were from Diagnostica Stago (France). The upper and lower normal limits (UNL and LNL) for each biomarker were calculated by the mean±2SD for the control group. Results: All vaccinated subjects showed significantly increased levels of PF4 (71% >UNL, p<0.001), D-Dimers (74% >UNL, p<0.01), vWF (60% >UNL, p<0.01), FVIII (62% >UNL, p<0.01) and shorter Procoag-PPL clotting time (96% <LNL, p<0.001), as compared to controls. Thrombin generation showed significantly higher Peak (60% >UNL, p<0.01), ETP (38% >UNL, p<0.01) and MRI (66% >UNL, p<0.01) but no differences in lag-time in vaccinated subjects as compared to the control group. Vaccinated subjects did not show any increase at the levels of TFa, TFPI, TM and E-selectin in comparison with the control group. The studied biomarkers were not significantly different between the VOnco and VHcw groups. Conclusion: The ROADMAP-COVID-19-Vaccine study shows that administration of the first dose of the BNT162b2 vaccine induced significant platelet activation documented by shorter Procoag-PPL associated with increased levels of PF4. Plasma hypercoagulability was less frequent in vaccinated individuals whereas there was no evidence of significant endothelial cells activation after vaccination. Interestingly, the presence of active cancer was not associated with an enhancement of platelet activation, hypercoagulability, or endothelial cell activation after the vaccination. Probably, the generated antibodies against the spike protein or lead to platelet activation in a FcyRIIa dependent manner that results in PF4 release. The implication of the mild inflammatory reaction triggered by the vaccination could be another possible pathway leading to platelet activation. Nevertheless, vaccination does not provoke endothelial activation even in patients with cancer. The findings of the ROADMAP-COVID-19-Vaccine study support the concept administration of mRNA based vaccines does not directly cause a systematic hypercoagulability. Disclosures Gligorov: Roche-Genentech: Research Funding; Novartis: Research Funding; Onxeo: Research Funding; Daichi: Research Funding; MSD: Research Funding; Eisai: Research Funding; Genomic Heatlh: Research Funding; Ipsen: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria.

scholarly journals The influence of Erythropoietin on platelet activation, thrombin generation and FVII/active FVII in patients with AMI

2014 ◽  
Vol 12 (1) ◽  
pp. 18 ◽  
Author(s):  
Gabriele Demetz ◽  
Magdalena Laux ◽  
Armin Scherhag ◽  
Tiny Hoekstra ◽  
Marit M Suttorp ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombin Generation

Injection of recombinant activated factor VII can induce transient increase in circulating procoagulant microparticles

2004 ◽  
Vol 91 (05) ◽  
pp. 873-878 ◽  
Author(s):  
Bénédicte Hugel ◽  
Benoit Guillet ◽  
Catherine Trichet ◽  
Anne Rafowicz ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Short Duration ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Transient Increase ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Therapeutic Doses

SummaryRecombinant activated factor VII (rFVIIa) is an effective haemostatic treatment in haemophiliacs with inhibitors. In vitro, FVIIa concentrations corresponding to those obtained with therapeutic doses of rFVIIa have been shown to induce normal thrombin generation and platelet activation in the absence of factors VIII or IX. To further study the in vivo haemostatic changes induced by rFVIIa, circulating procoagulant microparticles (MP) were measured in patients treated with discontinuous injections of Novoseven®. In 6 out of 15 patients, a transient peak of procoagulant MP was observed after injection, occurring 15 min to 2 h after infusion. It was composed primarily of platelet-derived MP and was of very short duration. This peak was not observed in haemophiliacs without inhibitor, who were treated with conventional replacement therapies. Our results provide further in vivo evidence that rFVIIa specifically activates platelets, either directly or as a consequence of a burst of thrombin generation that could account for its haemostatic efficacy.

scholarly journals Hemoperfusion leads to impairment in hemostasis and coagulation process in patients with acute pesticide intoxication

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Samel Park ◽  
Md-Imtiazul Islam ◽  
Ji-Hun Jeong ◽  
Nam-Jun Cho ◽  
Ho-yeon Song ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombin Generation ◽  
Degradation Products ◽  
Treatment Modalities ◽  
Platelet Surface ◽  
Distribution Width ◽  
Risk Of Bleeding ◽  
Increased Risk ◽  
Significant Change

Abstract Hemoperfusion (HP) is one of the important treatment modalities in extracorporeal therapy for patients with acute intoxication. Its use has declined during the past 20 years despite its efficacy, because of its side effects, especially an increased risk of bleeding. Mechanisms of hemostasis impairment have not been clearly elucidated and studies demonstrating the mechanism are lacking. It is not clear which step of the hemostatic process is impaired during HP, and whether it leads to an increased risk of bleeding. We performed both in vivo and in vitro studies to elucidate the mechanism of impairment in the hemostatic process. In patients with acute pesticide intoxication who underwent HP, the platelet count decreased rapidly during the first 30 minutes from 242.4 ± 57.7 × 103/μL to 184.8 ± 49.6 × 103/μL, then gradually decreased even lower to 145.4 ± 61.2 × 103/μL over time (p < 0.001). As markers of platelet activation, platelet distribution width increased continuously during HP from 41.98 ± 9.28% to 47.69 ± 11.18% (p < 0.05), however, mean platelet volume did not show significant change. In scanning electron microscopy, activated platelets adhered to modified charcoal were observed, and delayed closure time after HP in PFA-100 test suggested platelet dysfunction occurred during HP. To confirm these conflicting results, changes of glycoprotein expression on the platelet surface were evaluated when platelets were exposed to modified charcoal in vitro. Platelet expression of CD61, fibrinogen receptor, significantly decreased from 95.2 ± 0.9% to 73.9 ± 1.6%, while those expressing CD42b, von Willebrand factor receptor, did not show significant change. However, platelet expression of CD49b, collagen receptor, significantly increased from 24.6 ± 0.7% to 51.9 ± 2.3%. Thrombin-antithrombin complex, a marker for thrombin generation, appeared to decrease, however, it was not statistically significant. Fibrin degradation products and d-dimers, markers for fibrinolysis, increased significantly during HP. Taken together, our data suggests that hemoperfusion leads to impairment of platelet aggregation with incomplete platelet activation, which was associated with reduced thrombin generation, accompanied by increased fibrinolysis.

The Effect of BIBT 986, a Novel Small Molecule Dual Inhibitor of Thrombin and Factor Xa, on Coagulation in a Model of Endotoxin Induced, Tissue Factor Triggered Coagulation Activation in Humans.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 912-912 ◽  
Author(s):  
Bernd Jilma ◽  
Judith M. Leitner ◽  
Francesco Cardona ◽  
Florian B. Mayr ◽  
Christa Firbas ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Thrombin Time ◽  
Coagulation Activation ◽  
Dual Inhibitor ◽  
Activation Markers ◽  
Markers Of Inflammation ◽  
Prolonged Aptt

Abstract Background: BIBT 986 is a novel potent anticoagulant that dually inhibits Factors Xa and IIa. We hypothesized that BIBT 986 would dose-dependently decrease endotoxin-induced, tissue factor triggered coagulation activation. Hence it was the aim of the study to compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation and to examine the safety of BIBT 986 in this setting. Methods: This study was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants were randomised to receive bolus primed continuous infusions of one of the three doses of BIBT 986 or placebo. All of them received a bolus infusion of 2ng/kg body weight lipopolysaccharide (LPS). Results: BIBT dose-dependently increased anti-Xa activity, activated partial thromboplastin time (APTT), ecarin clotting time (ECT), thrombin time (TT) and the international normalisation ratio (INR). Importantly, BIBT 986 dose-dependently blocked the LPS-induced coagulation as assessed by the in vivo markers of thrombin generation and action: BIBT 986 doses that prolonged APTT by 25% were already effective. The BIBT dose that prolonged APTT by 100%, completely suppressed the increase in prothrombin fragment (F1+2), thrombin-antithrombin complexes (TAT) and D-dimer. BIBT 986 had no influence on activation markers of inflammation, fibrinolysis, endothelial or platelet activation. Conclusion: Infusion of BIBT 986 was safe and well tolerated. BIBT 986 specifically and dose-dependently blocked LPS-induced, tissue factor trigger coagulation. When compared to different anticoagulants tested previously in this standardized model, BIBT 986 was more effective in suppressing thrombin generation (F1+2 levels) than standard doses of danaparoid, dalteparin or lepirudin. BIBT 986 represents the first drug of a new class of dual FXa and FIIa inhibitors, and displays high potency.

The Effect of Thalassemia and Other RBC Hemolytic Disorders and Splenectomy on the Frequency of Pulmonary Hypertension

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2077-2077
Author(s):  
Sylvia T Singer ◽  
Frans Kuypers ◽  
Jeffrey Fineman ◽  
Sandra K Larkin ◽  
Michael Jeng ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Vascular Function ◽  
Thrombin Generation ◽  
Conflicts Of Interest ◽  
Thalassemia Major ◽  
Phosphatidyl Serine ◽  
Beta Thalassemia ◽  
Large Variability ◽  
History Of ◽  
Potent Vasoconstrictor

Abstract Abstract 2077 Introduction: Pulmonary arterial hypertension (PAH) has been accepted to be a clinical entity associated with hemoglobinopthies, mostly reported in sickle disease and thalassemia intermedia (TI). Anecdotal cases of PAH in other chronic hemolytic disorders have been reported; many of which have been associated with a prior splenectomy. The pathogenesis of PAH in the non sickle-cell RBC hemolytic disorders has not been well defined and the large variability in its frequency and severity are not clear. We aimed to characterize biomarkers in thalassemia and in other RBC disorders and evaluate the specific role of splenectomy (spleen.) in these diseases. Patients and Method: A total of 106 patients were analyzed: Forty two were regularly transfused thalassemia major (TM), 34 had TI (16 with Hb E/beta thalassemia, 11 with beta thalassemia, and 7 with hemoglobin H-Constant Spring (Hb H-CS); 18 with hereditary spherocytosis (HS) or pyruvate kinase (PK) deficiency, 2 with an unstable Hb (Hb Koln), and 10 with a history of splenectomy for non-RBC related reasons (trauma or chronic ITP). PAH was determined by using a Doppler echocardiogram showing a tricuspid regurgitation jet velocity (TRV) of >2.5m/s. Markers of platelet activation (P- selectin, soluble CD40 (sCD40L); abnormal exposure of Phosphatidyl Serine (PS) on RBCs, thrombin generation (thrombin-anti-thrombin, TAT); increased ventricular pressure strain (brain natriuretic peptide (BNP); plasma free Hb, LDH and NOx, and endothelin-1, soluble vascular cell adhesion molecule (sVCAM) were analyzed. Result: Nineteen (56%) of the TI patients (15 with beta-TI and 4 with Hb H-CS) had abnormally elevated TRV (Mean 3.0±0.5). The 2 patients with Hb Koln had increased TRV. There were no PAH cases detected among patients with membrane or RBC enzyme deficiencies, neither was there an increased TRV in patients who had been splenectomized without a RBC disorder. There were also no cases of increased TRV in the transfused TM cohort. Patients with TI, in addition to a prior splenectomy and increased hemolysis had increased platelet activation, abnormal RBC PS exposure and anemia. TI patients also had an increase in ET-1 levels, a potent vasoconstrictor. The 2 patients with Hb Koln had increased thrombin generation in addition to hemolysis and absence of spleen. Conclusions: PAH was not detected in splenectomized patients with only a mild chronic hemolytic disorder or in those without a RBC disorder. In addition to the absence of spleen, a higher rate of hemolysis, resulting in NO scavenging and increase in ET-1 and the involvement of platelet activation or thrombin generation are likely required for the development of dysregulation of the pulmonary vascular function. PAH is rare in TI patients which have not undergone splenectomy; absence of spleen likely enhances the effects of thrombocytosis and platelet activation. Our data indicates that PAH is common in patients with Hb H-CS, mostly splenectomized, and should be screened for. In addition our data shows that blood transfusions reduce the elements of anemia, hemolysis and coagulation activation and prevent the development of PAH in splenectomized and non-splenectomized patients. Disclosures: No relevant conflicts of interest to declare.

Design Of a Most Efficient Inhibitor Of TFPI By Molecular Fusion Of Two Inhibitory Peptides

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3564-3564
Author(s):  
Michael Dockal ◽  
Rudolf Hartmann ◽  
Thomas Polakowski ◽  
Johannes Brandstetter ◽  
Willibald Kammlander ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endothelial Cells ◽  
Cell Surface ◽  
Platelet Activation ◽  
Research Funding ◽  
Thrombin Generation ◽  
Fusion Peptide ◽  
Peptide Inhibitors ◽  
Model Systems ◽  
Inhibitory Peptide

Abstract TFPI is an important inhibitor of the extrinsic coagulation pathway. It efficiently inhibits TF-FVIIa and FXa by quaternary complex formation. Plasma contains various truncated forms of TFPI which are poor inhibitors, and full length (fl)TFPI (0.3 – 0.5 nM) which is the most active TFPI in plasma. flTFPI is released from platelets upon activation, and increases flTFPI concentrations locally up to 30-fold. Most intravascular TFPI (∼80%) is associated with endothelial cells. Both endothelial forms, TFPIa and TFPIb, are similarily effective inhibitors of FX activation on the endothelial cell surface. Inhibition of TFPI in hemophilia models with blocking antibodies, aptamers or peptide inhibitors improves hemostasis and may become an option to treat hemophilia. Recently, we presented peptide inhibitors of TFPI that enhance coagulation in hemophilia models. Two optimized peptides, JBT-A7 and JBT-B5, efficiently blocked inhibitory activity of TFPI and bound to distinct binding sites. We demonstrated the crystal structure of JBT-A7, a linear TFPI inhibitory peptide composed of 20 amino acids, bound to NtermK1 (TFPI 1-83). JBT-B5, a cyclic TFPI inhibitory peptide of 23 amino acids, co-crystallized with TFPI KD1-KD2 (TFPI 22-150). Overlaying the KD1 structure in the KD1-KD2/JBT-B5 and the NTermK1/JBT-A7 complex provided atomic details for linking the two peptide entities. Binding of peptides to TFPI and TFPI fragments was studied by BioCore. The TFPI inhibitory potential of the resulting fusion peptide was tested in model systems (FXa inhibition and TF-FVIIa catalyzed FX activation) and global hemostatic assays (TF-triggered thrombin generation) using hemophilia plasma. To model situations of increased TFPI concentration, both model and plasma assays were carried out at TFPI concentrations up to 10 nM, which is 40-50-fold higher than the physiological flTFPI plasma concentration. To characterize the inhibition of platelet TFPI, we used platelets isolated from blood samples and platelet rich plasma from different donors. Binding of a biotinylated fusion peptide on living HUVE cells was assessed by fluorescence activated cell sorting (FACS) and fluorescence microscopy. Inhibition of cell surface TFPI was analyzed on cultivated HUVECs stimulated with TNFa for TF expression. We monitored FXa generation by the TFPI-dependent cell surface FX activation complex by conversion of an FXa-specific fluorogenic substrate. The overlay of the crystal structures of KD1-KD2/JBT-B5 and the NTermKD1/JBT-A7 complexes revealed non-overlapping epitopes and close proximity of the termini of both peptides. The distance could be bridged by an approximately ten amino acid linker. A fusion peptide with a 10-serine-linker was synthesized and showed highly improved dissociation in Biacore experiments and most efficiently inhibited TFPI activity in the model assays. In contrast, single peptides only partially inhibit TFPI especially at high TFPI concentrations. In thrombin generation assays using hemophilia plasma, the fusion peptide showed a substantially higher ability than the single peptides to increase the thrombin peak even at elevated TFPI. The fusion peptide efficiently inhibited TFPI released from platelets and improved thrombin generation in TFPI deficient plasma reconstituted with platelets as the only source of TFPI released upon platelet activation. The fusion peptide was also shown to bind TFPI on the surface of living HUVECs. This is consistent with its binding epitopes on KD1 and KD2 which result in inhibition of cell surface TFPI in a cell based FX activation assay. Thus, we demonstrate that a molecular fusion peptide most efficiently inhibits all physiologic forms of TFPI. X-ray structures of binary and ternary peptide TFPI complexes provided atomic details for linking two single peptides to generate a fusion peptide that most efficiently blocks TFPI in plasma, released from platelets and associated with endothelial cells. It most efficiently neutralizes TFPI even at substantially elevated concentrations occurring at sites of platelet activation. Our observations support the notion that targeting TFPI with TFPI inhibitors is a promising novel strategy to mitigate the bleeding risk in hemophilia patients. Disclosures: Dockal: Baxter Innovations GmbH, Vienna, Austria: Employment. Hartmann:Baxter Innovations GmbH, Vienna, Austria: Employment. Polakowski:3B Pharmaceuticals, Berlin, Germany: Employment. Brandstetter:Baxter Innovations GmbH, Vienna, Austria: Research Funding. Kammlander:Baxter Innovations GmbH, Vienna, Austria: Employment. Panholzer:Baxter Innovations GmbH, Vienna, Austria: Employment. Redl:Baxter Innovations GmbH, Vienna, Austria: Employment. Osterkamp:3B Pharmaceuticals, Berlin, Germany: Employment. Rosing:Baxter Innovations GmbH, Vienna, Austria: Consultancy, Research Funding. Scheiflinger:Baxter Innovations GmbH, Vienna, Austria: Employment.

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