Orth an der Donau, Austria
Orth an der Donau, Austria

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Havlik M.,Vienna University of Technology | Marchetti-Deschmann M.,Vienna University of Technology | Friedbacher G.,Vienna University of Technology | Winkler W.,Vienna University of Technology | And 4 more authors.
Analytical Chemistry | Year: 2015

Biophysical properties including particle size distribution, integrity, and shape of whole virus vaccine particles at different stages in tick-borne encephalitis (TBE) vaccines formulation were analyzed by a new set of methods. Size-exclusion chromatography (SEC) was used as a conservative sample preparation for vaccine particle fractionation and gas-phase electrophoretic mobility macromolecular analyzer (GEMMA) for analyzing electrophoretic mobility diameters of isolated TBE virions. The derived particle diameter was then correlated with molecular weight. The diameter of the TBE virions determined after SEC by GEMMA instrumentation was 46.8 ± 1.1 nm. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were implemented for comparison purposes and to gain morphological information on the virion particle. Western blotting (Dot Blot) as an immunological method confirmed biological activity of the particles at various stages of the developed analytical strategy. AFM and TEM measurements revealed higher diameters with much higher SD for a limited number of virions, 60.4 ± 8.5 and 53.5 ± 5.3 nm, respectively. GEMMA instrumentation was also used for fractionation of virions with specifically selected diameters in the gas-phase, which were finally collected by means of an electrostatic sampler. At that point (i.e., after particle collection), AFM and TEM showed that the sampled virions were still intact, exhibiting a narrow size distribution (i.e., 59.8 ± 7.8 nm for AFM and 47.5 ± 5.2 nm for TEM images), and most importantly, dot blotting confirmed immunological activity of the collected samples. Furthermore dimers and virion artifacts were detected, too. (Graph Presented). © 2015 American Chemical Society.


Bonazza K.,Vienna University of Technology | Rottensteiner H.,Baxalta Innovations | Schrenk G.,Baxalta Innovations | Frank J.,Vienna University of Technology | And 4 more authors.
Analytical Chemistry | Year: 2015

Vital functions of mammals are only possible due to the behavior of blood to coagulate most efficiently in vessels with particularly high wall shear rates. This is caused by the functional changes of the von Willebrand Factor (VWF), which mediates coagulation of blood platelets (primary hemostasis) especially when it is stretched under shear stress. Our data show that shear stretching also affects other functions of VWF: Using a customized device to simulate shear conditions and to conserve the VWF molecules in their unstable, elongated conformation, we visualize at single molecule level by AFM that VWF is preferentially cleaved by the protease ADAMTS13 at higher shear rates. In contrast to this high shear-rate-selective behavior, VWF binds FVIII more effectively only below a critical shear rate of ∼30.000 s-1, indicating that under harsh shear conditions FVIII is released from its carrier protein. This may be required to facilitate delivery of FVIII locally to promote secondary hemostasis. © 2015 American Chemical Society.


PubMed | Baxalta Innovations, Erasmus Medical Center, Institute of Hematology and Transfusion Medicine, Baxalta U.S. Inc and 4 more.
Type: Clinical Trial, Phase III | Journal: Blood | Year: 2015

This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.


PubMed | Baxalta Innovations and Vienna University of Technology
Type: Journal Article | Journal: Analytical chemistry | Year: 2015

Vital functions of mammals are only possible due to the behavior of blood to coagulate most efficiently in vessels with particularly high wall shear rates. This is caused by the functional changes of the von Willebrand Factor (VWF), which mediates coagulation of blood platelets (primary hemostasis) especially when it is stretched under shear stress. Our data show that shear stretching also affects other functions of VWF: Using a customized device to simulate shear conditions and to conserve the VWF molecules in their unstable, elongated conformation, we visualize at single molecule level by AFM that VWF is preferentially cleaved by the protease ADAMTS13 at higher shear rates. In contrast to this high shear-rate-selective behavior, VWF binds FVIII more effectively only below a critical shear rate of 30.000 s(-1), indicating that under harsh shear conditions FVIII is released from its carrier protein. This may be required to facilitate delivery of FVIII locally to promote secondary hemostasis.


PubMed | Baxalta Innovations, Vienna University of Technology and University of Natural Resources and Life Sciences, Vienna
Type: Journal Article | Journal: Analytical chemistry | Year: 2015

Biophysical properties including particle size distribution, integrity, and shape of whole virus vaccine particles at different stages in tick-borne encephalitis (TBE) vaccines formulation were analyzed by a new set of methods. Size-exclusion chromatography (SEC) was used as a conservative sample preparation for vaccine particle fractionation and gas-phase electrophoretic mobility macromolecular analyzer (GEMMA) for analyzing electrophoretic mobility diameters of isolated TBE virions. The derived particle diameter was then correlated with molecular weight. The diameter of the TBE virions determined after SEC by GEMMA instrumentation was 46.8 1.1 nm. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were implemented for comparison purposes and to gain morphological information on the virion particle. Western blotting (Dot Blot) as an immunological method confirmed biological activity of the particles at various stages of the developed analytical strategy. AFM and TEM measurements revealed higher diameters with much higher SD for a limited number of virions, 60.4 8.5 and 53.5 5.3 nm, respectively. GEMMA instrumentation was also used for fractionation of virions with specifically selected diameters in the gas-phase, which were finally collected by means of an electrostatic sampler. At that point (i.e., after particle collection), AFM and TEM showed that the sampled virions were still intact, exhibiting a narrow size distribution (i.e., 59.8 7.8 nm for AFM and 47.5 5.2 nm for TEM images), and most importantly, dot blotting confirmed immunological activity of the collected samples. Furthermore dimers and virion artifacts were detected, too.


PubMed | Erasmus Medical Center and Baxalta Innovations
Type: Journal Article | Journal: Journal of thrombosis and haemostasis : JTH | Year: 2016

Essentials An association between ADAMTS-13 and coronary heart disease (CHD) has been suggested. 5688 participants 55 years from the Rotterdam Study without a history of CHD were included. Over a median follow-up time of 9.7 years, 456 individuals suffered from CHD. Low ADAMTS-13 activity was associated with an increased CHD risk.Background The metalloprotease ADAMTS-13 cleaves high-molecular-weight von Willebrand factor multimers into smaller, less procoagulant forms. Low ADAMTS-13 activity is associated with an increased risk of ischemic stroke but its pathogenic role in coronary heart disease (CHD) is unclear. Objectives We aimed to determine the association between ADAMTS-13 activity and the risk of CHD in a large prospective population-based cohort study. Methods A total of 5688 participants of the Rotterdam Study, a population-based cohort study involving individuals aged 55 years without a history of CHD, were included. ADAMTS-13 activity was measured by the FRETS-VWF73 assay and VWF:Ag levels by ELISA. We assessed the association between ADAMTS-13 activity, VWF:Ag levels and CHD using Cox proportional hazard regression analysis, adjusting for cardiovascular risk factors. Results Over a median follow-up time of 9.7 years, 456 individuals suffered from CHD. A low ADAMTS-13 activity (quartile 1) was associated with an increased CHD risk (HR 1.42, 95% CI 1.07-1.89) compared with the reference highest quartile. Conclusions Low ADAMTS-13 activity is associated with an increased risk of CHD in the elderly, independently of VWF and established cardiovascular risk factors.

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