Recombinant Porcine Factor VIII Corrects Thrombin Generation and Improves Clot Structure In Vitro in Plasma Containing Anti-Factor VIII Inhibitory Antibodies

Abstract Abstract 2282 Introduction: Treatment of bleeding episodes in patients with hemophilia A who have developed inhibitory antibodies can be challenging. Using human factor VIII (FVIII) and, historically, porcine FVIII in patients with a low inhibitor titer are therapeutic options, and provide ease of monitoring. A B-domain deleted recombinant porcine FVIII (rpFVIII; OBI-1), which may possess low cross-reactivity to anti-human FVIII antibodies, is being investigated for the treatment of bleeding episodes in individuals with congenital hemophilia A and inhibitors, and in those with acquired hemophilia. The in vitro capacity of this molecule to correct hemostasis has been further characterized. Methods: This is an international, multicenter in vitro study. Individuals with hemophilia A and inhibitor antibodies were recruited during routine out-patient visits between January 2011 and March 2011. Written and signed informed consent was obtained prior to venepuncture. Blood was obtained from volunteers with congenital hemophilia A and inhibitors attending routine visits at participating hemophilia treatment centers. A single blood sample was obtained from consenting individuals under protocols approved by Institutional Review Boards/Ethical Committees. In vitro spiking experiments with OBI-1 were conducted using FVIII-deficient plasma with and without anti-FVIII inhibitory activity. Three control inhibitor plasmas were provided, composed of FVIII deficient plasma to which the anti-C1 monoclonal antibody (MAb) to human FVIII (Sanquin, Amsterdam, the Netherlands) was added at two concentrations to reach anti-human FVIII inhibitory activity of 4.9 Bethesda Units (BU)/mL and 32.8 BU/mL with anti-porcine anti-FVIII inhibitory activity of 2.7 BU/mL and 19.1 BU/mL, respectively; and FVIII deficient plasma to which “polyclonal” mixture of the anti-C1 MAb, along with an anti-A2 and 2 anti-C2 MAbs was added. Plasma from eight patients with hemophilia A and inhibitors was tested. Hemostatic correction by OBI-1 was assessed by thrombin generation measurement (Calibrated Analytical Thrombography assay, Synapse BV, Maastricht, The Netherlands) and clot structure using electron microscopy. Epitope mapping of the inhibitor patient plasma was undertaken at a central laboratory (Atlanta, Georgia, USA) using an Enzyme-Linked Immunosorbent Assay (ELISA) with human/porcine FVIII hybrids as the antigen. Results: The results showed a dose-dependent and anti-porcine titer dependent correction of thrombin generation parameters (peak and ETP) with OBI-1 at concentrations equivalent to 100 IU/dL, 200 IU/dL, and 400 IU/dL, which paralleled a correction of the clot structure (number and diameter of fibrin fibres). These results were only dependent on the anti-porcine titer. In samples with high titers of anti-porcine inhibitor (&gt;10 BU), little or no restoration of the diminished thrombin generation was observed when various OBI-1 concentrations were added to the plasma. In the plasmas with high anti-human titers (≥10 BU/mL) the dominant epitope was C2 in 3 plasmas, A2 in 1 plasma, and indeterminate in 3 plasmas. The plasmas with no restoration of the thrombin generation with even the highest dose of OBI-1 all had antibody detected to more than one domain of FVIII or were not able to be mapped due to high porcine cross-reactivity. Conclusion: In vitro data obtained with spiking experiments using OBI-1 indicate that it has the potential to correct surrogate markers of hemostasis depending on the anti-porcine FVIII titer which may translate into in vivo effectiveness. Further investigation into the epitope specificity of responsive and non-responsive inhibitor plasmas correlation with effectiveness is warranted. Disclosures: Negrier: Inspiration Biopharmaceuticals: Honoraria, Research Funding. Meeks:Inspiration Biopharmaceuticals: Research Funding. Oldenburg:SOBI: Membership on an entity's Board of Directors or advisory committees; Catalyst: Membership on an entity's Board of Directors or advisory committees; Inspiration: Consultancy, Honoraria, Research Funding; LFB: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria; Octapharma: Consultancy, Honoraria, Research Funding. Bordet:Inspiration Biopharmaceuticals: Research Funding. Poetzsch:Inspiration Biopharmaceuticals: Research Funding. Al Dieri:Synapse BV: Employment. Dargaud:Inspiration Biopharmaceuticals: Research Funding. Hemker:Synapse BV: Employment. Eckmann:Sanquin Diagnostic Services: Employment. Gomperts:Inspiration Biopharmaceuticals: Employment. Lee:Inspiration Biopharmaceuticals: Employment. </jats:sec

Randomized Controlled Trial of Radiation Protection With a Patient Lead Shield and a Novel, Nonlead Surgical Cap for Operators Performing Coronary Angiography or Intervention

Background— Interventional cardiologists receive one of the highest levels of annual occupational radiation exposure. Further measures to protect healthcare workers are needed. Methods and Results— We evaluated the efficacy of a pelvic lead shield and a novel surgical cap in reducing operators’ radiation exposure. Patients undergoing coronary angiography or percutaneous coronary intervention (n=230) were randomized to have their procedure with or without a lead shield (Ultraray Medical, Oakville, Canada) placed over the patient. During all procedures, operators wore the No Brainer surgical cap (Worldwide Innovations and Technology, Kansas City, KS) designed to protect the head from radiation exposure. The coprimary outcomes for the lead shield comparison were (1) operator dose (µSv) and (2) operator dose indexed for air kerma (µSv/mGy). For the cap comparison, the primary outcome was the difference between total radiation dose (µSv; internal and external to cap). The lead shield use resulted in a 76% reduction in operator dose (mean dose, 3.07; 95% confidence interval [CI], 2.00–4.71 µSv lead shield group versus 12.57; 95% CI, 8.14–19.40 µSv control group; P &lt;0.001). The mean dose indexed for air kerma was reduced by 72% (0.004; 95% CI, 0.003–0.005 µSv/mGy lead shield group versus 0.015; 95% CI, 0.012–0.019 µSv/mGy control group; P &lt;0.001). The cap use resulted in a significant reduction in operator head radiation exposure (mean left temporal difference [external–internal] radiation dose was 4.79 [95% CI, 3.30–6.68] µSv; P &lt;0.001). Conclusions— The use of a pelvic lead shield and the cap reduced significantly the operator radiation exposure and can be easily incorporated into clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02128035. </jats:sec

FINDING DISTANT GALACTIC H ii REGIONS

The WISE Catalog of Galactic HII Regions contains $\sim2000$ HII region candidates lacking ionized gas spectroscopic observations. All candidates have the characteristic HII region mid-infrared morphology of WISE $12\,\,\mu\,m$ emission surrounding $22\,\mu\,m$ emission, and additionally have detected radio continuum emission. We here report Green Bank Telescope (GBT) hydrogen radio recombination line (RRL) and radio continuum detections at X-band (9GHz; 3cm) of 302 WISE HII region candidates (out of 324 targets observed) in the zone $225^{\circ} > l > -20^{\circ}$, $|b| \le 6^{\circ}$. Here we extend the sky coverage of our HII region Discovery Survey (HRDS), which now contains nearly 800 HII regions distributed across the entire northern sky. We provide LSR velocities for the 302 detections and kinematic distances for 131 of these. Of the 302 new detections, five have ($l, b, v$) coordinates consistent with the Outer Scutum-Centaurus Arm (OSC), the most distant molecular spiral arm of the Milky Way. Due to the Galactic warp, these nebulae are found at Galactic latitudes $>1^{\circ}$ in the first Galactic quadrant, and therefore were missed in previous surveys of the Galactic plane. One additional region has a longitude and velocity consistent with the OSC but lies at a negative Galactic latitude (G039.183$-$01.422; $-$54.9 kms). With Heliocentric distances >22 kpc and Galactocentric distances >16 kpc, the OSC HII regions are the most distant known in the Galaxy. We detect an additional three HII regions near $l \simeq 150^{\circ}$ whose LSR velocities place them at Galactocentric radii >19 kpc. If their distances are correct, these nebulae may represent the limit to Galactic massive star formation.Comment: Accepted by ApJS; 30 pages, 6 figures, 6 tables Check out the data here: http://astro.phys.wvu.edu/wise/ and here: http://www.cv.nrao.edu/hrds