Neutralization of inhibitory antibodies and restoration of therapeutic ADAMTS-13 activity levels in inhibitor-treated rats by the use of defined doses of recombinant ADAMTS-13.

Background: Acquired thrombotic thrombocytopenic purpura (TTP) is caused by an autoantibody-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS-13. Acute episodes of the disease are treated with a combination of immunosuppression and repeated cycles of plasma exchange to remove anti-ADAMTS-13 autoantibodies and, at the same time, replenish functional ADAMTS-13. Although this is often effective, the mortality rate has remained between 10% and 20%, highlighting the need for safer treatment options.

Potential for Recombinant ADAMTS13 as an Effective Therapy for Acquired Thrombotic Thrombocytopenic Purpura.

Objective: The metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) regulates the size of von Willebrand factor multimers. A deficiency in ADAMTS13 activity is associated with the life-threatening disease thrombotic thrombocytopenic purpura (TTP). The vast majority of patients have acquired TTP, where circulating anti-ADAMTS13 autoantibodies are causative for the decreased ADAMTS13 activity.

Porcine recombinant factor VIII (Obizur; OBI-1; BAX801): product characteristics and preclinical profile.

Introduction: Acquired haemophilia A (AHA) is a rare, often severe, auto-immune bleeding disorder caused by the development of inhibitory antibodies (inhibitors) to factor VIII (FVIII). Bypassing agents, recombinant activated FVII or activated prothrombin complex concentrate, are currently recommended as first-line treatments to control bleeding events in patients with AHA.

Aim: A plasma-derived porcine FVIII (Hyate:C, Ipsen, UK) was used as a first-line treatment for AHA but was discontinued in 2004 due to viral safety concerns.

Nonacog gamma, a novel recombinant factor IX with low factor IXa content for treatment and prophylaxis of bleeding episodes.

Nonacog gamma is a new recombinant factor IX to treat factor IX deficiency. It is indicated for control of bleeding episodes, perioperative management and routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia B. Nonacog gamma was first approved in the USA in June 2013 under the trade name RIXUBIS followed by market approvals in Australia and the EU in 2014, and marketing authorization decision is pending in Japan.

Hemostatic efficacy of a novel, PEG-coated collagen pad in clinically relevant animal models.

Purpose: Currently available hemostatic pads are effective in treating oozing bleeds, but otherwise ineffective in more severe bleeding. This study investigates the hemostatic efficacy of a new hemostatic pad with advanced sealing properties using protein-reactive polyethylene glycol-coated collagen (PCC, Hemopatch) versus an oxidized regenerated cellulose (ORC, Tabotamp/Surgicel Original) in a leporine arterial bleeding model of vascular reconstruction and a porcine hepatic model of general surgery.

Methods: In both models, paired lesions were created and treated according to a randomized scheme and evaluated up to 10 min after application (40 lesions/group/model).

Randomized, controlled comparison of advanced hemostatic pads in hepatic surgical models.

Blood loss during hepatic surgery leads to poor patient outcomes. This study investigates the hemostatic efficacy of a novel sealing hemostatic pad (polyethylene glycol-coated collagen, PCC) and a fibrin sealant pad (fibrin-thrombin coated collagen, FTC) in a leporine hepatic segmentectomy and a porcine hepatic abrasion model. A segmentectomy was used to compare hemostatic success and hematoma incidence in 20 rabbits (10/group).

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography.

BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation.

A longer acting recombinant FVIII is expected to serve patients' demand for a more convenient prophylactic therapy. We have developed BAX 855, a PEGylated form of Baxter's rFVIII product ADVATE™ based on the ADVATE™ manufacturing process. The conjugation process for preparing BAX 855 uses a novel PEG reagent.

Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice.

Coronary heart disease is a major cause of death in the western world. Although essential for successful recovery, reperfusion of ischemic myocardium is inevitably associated with reperfusion injury. To investigate a potential protective role of ADAMTS13, a protease cleaving von Willebrand factor multimers, during myocardial ischemia/reperfusion, we used a mouse model of acute myocardial infarction.

A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13.

Deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a VWF-cleaving protease, is the key factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy. It is well established that ADAMTS13 deficiency results in elevated plasma levels of ultra-large VWF multimers (ULVWF), which are prone to induce platelet aggregation; however, the actual trigger of TTP development remains uncertain. Here we describe a new animal model in which some TTP-like symptoms can be triggered in ADAMTS13 knockout mice by challenge with 2000 units/kg body weight of recombinant human VWF containing ULVWF multimers.

T cell-independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist.

Memory B cells are involved in long-term maintenance of antibody-dependent immunologic disorders. Therefore, it is essential to understand how the restimulation of FVIII-specific memory B cells in hemophilia A with FVIII inhibitors is regulated. We asked whether concurrent activation of the innate immune system by an agonist for toll-like receptor (TLR) 7 is able to facilitate the differentiation of FVIII-specific memory B cells in the absence of T-cell help.

Maintenance and break of immune tolerance against human factor VIII in a new transgenic hemophilic mouse model.

Replacement of the missing factor VIII (FVIII) is the current standard of care for patients with hemophilia A. However, the short half-life of FVIII makes frequent treatment necessary. Current efforts focus on the development of longer-acting FVIII concentrates by introducing chemical and genetic modifications to the protein.

Optimization, refinement and reduction of murine in vivo experiments to assess therapeutic approaches for haemophilia A.

The tail cut bleeding model (CUT) is routinely used in factor VIII-deficient mice to assess pharmacodynamic effects of therapeutic strategies for haemophilia A. Results from this model are highly variable, many modifications to the model are reported and at times the animals' wellbeing may be compromised by recording survival as an endpoint. We therefore investigated if the ferric chloride carotid occlusion model (COM) used for thrombosis research can be applied to enhance data quality and animal welfare in haemophilia A research.

Retinal cone topography of artiodactyl mammals: influence of body height and habitat.

This study addresses the correlation of retinal topography with factors such as the visual environment, life style, and behavior for a major mammalian group, the artiodactyls. To provide a broader basis for semiquantitative comparison, short-wavelength-sensitive (S)- and middle-to-long-wavelength-sensitive (M)-opsin cone receptor populations from 25 species from five artiodactyl families and of the African elephant were labeled and sampled. The resulting topographic maps were analyzed with respect to the position and extension of high-density regions.

Independent variation of retinal S and M cone photoreceptor topographies: A survey of four families of mammals.

In mammals, cone photoreceptor subtypes are thought to establish topographies that reflect the species-relevant properties of the visual environment. Middle- to long-wavelength-sensitive (M) cones are the dominant population and in most species they form an area centralis at the visual axis. Short-wavelength-sensitive (S) cone topographies do not always match this pattern.