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Introduction Tissue factor pathway inhibitor (TFPI) is an important inhibitor of the extrinsic coagulation pathway as it inhibits factor Xa (FXa) and the tissue factor (TF) – FVIIa complex. Inhibition of TFPI with blocking antibodies, aptamers, or peptide inhibitors improves hemostasis and may become an option to treat patients with hemophilia including those with inhibitors. We developed a TFPI-antagonistic fusion peptide (FP) consisting of a linear and a cyclic peptide connected by a linker. The two peptide entities bind to different epitopes on TFPI and together synergistically inhibit TFPI. The FP was further improved by half-life extending (HL) non-covalent albumin binding. HL-FP was characterized for in vitroinhibition of TFPI, pharmacokinetics, and improvement of coagulation in animal models of hemophilia. Methods HL-FP was characterized in a set of in vitro assays for binding to and inhibition of TFPI. Interaction with immobilized TFPI was studied by BiaCore. Functional inhibition was analyzed in model assay systems such as inhibition of FXa and FX activation by TF/FVIIa and plasma assays according to the calibrated automated thrombography (CAT) protocol at low TF in hemophilia plasma. Addition of TFPI simulated conditions of potentially elevated TFPI plasma concentrations. In a single dose PK study, mice (n=6 per time point) received 400 nmol/kg of the HL-FP intravenously (i.v.) or subcutaneously (s.c.). Plasma was sampled up to 38 h after dosing and HL-FP level quantified by a compound specific LC-MS protocol. To provide an ex vivo activity measure, FVIII inhibitory antibodies were added to mouse plasma to mimic a hemophilic condition and then analyzed by calibrated automated thrombography (CAT). A 2-week repeated i.v. dose study in mice investigated TFPI accumulation due to HL-FP. HL-FP was dosed at 40, 400, and 2000 nmol/kg and mouse plasma TFPI levels determined by ELISA. The efficacy of the HL-FP was studied in a hemophilia A mouse tail cut model and in a marmoset monkey model of ex vivoimprovement of coagulation. FVIII knockout mice (n=16 per group) were dosed i.v. with 12-400 nmol/kg HL-FP in the presence of a sub-therapeutic level of recombinant FVIII (10 U/kg) and blood loss (mg) was assessed. Marmoset monkeys (N=4) received 400 nmol/kg HL-FP i.v. and plasma samples obtained 1 h after dosing were analyzed by CAT in the presence of FVIII inhibitory antibodies. Results HL-FP bound to and efficiently inhibited TFPI as demonstrated in several in vitro test systems. Binding affinity of < 1nM correlated well with functional inhibition of TFPI in model assays, resulting in IC50s of ~0.7nM. The HL-fusion peptide (HL-FP) efficiently inhibited plasma TFPI, which resulted in an improvement of all thrombin generation parameters in plasma of hemophilia A and B patients, with EC50s ranging from 6 to 20nM. HL-FP increased peak thrombin levels of hemophilia plasma to or slightly above a range established for individual normal plasma. Non-covalent binding to albumin substantially increased the half-life to ~4 h with ~ 50% s.c. bioavailability in mice. The ex vivo procoagulant activity determined by CAT correlated well with HL-FP plasma concentrations. In the repeated dose study, the HL-FP was well tolerated and did not accumulate TFPI, which strongly indicates that HL-FP did not interfere with TFPI clearance receptor interactions. HL-FP significantly reduced bleeding in the hemophilia mouse tail cut bleeding model at a dose as low as 40 nmol/kg. In marmoset monkeys, HL-FP efficiently improved ex vivo plasma thrombin generation, even at low peptide plasma concentrations (25- 55 nM). Summary We developed a TFPI inhibitor composed of two TFPI antagonistic peptides that completely inhibits TFPI. Introduction of an entity non-covalently bound to albumin provides intermediate half-life extension and s.c. bioavailability. This HL-FP improved coagulation and hemostasis in animal models of hemophilia and did not interfere with TFPI clearance receptor interactions. TFPI-antagonistic peptides with a prolonged half-life, resistance to elevated TFPI, and minimal interference with TFPI clearance. Our HL-FP appears to be useful in preventing bleeding in hemophilia and provides a FVIII and FIX independent approach for non-i.v. treatment. Disclosures Dockal: Baxter Innovations GmbH, Vienna, Austria: Employment. Hartmann:Baxter Innovations GmbH, Vienna, Austria: Employment. Polakowski:3B Pharmaceuticals GmbH, Berlin, Germany: Employment. Panholzer:Baxter Innovations GmbH, Vienna, Austria: Employment. Kammlander:Baxter Innovations GmbH, Vienna, Austria: Employment. Osterkamp:3B Pharmaceuticals, Berlin, Germany: Employment. Reineke:3B Pharmaceuticals GmbH, Berlin, Germany: Employment. Schiviz:Baxter Innovations GmbH, Vienna, Austria: Employment. Hoellriegl:Baxter Innovations GmbH, Vienna, Austria: Employment. Scheiflinger:Baxter Innovations GmbH, Vienna, Austria: Employment.

Abstract 2216 Baxter is currently developing a recombinant ADAMTS13 (rADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) product for potential prophylaxis and treatment of thrombotic thrombocytopenic purpura (TTP). We established a disease model in ADAMTS13 ko mice (B6.129-ADAMTS13tm1Dgi), in which the animals simultaneously and consistently develop TTP-like symptoms by challenge with a high dose of human recombinant von Willebrand factor (rVWF) containing ultra-large VWF multimers. To test the prophylactic efficacy of Baxter's rADAMTS13, groups of 10 ADAMTS13 ko mice received single doses of rADAMTS13 (1, 5, 40, 80 or 200U/kg) before challenge with rVWF. Doses of 1 and 5mL/kg fresh frozen plasma corresponding to 1 and 5U/kg ADAMTS13 served as positive controls. In a second study, the prophylactic and therapeutic efficacy of Baxter's rADAMTS13 was tested over time. Groups of 10 ADAMTS13 ko mice received a single dose of 200 FRETS-U/kg rADAMTS13 5min-120h before, or 15–180min after challenge with rVWF. In both studies, buffer was used as a negative control. Efficacy was defined as the degree of prevention of platelet drop and LDH increase. Schistocytosis and organ damage were also assessed. Morbidity in negative controls was 100%: all animals receiving rVWF containing ultra-large VWF multimers were severely thrombocytopenic, showed increased LDH levels, schistocytosis and organ damage. Prophylactic treatment with rADAMTS13 prevented LDH increase (p Efficacy of rADAMTS13 was treatment interval-dependent in both studies. Platelet count at termination of all rADAMTS13-treated animals was statistically higher than that of buffer-treated controls (p≤0.0001). However, animals receiving prophylactic treatment 120h before administration of rVWF showed severe thrombocytopenia; clinically relevant protection was only seen with treatment intervals ≤72h. Therapeutic treatment with rADAMTS13 stabilized platelet count and prevented further thrombocytopenia. LDH, schistocytosis and organ damage confirmed the treatment interval-dependent improvement in platelet count. In summary, Baxter's rADAMTS13 was effective in an rVWF-induced animal model closely mimicking the situation in patients with hereditary TTP. Comparison with FFP, the current standard of treatment of TTP, showed Baxter's rADAMTS13 to have similar or slightly improved efficacy. Disclosures: Schiviz: Baxter Innovations GmbH: Employment. Resch:Baxter Innovations GmbH: Employment. Farnleitner:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Abstract 2233 Baxter has developed a new recombinant factor IX (rFIX) product (BAX 326) for treating patients with hemophilia B. The aim of the presented studies was to evaluate the function, safety and efficacy of BAX 326 compared to a commercially available rFIX regarding differences in activated FIX (FIXa) content. The FIXa concentration of BAX 326 was about 10 fold less than that of a commercial rFIX product. To address the influence of FIXa on functional FIX in vitro assays, the FIXa concentration of BAX 326 was increased. Samples were analyzed by one-stage clotting assay, non-activated partial thromboplastin time assay and thrombin generation assay. In all three assays, FIXa affected the potency determination for FIX, indicating that rFIX products should preferentially contain a low FIXa content. The thrombogenic potential of BAX 326 was assessed in rabbits using a modified Wessler Test at 750 IU/kg (10-fold human clinical dose). No thrombogenic potential was observed with BAX 326 (individual scores of 0), whereas the mean score for the commercially available rFIX was 0.5. After increasing the FIXa concentration of BAX 326 to equalize it with the commercially available rFIX, a mean score of 0.42 (individual scores 0 – 0.5) was determined. These data strongly suggest that the differences in preclinical thrombogenicity were caused by the higher FIXa content of the commercially available rFIX, thereby confirming earlier findings [1]. Efficacy of the rFIX products was studied in hemophilia B (FIX ko) mice that received prophylactic treatment with 75 IU/kg of BAX 326 or the commercially available rFIX. Treated animals were analyzed in two primary pharmacodynamic models: a carotid occlusion model and one using thrombelastography. In both models, results for the two groups were similar, demonstrating that despite its lower FIXa content, BAX 326 was as efficacious as a commercially available rFIX at 75 IU/kg (p Disclosures: Auer: Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Schrenk:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Abstract 4346 The pharmacokinetic profile of BAX 855, a longer acting PEGylated variant of Baxter’s recombinant FVIII based on the ADVATE™ manufacturing process, was assessed in comparison to ADVATE™ after a single intravenous bolus injection at a target dose of 200 IU/kg BW in mice and rats and 350 IU/kg BW in cynomolgus monkeys. Mean residence time (MRT), terminal half-life (HL), total clearance standardized per kg body mass (Cl), the AUC0-tlast (the area under the concentration vs. time curve from 0 to the last measured time point), the in vivo recovery (IVR) and volume of distribution at steady state (Vss) for FVIII activity (mice and cynomolgus monkey), FVIII antigen (rats) and FVIII-bound PEG were evaluated in all three models. Blood was sampled at baseline and each of the time points after a single intravenous bolus injection of BAX 855 or ADVATE™. A serial sacrifice design was used for the PK in mice. Sixteen FVIII ko mice (B6;129S4-F8tm2Kaz; m/f) for BAX 855 and eight FVIII ko mice for ADVATE™ per time point were bled by cardiac puncture under anesthesia for blood sampling 5 minutes – 48 hours after a single intravenous bolus injection. A single treatment design was used for the single dose PK in Sprague Dawley rats: 8m + 8f for BAX 855 and 4m + 4f for ADVATE™. A single treatment design was also used for the cynomolgus monkeys: 4m + 4f for BAX 855 and 2m + 2f for ADVATE™. Blood samples were drawn from rats and cynomolgus monkeys for citrated plasma (for analysis of baseline FVIII levels) before administration and 5 minutes - 48 hours (rats) and 5 minutes to 96 hours (cynomolgus monkeys) after administration. The citrated plasma samples were analyzed for FVIII activity (chromogenic assay) in mice and cynomolgus monkeys, for FVIII–bound PEG (using a PEG-FVIII ELISA) in all models and FVIII antigen (using a FVIII ELISA) in rats. In all three models a prolongation in MRT of Baxter’s and Nektar’s new BAX 855 compared with ADVATE™ could be demonstrated. FVIII activity analysis showed an increase of MRT in mice from 4.9 to 7.9 hours and in cynomlogus monkeys from 7.5 to 11.5 hours. This prolongation was also reflected in the terminal half-lives (4.3 to 5.9 hours in mice and 5.7 to 9.4 hours in cynomolgus monkeys). According to this prolongation a lower clearance [mL/h/kg] could be observed for BAX 855 than for ADVATE™ (22.1 to 12.2 in mice and 8.1 to 4.9 in monkeys). Similar levels in all PK parameters could be shown when measuring FVIII-bound PEG in all three preclinical models and FVIII antigen analysis in rats. These PK data provide evidence that PEGylation of human rFVIII increases the circulation time. Disclosures: Hoebarth: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Wolfsegger:Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Weber:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Schwarz:Baxter BioScience: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

Abstract 24 Tissue factor pathway inhibitor (TFPI) is an activated (a) factor X (FXa)-dependent inhibitor of the extrinsic factor X (FX) activation complex and efficiently regulates the extrinsic pathway of coagulation. We are developing peptide inhibitors of TFPI with a view to improving hemostasis in hemophilia. The goal is to inhibit the interaction of TFPI with the factor Xa (FXa)-tissue factor (TF)-factor VIIa (FVIIa) complex, and thereby enhance thrombin formation to the extent that a stable clot is formed. Successful development of these peptides could allow treatment of hemophilia via a non-intravenous route of administration. By screening mRNA display libraries, we identified a de novo peptide which binds to and efficiently inhibit TFPI. The peptide was optimized by iterative amino acid substitution resulting in affinity-improved peptide with a well-characterized structure-activity relation. The affinity of the peptide was analyzed by Biacore and ELISA experiments. One of our optimized peptides bound to immobilized TFPI with an affinity below 1 nM. Kunitz domain 1 of TFPI was identified as the interaction site by NMR studies. We characterized the inhibitory activity of this TFPI binding peptide using in vitro model assay systems including inhibition of FXa and of the extrinsic tenase (TF-FVIIa-PL-Ca2+ complex). Inhibition of cell-associated TFPI was verified in a TF- and TFPI-dependent cell-based assay using TNFalpha-stimulated human umbilical vein endothelial cells (HUVECs) as a source of TF and TFPI. Inhibition of plasma TFPI was probed by thrombin generation experiments using FVIII-deficient patient plasma and ROTEM experiments using FVIII-inhibited whole blood. Furthermore, a cross-reactivity of the peptide to murine TFPI was demonstrated in thrombin generation experiments and in murine FXa inhibition model assays. Conjugation of a 40-kDa polyethyleneglycol (PEG) to the peptide base structure resulted in a peptide with significantly reduced renal clearance. The in vivo terminal half-life of this 40kD-PEG modified peptide was 21.5h and 19.8h after 1 mg/kg i.v and s.c. administration, respectively, with 73% bioavailability after s.c. administration. In a tail-tip bleeding model, administration of an anti-murine-TFPI antibody and 40kD-PEG-peptide in combination with sub-therapeutical doses of recombinant coagulation factors (10 IU/kg of rFVIII in FVIII ko mice and rFIX in FIX ko mice) led to a marked reduction of blood loss compared with buffer-treated or rFVIII/rFIX-treated mice. In addition, we established a murine nail-cut model using C57Bl6 wild-type mice for testing in vivo efficacy in a normal FVIII background as well. The TFPI sensitivity of the nail-cut model was verified by an anti-murine TFPI antibody. 40kD-PEG-peptide significantly reduced blood loss after i.v. and s.c. administration in all treatment groups compared with vehicle-treated animals. Furthermore, the i.v. administration of the peptide was well tolerated in all animals across all treatment groups without any signs of acute toxicity. In conclusion, we identified a low-molecular-weight peptide which efficiently inhibit all forms of naturally occurring TFPI proteins, including plasma TFPI and TFPI in vivo. Our results demonstrate that targeting TFPI efficiently improves hemostasis in hemophilia and provide an in vivo proof of concept for a non i.v. route of administration. Thus, the TFPI inhibitory peptides could be useful to prevent bleeding in hemophilia patients. Moreover, this new approach would probably allow treatment of inhibitor patients. Disclosures: Dockal: Baxter Innovations GmbH: Employment. Hartmann:Baxter Innovations GmbH: Employment. Polakowski:3B Pharmaceuticals GmbH: Employment. Frank:3B Pharmaceuticals GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment. Reinecke:3B Pharmaceuticals GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.

Abstract 4350 Factor VIII (FVIII) is a critical component of the intrinsic coagulation pathway. FVIII concentrates are used in patients with hemophilia A to provide a hemostatic FVIII level sufficient to treat and prevent bleeding episodes. Multiple prophylactic administrations per week are necessary to maintain a FVIII level of at least 1% of normal to effectively prevent or reduce spontaneous bleeding episodes. A longer acting FVIII concentrate would reduce the frequency of infusions. Baxter and Nektar have developed a longer-acting PEGylated variant (BAX 855) of Baxter’s recombinant FVIII (ADVATE process). The aim of the presented studies was to evaluate the efficacy of BAX 855 in two primary pharmacodynamics in hemophilia A mice: a tail-tip bleeding model (TTBM) and a carotid occlusion model (COM). BAX 855 was tested at a dose of 200 IU/kg rFVIII. ADVATE™ served as the active reference item, and formulation buffer as the negative control item. Mice received intravenous treatment with either BAX 855 or ADVATE™ 12–40h prior to the experiment. Buffer was administered 5–15min prior to the experiment. Animals were anesthetized using ketamine and xylazine. In the TTBM (n=16) the tip of the tail was cut off and total blood loss [mg] was assessed over 60 minutes. In the COM study (n=10) the left carotid artery was exposed and the endothelium was denuded by topical application of FeCl3. Time to occlusion [min] was assessed. Buffer-treated animals had a median blood loss of 951 mg in the TTBM and did not show vessel occlusion within 30 min in the COM. In the TTBM, a prophylactic effect of ADVATE™ could be observed for up to 18 h, leading to a reduction in blood loss to 121 mg after this treatment interval. Prophylactic efficacy after treatment with BAX 855 could be observed for up to 40 h with a median blood loss of 73 mg after 30 h and 436 mg after 40 h. In the COM, treatment with ADVATE™ 12 h before the experiment shortened the time to occlusion to 3.8 min. With BAX 855, a similar efficacy could be observed for up to 24 h after administration (5.2 min). In summary, the results of our studies show that BAX 855 is efficacious in these two mouse models of hemophilia A and that the efficacy of BAX 855 is prolonged compared with an unmodified rFVIII. Furthermore, the intravenous injection of BAX 855 was well tolerated in all animals across all treatment groups without any signs of acute toxicity. Disclosures: Schiviz: Baxter Innovations GmbH: Employment. Barbara:Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment.

Abstract 2262 Fucoidans are sulfated polysaccharides extracted and purified from brown seaweeds. Described as non-anticoagulant polysaccharides (NASPs), they have been shown to improve clotting in FVIII- and FIX-deficient plasma (Liu et al. Thromb Haemost 2006;95:68), making them good candidates for hemophilia treatment. NASP orally administered to hemophilia A dogs over several weeks resulted in correction to normal ranges in thromboelastography (TEG) parameters and improvement of the cuticle bleeding time (Prasad et al. Blood 2008;111:672). We screened extracts of eleven brown algae species to select the most active, high-quality, homogeneous fucoidan. In-depth structural analysis and assessment of the pro-/anticoagulant and TFPI-inhibiting activities of a selected set of fucoidan preparations was performed. The effect of the best fucoidan candidate was studied in a novel guinea pig model by whole blood TEG monitoring supported by calibrated automated thrombographic (CAT) analysis. Comparative structural studies of fucoidans included monosaccharide composition and elemental analysis, molecular weight and overall structural determination by NMR. 13C-NMR spectroscopy gave a comprehensive picture of fucoidan structure including fucose and alginate content and the relative heterogeneity of the preparation distinguishing between fucoidans of different algae species. Heterogeneity of the materials was highest in U. pinnatifida and L. japonica and lowest in F. vesiculosus (F.v.) samples. Procoagualant activity was shown by CAT and rotation thromboelastometry. Clotting parameters of FVIII-inhibited human blood or plasma were corrected to normal levels at 1 and 3 μg/mL depending on the fucoidan. In addition, the fucoidans were analyzed by BiaCore and a modified dilute prothrombin time assay to show binding to TFPI and inhibition of full-length TFPI activity. The screening process supported the identification and optimization of new fucoidan-specific analytical methods. Furthermore, a CAT protocol optimized for guinea pig plasma was used to show the procoagulant effect of the overall best fucoidan candidate. We spiked F.v. fucoidan into FVIII-inhibited guinea pig plasma between 1 and 100μg/mL and triggered thrombin generation with low amounts of tissue factor. The FVIII-inhibited guinea pig plasma was corrected to normal CAT parameters at ∼30μg/mL NASP. Based on our findings in the CAT assay, we designed a dosage pattern for studying the procoagulant effect using TEG in FVIII-inhibited Dunkin Hartley guinea pigs (n=10) after intravenous administration of 0.1 to 1.6mg/kg NASP. The primary endpoint assessed was R-time (time to clotting). FVIII-inhibited guinea pigs showed a median R-time of ≥120min (no clotting), while R-time was reduced in a non-linear dose-dependent manner after administration of NASP down to 69min (0.4mg/kg NASP). Thus, the results generated in in vitro tests, were confirmed in vivo. This new animal model of induced hemophilia will support the development of alternative hemophilia therapeutics. Disclosures: Dockal: Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Zhang:Baxter Healthcare Corporation: Employment. Till:Baxter Innovations GmbH: Employment. Knappe:Baxter Innovations GmbH: Employment. Palige:Baxter Innovations GmbH: Employment. Schiviz:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Szabo:Baxter Healthcare Corporation: Employment. Muchitsch:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.

Abstract 4659 Baxter has developed a recombinant FVIIa (rFVIIa) product for the treatment of patients with hemophilia A and hemophilia B with inhibitors. The aim of the presented preclinical studies was to evaluate the efficacy of Baxter's rFVIIa. Four animal models that are considered to relevantly reflect the conditions in different patient populations were used: hemophilia A (FVIII ko) mice, hemophilia B (FIX ko) mice, factor VIII (FVIII)-inhibited rabbits and warfarin-pretreated rats. In all studies, Baxter's rFVIIa was tested at different doses to obtain dose-effect curves. A commercially available rFVIIa served as the active control item, buffer served as the negative control item. All test and control items were administered intravenously. Mice received prophylactic treatment 5 minutes prior to start of the experiment, rabbits and rats received therapeutic treatment after the injuries were inflicted. Twenty FVIII ko mice (B6;129S4-F8tm1Kaz; 10m/10f) and 20 FIX ko mice (B6;129P2-F9tm1Dws; 10m/10f) per group were used in a tail-tip bleeding model. Baxter's rFVIIa was tested at doses of 0.6, 1.2 and 2.7 mg/kg, the active control item was tested at a dose of 2.7 mg/kg. Ten FVIII ko mice (B6;129S4-F8tm1Kaz; 5m/5f) per group were used to assess the influence of rFVIIa on the thrombelastogram of hemophilic mice. Both items were tested at doses of 0.1, 0.6 and 1.2 mg/kg. Six rabbits (New Zealand White; 6m) per group were used in a nail-cut model. The animals were pretreated with a goat polyclonal FVIII-antibody (34,000 BU/kg i.v., 45 minutes prior to start of the experiment), leading to deficiency of endogenous FVIII. Baxter's new rFVIIa was tested at doses of 0.1, 1.0, 2.0, 2.5 and 3.0 mg/kg, the active control item at 2.0 mg/kg. Six rats (Sprague Dawley; 6m) per group were used in a tail-tip bleeding model. The animals were pretreated with warfarin (11 mg p.o., 1 day prior to start of the experiment), leading to a deficiency of vitamin K-dependent coagulation factors II, VII, IX and X, protein C and protein S. Baxter's new rFVIIa was tested at 0.25, 1.0 and 2.0 mg/kg, the active control item at 2.0 mg/kg. A dose-dependent hemostatic effect of Baxter's new rFVIIa could be shown in all primary pharmacodynamic studies performed. Furthermore, statistical evaluation of the efficacy of Baxter's new rFVIIa did not reveal any statistically significant differences from the commercially available rFVIIa product after treatment at the same doses. In summary, the results of our studies show that Baxter's new rFVIIa is prophylactically and therapeutically effective in animal models of efficacy closely reflecting the conditions in hemophiliacs with inhibitors and patients suffering from FVII-deficiency. Disclosures: Schiviz: Baxter Innovations GmbH: Employment. Lawo:Baxter Innovations GmbH: Employment. Resch:Baxter Innovations GmbH: Employment. Leidenmuehler:Baxter Innovations GmbH: Employment. Bischetsrieder:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Hoellriegl:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.

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). Arterial needle holes were created in the femoral arteries of anesthetized rabbits and hepatic lesions were created into hepatic parenchyma of anesthetized pigs. Both models were heparinized to mimic clinical comorbidity. Results: In the leporine vascular surgical model, PCC provided superior hemostatic success compared to ORC at 2 min (Odds Ratio of Success: 85, 95% CI: 25.8–282) and similar hemostatic success at 10 min. In the porcine hepatic model, PCC provided superior hemostatic success compared to ORC at 2 (98 vs 55%, P