Background: Direct fXa inhibitors appear to have similar or superior anticoagulant efficacy and safety relative to warfarin (and in some cases low molecular weight heparin) in the management of venous thromboembolism and stroke prevention in atrial fibrillation. However, they are limited by the lack of a specific antidote to reverse anticoagulation in cases of major bleeding episodes or prior to urgent/emergency surgery. Andexanet alfa (AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct and indirect fXa inhibitors, therefore acting as a decoy to bind and sequester fXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban and enoxaparin in healthy subjects and demonstrated that AnXa was able to rapidly and extensively reverse pharmacodynamic (PD) markers of anticoagulation. Here we report new clinical data demonstrating that AnXa rapidly reverses the PD markers of edoxaban-mediated anticoagulation – anti-fXa activity and inhibition of thrombin generation. Methods: This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of edoxaban (edox, the most recent fXa inhibitor for which an NDA/MAA was submitted) as well as its pharmacokinetics (PK) and safety profile in healthy subjects. Reversal of edox anticoagulation is being studied with up to 3 different dose cohorts/regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Edox is administered at an oral dose of 60 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last edox dose. PD and safety data are collected through Day 48 with PK data through Day 10. Results and Conclusions: We report here available data from the first 2 AnXa dose cohorts (600 mg bolus, n=9; 800 mg bolus followed by 8 mg/min infusion for 1 hr, n=9). Immediately after completion of the 600 mg or 800 mg bolus, anti-fXa activity decreased dose-dependently by 52% and 73%, respectively, from the pre-AnXa level, remained constant during the infusion, and returned to placebo levels by approximately 2 hours after treatment. In addition, edox-induced inhibition of thrombin generation and prolongation of clotting times were also reversed by AnXa in a dose-dependent manner. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. One subject was discontinued on Day 5 prior to AnXa dosing due to a vasovagal reaction. These data are consistent with previously reported results for other fXa inhibitors in that AnXa rapidly reverses PD markers of anticoagulation, restores normal thrombin generation, and is well tolerated. Disclosures Crowther: CSL Behring: Honoraria; Shire: Honoraria; Celgene: Honoraria; Bayer: Honoraria; AKP America: Consultancy; Leo Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Portola Pharmaceuticals, Inc.: Consultancy; The Heart and Stroke Foundation of Ontario: Career Investigator Award, Career Investigator Award Other. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Lu:Portola Pharmaceuticals Inc: Employment. Leeds:Portola Pharmaceuticals, Inc: Employment. Lin:Portola Pharmaceuticals, Inc.: Employment. Pratikhya:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals Inc: Employment; Portola Pharmaceuticals Inc: Equity Ownership. Connolly:Portola Pharmaceuticals Inc: Consultancy. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership.

Background: Unfractionated heparin is used in the management of venous thromboembolism, stroke prevention in atrial fibrillation as well as in cardiac surgeries (e.g., valve replacement and other procedures requiring cardiopulmonary bypass). Bleeding is the major complication that may result from these therapies. Although protamine sulfate can be used to neutralize heparin, its administration can cause severe hypotensive and anaphylactic reactions. Andexanet alfa (AnXa) is a recombinant modified human fXa under development for the reversal of both direct and antithrombin III (ATIII)-dependent indirect fXa inhibitors. We previously reported nonclinical and Phase 2 clinical data in healthy subjects with enoxaparin, a low molecular weight heparin (LMWH). Here we report new in vitro data demonstrating that AnXa can also effectively reverse anticoagulation of unfractionated heparin. Methods: Inhibition of human fXa or thrombin (IIa) by ATIII in the presence of heparin was studied in an enzymatic assay in buffered solution. The reaction mixture contained fXa or IIa (20 nM), ATIII (200 nM), different amounts of unfractionated heparin and AnXa. At different time points, a small aliquot of the reaction mixture was taken and quenched into a 96-well assay plate containing protamine (50 µg/mL) and a chromogenic substrate (100 µM) for fXa (Spectrozyme-Xa) or IIa (S2238). Residual fXa or IIa activity was measured in a plate reader by monitoring the initial rate of substrate cleavage at 405 nm. Reversal of heparin anti-fXa and anti-IIa activities by AnXa in human plasma was evaluated using modified anti-fXa and anti-IIa chromogenic assays. Reversal of heparin-induced clotting prolongation of human plasma was measured by a 96-well format turbidity assay using an aPTT reagent and Ca2+. The reversal effect of AnXa on heparin anticoagulation and clot formation was further characterized by thromboelastography (TEG) in human plasma or whole blood. Reversal of heparin was compared to enoxaparin. Protamine sulfate was included as a control. Di-arginine piperazine (PER977), a positively charged small molecule, was also tested for comparison. Results: AnXa dose-dependently reversed the anti-fXa activity of heparin in the enzymatic assay and in human plasma. Interestingly, AnXa was also able to reverse the heparin anti-IIa activity in the same assays. In the enzymatic assay with IIa and ATIII, heparin accelerated the reaction of IIa inhibition by ~1000-fold. AnXa dose-dependently reversed the IIa inhibition to its basal level seen without heparin. The reversal effect of AnXa on IIa inhibition could be blocked by addition of a small molecule direct fXa inhibitor (e.g. rivaroxaban) in the same enzymatic assay. This suggests that interaction of AnXa with the primary binding site on the surface of heparin-activated ATIII (i.e., the reactive center loop (RCL)) might play a major role in the anti-IIa reversal as binding to the RCL was the minimal requirement for the inhibition of both fXa and IIa by ATIII. In human plasma, AnXa reversed the anti-IIa activity of heparin (0.8 IU/mL) with an estimated EC50 comparable to anti-fXa reversal (anti-fXa:126 nM; anti-IIa: 131nM). These results indicate that AnXa was able to compete with not only fXa, but also IIa, for binding to heparinized-ATIII and reverse both the anti-fXa and anti-IIa activities of heparin. In addition, AnXa dose-dependently and completely reversed prolongation of clotting by heparin (0.8 IU/mL) in human plasma as measured by the turbidity assay as well as parameters of heparin (1.0 IU/mL) anticoagulation as measured by TEG in either plasma or whole blood. As expected, protamine sulfate (5-10 µg/mL) neutralized heparin (1.0 IU/mL) anticoagulation in plasma in the TEG assay. At higher concentrations, protamine prevented clot formation, consistent with protamine's known anticoagulant effect when overdosed. No reversal activity was observed by PER977 in the same TEG assays using either plasma or whole blood. Conclusions: The current and previously reported data demonstrate that AnXa could be a universal fXa inhibitor antidote to reverse a broad range of newer direct oral fXa inhibitors, ATIII-dependent indirect inhibitors, such as fondaparinux and enoxaparin, as well as unfractionated heparin. The mechanism for reversal of ATIII-dependent inhibitors by AnXa is distinct from other positively charged molecules that bind directly to heparin. Disclosures Lu: Portola Pharmaceuticals, Inc.: Employment. Lin:Portola Pharmaceuticals, Inc.: Employment. Curnutte:Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership; Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals, Inc.: Employment.

Background Andexanet alfa (andexanet) is a modified human factor Xa (FXa) approved for anticoagulation reversal in patients with life‐threatening bleeding treated with rivaroxaban or apixaban. Four‐factor prothrombin complex concentrates (4F‐PCCs) are approved for reversal of vitamin K antagonist–induced anticoagulation but not FXa inhibitors. The mechanism and effectiveness of 4F‐PCCs for FXa inhibitor reversal are unclear. Objective To investigate the mechanism and impact of 4F‐PCCs on reversal of rivaroxaban and apixaban in vitro compared to andexanet. Methods The effect of 4F‐PCCs (or individual factors) on tissue factor‐initiated thrombin generation (TF‐TG) was evaluated in human plasma, with or without rivaroxaban or apixaban, and compared with andexanet under the same conditions. Results In the TF‐TG assay, 4F‐PCC completely reversed warfarin anticoagulation. Andexanet normalized TF‐TG over a wide range of apixaban and rivaroxaban concentrations tested (19‐2000 ng/mL). However, 4F‐PCC (or individual factors) was unable to normalize endogenous thrombin potential (ETP) or peak thrombin (Peak) in the presence of apixaban or rivaroxaban (75‐500 ng/mL). TF‐TG was only normalized by 4F‐PCC at inhibitor concentrations <75 ng/mL (ETP) or <37.5 ng/mL (Peak). These data can be explained by the estimated thresholds of FXa activity required to support normal TF‐TG based on the inhibitor:FXa ratios and levels of uninhibited FXa. The data are consistent with healthy volunteer studies where TF‐TG is not normalized until inhibitor levels are substantially decreased. Conclusions Both the theoretical calculations and experimental data demonstrated that 4F‐PCCs are only able to normalize TG over a low and narrow range of FXa inhibitor concentrations (<75 ng/mL).

IntroductionIncreasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors.ObjectiveTo evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban.Materials and methodsIn vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury.ResultsAndexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035).ConclusionThese data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Introduction: Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) molecule that acts as a decoy to bind and sequester FXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, and demonstrated that andexanet rapidly reversed pharmacodynamic (PD) markers of anticoagulation. Here, we report new clinical data demonstrating the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). Methods: In an ongoing, Phase 2, randomized, double-blind study in healthy subjects, andexanet (n=12) or placebo (n=6) was administered intravenously following dosing of 80 mg qd po betrixaban to steady state (7 days). In Cohort 1 (andexanet bolus only), subjects (n=6) received an 800 mg bolus of andexanet 3 hours after the last dose of betrixaban on day 7 or matching placebo (n=3). In Cohort 2 (andexanet bolus plus 2-hour infusion), subjects (n=6) received an 800 mg bolus of andexanet 4 hours after the last betrixaban dose, followed immediately by a 2-hour infusion of andexanet (8 mg/min), or matching placebo (n=3). Study endpoints included assessments of safety and multiple PD markers of anticoagulation reversal, including reduction in anti-FXa activity, decrease in unbound betrixaban plasma concentration, and restoration of thrombin generation. Results: Following treatment with betrixaban in Cohort 1, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity from 29.9 ± 11.6 to 6.5 ± 4.5 ng/mL while the anti-FXa levels following placebo were largely unchanged (45.2 ± 44.8 to 43.6 ± 37.7 ng/mL). Unbound betrixaban plasma concentration decreased from 12.3 ± 5.6 to 3.6 ± 2.7 ng/mL with andexanet, but remained constant following placebo administration (18.3 ± 17.9 to 19.3 ± 18.1 ng/mL). Similar results were observed in Cohort 2 following andexanet bolus (2 minutes after the bolus), and the effects were maintained during the 2-hour infusion of andexanet. For Cohort 1, thrombin generation was restored (within the mean pre-anticoagulant value ± 2 standard deviations) in 6/6 (100%) of the andexanet-administered subjects vs. 1/3 (33.3%) of the placebo subjects. For Cohort 2, thrombin generation was restored in 5/6 (83.3%) of the andexanet subjects vs. 1/3 (33.3%) of the placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. Conclusions: Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies indicate that andexanet could be a universal antidote for all four direct FXa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) as well as indirect FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA™-4) study in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population. Disclosures Crowther: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Celgene: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichii: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daichii: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Celgene: Honoraria; Daichii: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lu:Portola: Employment, Patents & Royalties. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Lin:Portola Pharmaceuticals: Employment. Conley:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Gold:Portola Pharmaceuticals: Employment. Connolly:Portola Pharmaceuticals: Consultancy. Curnutte:Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership; Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.