Currently used anticoagulants prevent thrombosis but increase bleeding. We show an anticoagulation therapy without bleeding risk based on a plasma protease factor XII function-neutralizing antibody. We screened for antibodies against activated factor XII (FXIIa) using phage display and demonstrated that recombinant fully human antibody 3F7 binds into the FXIIa enzymatic pocket. 3F7 interfered with FXIIa-mediated coagulation, abolished thrombus formation under flow, and blocked experimental thrombosis in mice and rabbits. We adapted an extracorporeal membrane oxygenation (ECMO) cardiopulmonary bypass system used for infant therapy to analyze clinical applicability of 3F7 in rabbits. 3F7 provided thromboprotection as efficiently as heparin, and both drugs prevented fibrin deposition and thrombosis within the extracorporeal circuit. Unlike heparin, 3F7 treatment did not impair the hemostatic capacity and did not increase bleeding from wounds. These data establish that targeting of FXIIa is a safe mode of thromboprotection in bypass systems, and provide a clinically relevant anticoagulation strategy that is not complicated by excess bleeding.

In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Summary.  Background:  One limitation of the direct thrombin inhibitor dabigatran is the lack of specific antidotes that allow acute bleeding events to be managed or urgent interventional procedures performed. Prothrombin complex concentrates (PCCs) have served as a standard treatment for the reversal of coumarin anticoagulation. Objectives:  This study was designed to determine in an animal model whether a PCC (Beriplex P/N) can effectively reverse the effects of dabigatran. An additional objective was to evaluate markers of dabigatran‐associated bleeding diathesis. Methods:  Anesthetized rabbits were treated with 0.4 mg kg−1 dabigatran followed by PCC doses of 20, 35 or 50 IU kg−1 or placebo. After a standardized kidney incision, volume of blood loss and time to hemostasis were determined. Results:  From an initial mean of 29 mL, blood loss progressively declined by 5.44 mL with a 95% confidence interval (CI) of 2.21–8.67 mL per 10 IU kg−1 increment in PCC dose (P = 0.002). At a PCC dose of 50 IU kg−1 blood loss was fully normalized. Increasing PCC doses shortened the median time to hemostasis from 20.0 to 5.7 min (P < 0.001). The rate of hemostasis was nearly trebled with each 10 IU kg−1 increment in PCC dose (rate ratio, 2.89; CI, 1.64–5.09). Conclusions:  In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran. Further investigation is warranted.

Objective-The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Our objective was to produce and characterize a human apolipoprotein AI (apoA-I) product optimized to treat clinical atherosclerotic disease. Approach and Results-A new formulation of full length, plasma-derived human apoA-I termed CSL112 was designed to maximize the cholesterol efflux from cells and exhibit favorable pharmacological properties. CSL112 is a disc-shaped particle that strongly elevates cholesterol esterification and shows good pharmacokinetics in rabbits. Infusion of CSL112 into rabbits caused a strong and immediate increase in the ATP binding cassette transporter A1 (ABCA1)-dependent efflux capacity of plasma, an increase in plasma unesterified cholesterol and rapid subsequent cholesterol esterification. In the presence of human plasma, CSL112 was significantly more potent than native HDL at enhancing cholesterol efflux from macrophages, and the efflux elevation was predominantly via the ABCA1 transporter. Consistent with this observation, addition of CSL112 to plasma led to generation of high levels of HDL-VS, a favorable substrate for ABCA1. The lipid profile of plasma did not affect these behaviors. In studies with whole human blood, CSL112 reduced expression of intercellular adhesion molecule 1 and cytokine secretion, and as with cholesterol efflux, these activities were substantially greater than those of native HDL assayed in parallel. Conclusions-CSL112 has favorable pharmacological properties and strongly elevates the ability of plasma to withdraw cholesterol from cells. Preferential elevation of ABCA1-dependent efflux may target atherosclerotic plaque for cholesterol removal and this property makes CSL112 a promising candidate therapy for acute coronary syndrome. Diditchenko et al CSL112 Raises Cholesterol Efflux Cells to Plasma 2203days, 7 and a single infusion of reconstituted HDL caused loss of ≈60% of cholesterol ester in femoral plaque in 5 to 7 days. 8 The ability of infused apoA-I to remove half of plaque cholesterol in a week suggests that it may act quickly enough to affect the high recurrent cardiovascular event rate seen in the month after ACS.Because of its promise in treatment of ACS, infused HDL therapy has been long pursued by the pharmaceutical industry.9,10 Here, we describe a novel formulation of human apoA-I (hApoA-I) intended to treat ACS. This formulation, termed CSL112, was designed to optimize cholesterol efflux by ATP binding cassette transporter A1 (ABCA1), a transporter induced by excess cellular cholesterol and present in atherosclerotic plaque. 11,12 Although CSL112 acted as a good substrate for ABCA1 in tissue culture, we found adding CSL112 to human plasma caused a more dramatic rise in ABCA1-dependent efflux capacity with activity substantially greater than that of native HDL from plasma. We propose that CSL112 is rapidly remodeled in plasma to a form that can accept cholester...

In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).