Annette Feussner

Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate

Background— The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban’s effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC). Methods and Results— This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban’s effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume. Conclusions— The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02047565.

The FVII activating protease cleaves single-chain plasminogen activators.

A serine protease isolated from plasma sharing structural characteristics with a hepatocyte growth factor activator-like protease has been demonstrated recently to activate FVII. Accordingly, it was named ‘FVII activator’. Until now an impact of this protease on the fibrinolytic system has not been reported. We islolated the protease from cryo-poor plasma by subsequent ion exchange chromatography and adsorption to immobilized heparin and/or aprotinin. Incubation of single-chain plasminogen activators (sc-PAs) with the FVII activator revealed significant activation of urokinase sc-PA (scu-PA) and tissue sc-PA (sct-PA) in vitro. It was enhanced in the presence of calcium and heparin. Compared to kallikrein, a more efficient activation of scu-PA was observed, whereas sct-PA appeared to be a poorer substrate for the FVI activator. At low protease concentrations and in the presence of heparin the scu-PA activation was comparable to plasmin. Employing recalcified whole blood thrombelastography, the lysis of initially formed fibrin was observed after addition of a combination of scu-PA and the FVII activator, whereas the scu-PA alone had a negligible effect at the concentration used. The study results as presented demonstrate that the FVII activator is a potent activator of sc-PAs in vitro. Whether it plays a physiological role in fibrinolysis deserves further investigation. Its comparatively high affinity to heparin assumes a function in cell surface or matrix events.

Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study

Hereditary angioedema (HAE) is a rare disease caused by C1‐esterase inhibitor (C1‐INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1‐INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1‐INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.

Biochemical comparison of four commercially available C1 esterase inhibitor concentrates for treatment of hereditary angioedema

For safe and efficacious treatment of hereditary angioedema, C1 esterase inhibitor (C1‐INH) concentrates should have high purity and high amounts of functional protein. As no pharmacopoeia requirements exist for C1‐INH concentrate lot release, biochemical characteristics as declared by the manufacturers may not be compared directly. This study compared the characteristics and purity profiles of four commercially available C1‐INH concentrates.

Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema

Long‐term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma‐derived C1‐esterase inhibitor (C1‐INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention.