This study confirms that the benefit/risk balance for this fibrinogen concentrate is favourable.

The Clottafact safety profile observed during the study matched the known profile of fibrinogen during use.

Antibody inhibitors against human thrombin are rare and have remained poorly characterized. We report the case of a 40-yrold patient who developed a potent thrombin inhibitor revealed by mild bleeding symptoms and marked prolongation of most laboratory clotting times. After two years of evolution, he died from cerebral hemorrhage. The inhibitor, a polyclonal IgG, was associated with hematological and immunological criteria of autoimmune disorder. Antithrombin IgG was isolated from the patient's plasma by protein A-and thrombin-affinity chromatography. Fab fragments inhibited amidolytic activity of a thrombin, and thrombin-thrombomodulin catalyzed protein C activation with a Ki of -10' M in a noncompetitive manner.Alpha to gamma conversion of thrombin resulted in a moderate loss of affinity for the inhibitor. Upon complex formation of thrombin with staphylocoagulase or a2-macroglobulin (a2M), inhibition was decreased by two orders of magnitude and acquired an apparent competitive character. In Western blot experiments, the antibody reacted with active alpha-thrombin, did not react with chloromethylketone-inhibited thrombin and reacted with a lower affinity with iPr2P-thrombin. The inhibitor did not block thrombin binding to benzamidine-, heparin-, or fibrin-Sepharose, but displaced proflavin from its complex with thrombin. Taken together, these results indicate that the patient's autoantibody recognized a conformational structure which includes, at least in part, the apolar binding site adjacent to the catalytic site of thrombin. (J. Clin. Invest. 1991. 88:290-296.)

Introduction: Direct oral anticoagulants, previously new oral anticoagulants (NOACs) had a favorable risk–benefit profile, both for stroke prevention or systemic embolic events in patients with atrial fibrillation (AF), or for venous thromboembolism (VTE) treatment. Although the rate of intracranial hemorrhage is lower, the risk for major bleeding is similar as for warfarin. Only few data are available for the management of major bleeding in clinical practice. The aim of this study is to present preliminary results regarding characterization and care of major bleeding through a French prospective registry. Methods: The GIHP (French Working group on Perioperative hemostasis) – NACO registry is a prospective observatory started in June 2013 in 32 emergency centers in France and Belgium. Only patients treated by NOACs and hospitalized for major bleeding or urgent surgery were registered. Results: In a midterm analysis in June 2014, 339 patients were included, among which 219 for major bleeding. 75 patients were treated by dabigatran (150 mg bid: 81%), and 142 by rivaroxaban (20 mg od: 54%) (2 patients were treated by Apixaban). The mean age was 76.4 +/- 11y, and mean BMI 26.3. Creatinine clearance was lower than 60 ml/min in 65%. Patients were treated for atrial fibrillation (80%) or VTE (20%). Among patients with AF, 67.2% had CHADS2 at 2 or less. 61.6% of patients received concomitantly at least one drug interfering with CYP or Pgp, and 26.9% received another antithrombotic drug at the time of bleeding. Major hemorrhagic sites were gastrointestinal (25%) and intracranial, either spontaneous (20%) or post-trauma (15%). AOD concentrations were determined in 46% of patients. 20% of the patients with major bleeding had a plasma concentration less than 50 ng/ml. As expected, there is no relationship between drug concentrations and standard hemostatic tests such as PT and aPTT. 38.4% of patients received PCC or aPCC, and 25.7% benefited for any additional procedures (surgery, endoscopy, embolization…). 42.2% of bleeding completely stopped after the administration of clotting factors. At 30d of follow up, 9.1% of patients presented a cardiovascular event, and all-cause mortality was 14.2%. Conclusion: This midterm analysis of the GIHP NACO registry shows consistent results with phase III studies, with some particularities compared to clinical trials, especially in the use of PCC. The registry allows the analysis of specific population such as trauma patients and highlights the care of such major hemorrhages. Disclosures Pernod: LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Off Label Use: PCC and aPCC ro reverse effect of antithrombotic drugs. Albaladejo:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Samama:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Sie:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding. Bosson:LFB: Research Funding; CSL: Research Funding; Octapharma: Research Funding.

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