title: Absence of in vitro Procoagulant Activity in Immunoglobulin Preparations due to Activated Coagulation Factors.
abstract: BACKGROUND
  Immunoglobulin (IG) products, including intravenous (IVIG) or subcutaneous (SCIG) immunoglobulins are considered safe and effective for medical therapy; however, a sudden and unexpected increase in thromboembolic events (TE) after administration of certain batches of IVIG products has been attributed to the presence of activated coagulation factors, mainly factor XIa. Our aims were to examine the presence of enduring procoagulant activity during the manufacturing process of IGs, with special focus on monitoring factor XIa, and to evaluate the presence of in vitro procoagulant activity attributed to coagulation factors in different lots of IVIG and SCIG.
  
  
  METHODS
  Samples of different steps of IG purification, 19 lots of IVIG and 9 of SCIG were analyzed and compared with 1 commercial preparation of IVIG and 2 of SCIG, respectively. Factors II, VII, IX, XI and XIa and non-activated partial thromboplastin time (NAPTT) were assayed.
  
  
  RESULTS
  The levels of factors II, VII, IX, X and XI were non-quantifiable once fraction II had been re-dissolved and in all analyzed lots of IVIG and SCIG. The level of factor XIa at that point was under the detection limits of the assay, and NAPTT yielded values greater than the control during the purification process. In SCIG, we detected higher concentrations of factor XIa in the commercial products, which reached values up to 5 times higher than the average amounts found in the 9 batches produced by UNC-Hemoderivados. Factor XIa in commercial IVIG reached levels slightly higher than those of the 19 batches produced by UNC-Hemoderivados.
  
  
  CONCLUSIONS
  IVIG and SCIG manufactured by UNC-Hemoderivados showed a lack of thrombogenic potential, as demonstrated not only by the laboratory data obtained in this study but also by the absence of any reports of TE registered by the post marketing pharmacovigilance department.
authors.affiliation: Área de Desarrollo de Productos y Procesos, Laboratorio de Hemoderivados, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Oviedo
authors.affiliation: Área de Desarrollo de Productos y Procesos, Laboratorio de Hemoderivados, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: María E
authors.initials: ME
authors.lastname: Bernardi
authors.affiliation: Área de Desarrollo de Productos y Procesos, Laboratorio de Hemoderivados, Universidad Nacional de Córdoba, Córdoba, Argentina; Departamento de Bioquímica Clínica (CIBICI-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Guglielmone
authors.affiliation: Área de Desarrollo de Productos y Procesos, Laboratorio de Hemoderivados, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: María S
authors.initials: MS
authors.lastname: Vitali
keywords: Factor XIa; Intravenous immunoglobulin; Procoagulant activities; Subcutaneous immunoglobulin; Thromboembolic events