title: Quantifying the thrombogenic potential of human plasma-derived immunoglobulin products.
abstract: Polyvalent immunoglobulin G (IgG) products obtained by fractionation of human plasma are used to treat a broad range of conditions, including immunodeficiency syndromes and autoimmune, inflammatory, and infectious diseases. Recent incidences of increased thromboembolic events (TEEs) associated with intravenous (IV) IgG (IVIG) led to recalls of some products and increased regulatory oversight of manufacturing processes in order to ensure that products are essentially free of procoagulant/thrombogenic plasma protein contaminants. Laboratory investigations have now identified activated factor XI (FXIa) as the likely causative agent of IVIG-related TEEs. Quantification of the thrombogenic potential is becoming a requirement made to fractionators (a) to validate the capacity of IVIG and subcutaneous IgG manufacturing processes to remove procoagulant contaminants and (b) to establish the safety of the final products. However, in the absence of a recommended test by the main regulatory authorities, several analytical approaches have been evaluated by fractionators, regulators, and university groups. This review focuses on the scientific rationale, merits, and applications of several analytical methods of quantifying the thrombogenic potential of IgG products and intermediates to meet the latest regulatory requirements.
authors.affiliation: National Bioproducts Institute, Pinetown, South Africa.
authors.forename: W A
authors.initials: WA
authors.lastname: Germishuizen
authors.affiliation: National Bioproducts Institute, Pinetown, South Africa.
authors.forename: D C
authors.initials: DC
authors.lastname: Gyure
authors.affiliation: National Bioproducts Institute, Pinetown, South Africa.
authors.forename: D
authors.initials: D
authors.lastname: Stubbings
authors.affiliation: Graduate Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, 250 Wuxing St., Taipei City 110, Taiwan. Electronic address: tburnou@attglobal.net.
authors.forename: T
authors.initials: T
authors.lastname: Burnouf
mesh_terms: D000818:Animals; D001688:Biological Products / Q000009:adverse effects* / Q000097:blood* / Q000592:standards; D001779:Blood Coagulation Factors / Q000009:adverse effects / Q000302:isolation & purification; D002626:Chemistry, Pharmaceutical; D004340:Drug Contamination / Q000517:prevention & control; D015945:Factor XIa / Q000009:adverse effects / Q000302:isolation & purification; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects* / Q000097:blood*; D016756:Immunoglobulins, Intravenous / Q000009:adverse effects / Q000592:standards; D007155:Immunologic Factors / Q000009:adverse effects / Q000097:blood; D018570:Risk Assessment; D013923:Thromboembolism / Q000097:blood / Q000209:etiology* / Q000276:immunology
chemical_list: D001688:Biological Products; D001779:Blood Coagulation Factors; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D015945:Factor XIa
keywords: FXIa; IVIG; Procoagulant; SCIG; Thrombosis