A Focus on Factor XI
A clear look at IVIG purity and its impact on the risk of thromboembolic adverse events.
IVIG: Intravenous immunoglobulin
The Importance of IG Purity
A long-standing goal in the manufacture of intravenous immunoglobulin (IVIG) products is to attain a high level of purity in the final product.
Manufacturing immunoglobulin products is a complex process because isolating a specific protein from plasma involves separating the chosen protein from hundreds of other proteins.1
Each manufacturer’s novel plasma collection, fractionation, and purification processes directly influence the biochemical characteristics and tolerability of an IVIG product.2
Impurities in IVIG solutions are linked to serious adverse events
The presence of the following impurities has been identified as a risk factor for serious adverse events, including hemolysis, anaphylactic shock, and thrombosis.3:
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Immunoglobulin A (IgA)
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Anti-A/Anti-B Hemagglutinins
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Anti-D Immunoglobulin
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Polymers
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Prekallikrein Activator
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Anti-Cardiolipin Antibodies
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Activated Coagulation Factor XI (FXIa)
Immunoglobulin A (IgA)
Immunoglobulin A (IgA) is the second most abundant immunoglobulin type found in the serum. IgA protects the body's mucous membranes, including the nose, airways, and gut, from bacteria and viruses.18
In patients with IgA deficiency who have developed anti-IgA antibodies, exposure to IgA as a contaminant in IVIG products may trigger anaphylactic reactions.19
Anti-A/Anti-B Hemagglutinins
Anti-A and anti-B hemagglutinins are naturally occurring antibodies (mostly IgM) present in the plasma of individuals who lack the corresponding blood group antigen. When present as contaminants in IVIG preparations, these antibodies have been linked to an increased risk of hemolytic reactions, particularly in patients with non-O blood groups.2
Anti-D Immunoglobulin
Anti-D immunoglobulin is a rhesus factor antibody formed by Rh-negative individuals following exposure to Rh-positive blood — most commonly through fetal-maternal blood exchange during pregnancy.20 Elevated titers of anti-D immunoglobulin in IVIG preparations have been associated with an increased frequency of immunoglobulin-related adverse effects.13
Polymers
Polymers or aggregates are IgG molecules that have stuck together, forming dimers, trimers or larger, high-molecular weight complexes. The presence of large size polymers in IVIG preparations can activate complement in the absence of antigen, with the potential to cause adverse reactions in patients such as flushing, headache, fever, chills, nausea, vomiting, muscle pain, dyspnea and tachycardia.13, 21
Prekallikrein Activator
Prekallikrein activator activity in IVIG reflects activation of the contact system (FXII–kallikrein pathway), which can generate bradykinin and contribute to hypotensive or infusion-related reactions.22
Anti-Cardiolipin Antibodies
Anti-cardiolipin antibodies (ACA) are a type of antibody that targets cardiolipin, a phospholipid found in cell membranes. ACA are often associated with autoimmune diseases and various clinical conditions such as antiphospholipid syndrome. If they are present in IVIG they can potentiate thromboses in situations of hypercoagulable states.12
Coagulation Cascade
FXIa plays a key role in the activation of the intrinsic coagulation cascade4
Studies have confirmed that even small quantities of FXIa, if present in IVIG, can result in thrombin generation4
FXIa has been identified as one of the root causes of IVIG-related TEEs2
An association between IVIG and either arterial or venous TEEs was suggested as long ago as 1986.5
A commercialized IVIG product was recalled from European and North American markets because of an increased incidence in thromboembolic adverse events (TEEs).2
The FDA held a workshop for regulatory agencies and the industry to investigate the causes of the increased TEE incidence.2
FXI/FXIa are determined to be the causative agent2
Following these events, manufacturers were urged to consider adding dedicated steps for the removal of FXIa and encouraged to test products at lot release for thrombogenicity.8
The FDA places a boxed warning regarding TEEs across the therapeutic class of IVIGs.9
In a study, published in 2013, that evaluated the cause of TEEs associated with immunoglobulin from 2006-2011, the majority of TEEs were deemed to be drug-related and were linked to a specific immunoglobulin G (IgG) product and the presence of FXIa.7
In collaboration with the World Health Organization, 17 laboratories from 11 different countries participated in a value-assignment collaborative study for the proposed 1st International Standard for Activated Blood Coagulation Factor XI (FXIa).10
Innovations in manufacturing processes have proven effective at reducing FXIa to below detectable limits.6, 17
See Results of One StudyExplore Purification Challenges
