Frequently Asked
Questions

FXIa is the activated form of coagulation factor XI and is a potent trigger of the intrinsic coagulation cascade. Even trace amounts of FXIa in IVIG products can generate thrombin and increase the risk of thromboembolic events.^{4, 8}

Thromboembolic adverse events (TEEs) are rare but serious complications of intravenous immunoglobulin (IVIG) therapy that can include stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism.^{7, 9, 13}

Investigations following increased reports of TEEs, including a major IVIG product recall in 2010, identified elevated FXIa levels in affected lots. These investigations directly linked FXIa contamination to increased thrombogenicity.^{2, 8}

Purification steps such as cation exchange chromatography under optimized conditions, caprylic acid precipitation, depth filtration, and pasteurization have been shown to significantly reduce FXI and FXIa from IVIG products.^{6, 12}

Patients with advanced age, cardiovascular disease, hypercoagulable conditions, diabetes, renal disease, obesity, immobility, antiphospholipid syndrome, estrogen use, indwelling vascular catheters, hyperviscosity, or a personal or family history of thrombosis are at increased risk.^{5, 13}

Greater IVIG purity reduces exposure to procoagulant and immunogenic impurities such as FXIa, IgA, and protein aggregates that have been linked to thrombosis, hemolysis, and other serious adverse events.^{1, 3}

Although there is a boxed warning for TEEs for all IVIG products, professional societies recommend matching IVIG product characteristics to patient risk factors and considering products with the lowest FXIa levels as part of a broader thrombosis risk-reduction strategy.¹¹

IVIG can increase clotting risk due to procoagulant impurities, particularly activated factor XI (FXIa) as well as increased blood viscosity, platelet activation, and inflammatory effects following infusion.^{4, 12, 13}

FXIa is a procoagulant impurity that can be present in IVIG products and has been identified as a root cause of IVIG-associated thromboembolic events. Even small amounts of FXIa can trigger thrombin generation by activating the intrinsic coagulation cascade, increasing thrombogenic potential.^{4, 8}

FXI is difficult to remove because it has a similar isoelectric point to immunoglobulin G (IgG). Therefore, both proteins behave similarly during traditional plasma fractionation and purification processes (ethanol fractionation or anion exchange chromatography), making them difficult to separate. As a result, FXI can persist at residual levels despite standard purification steps.^{1, 12}

In response to evidence, regulatory agencies, including the U.S. FDA, added boxed warnings for thromboembolic events to IVIG products and now encourage thrombogenicity testing and manufacturing steps that reduce FXIa.^{2, 8}

Selecting IVIG products with undetectable FXIa levels and manufacturing processes proven to remove procoagulant impurities is an important risk-mitigation strategy, particularly in high-risk patients.^{6, 11, 17}

IVIG products can vary in thrombogenic risk because each manufacturer uses unique plasma collection and purification methods that influence residual FXIa and other impurities.^{2, 12}