Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations

Abstract

A small number of thromboembolic events, including deep venous thrombosis and myocardial infarction, have been reported in patients receiving IVIG. These events have primarily occurred in patients receiving high-dose IVIG and have been attributed to an increase in blood viscosity. To test the hypothesis that a procoagulant might be present in IgG preparations, twenty-nine samples of intravenous immunoglobulin (IVIG) from eight different manufacturers were assayed for procoagulant activity. Twenty-six of these samples shortened the clotting time of factor XI-deficient plasma. Of these, fourteen samples had factor XI activities greater than 0.001 U/ml of normal pooled plasma. The remaining samples possessed less than 0.001 U/ml of normal plasma activity. The procoagulant activity in these samples could be inhibited by an anti-factor XI polyclonal antibody, suggesting that the procoagulant activity was factor XI. The procoagulant activity increased in two samples after storage at 4°C for 4 weeks, likely as a result of factor XIa autoactivation. Additionally, activity in some IVIG samples was able to directly activate factor IX, indicating that activated factor XI was present in these samples. Finally, the degree of factor XI(a) contamination in the samples was correlated with the manufacturer, suggesting that variations in the manufacturing process or source plasma affect the level of factor XI in the IVIG product. Because addition of small amounts of factor XIa to plasma can lead to production of significant amounts of thrombin, we suggest that factor XIa present in some IVIG preparations could contribute to the in vivo risk of thrombosis after IVIG therapy. Am.

Quantitative determination of activated coagulation factor XI as an impurity in therapeutic immunoglobulins from Chinese blood fractionation companies

“…The study of thromboembolic factors is a focus of blood disease research. Previous studies have shown that functional FXIa, as a major contaminant in IVIG lots involved in TEEs, is first suspected and confirmed and then quantified (Wolberg et al, 2000). Grundmann et al (2010), Marzo et al (2011), andEtscheid et al (2012) have reported that the readout parameter TTP is below 10 min, FXIa concentration is above 0.5 nM, FXI clotting activity is detected (0.08-0.10 IU/mL), and NAPTT is below 150 s with IVIG batches associated with TEEs, but batches from other manufacturers exhibit TTP values above 30 min, FXIa concentration below 0.5 nM, FXI clotting activity below 0.04 IU/mL, and NAPTT above 200 s.…”

“…A small number of thromboembolic events (TEEs) occurring after the administration of IVIG preparations and infusions have been reported (Dalakas, 1994;Rosenbaum, 1997;Hefer and Jaloudi, 2004;Vo et al, 2006). These TEEs have been attributed to an increased residual content of activated procoagulant components -mainly activated coagulation factor XI (FXIa) -in IVIG (Bolton-Maggs et al, 1995;Wolberg et al, 2000). A number of tests have long been used to assess the procoagulant activity of blood derivatives, particularly those with a significant risk of thrombogenicity.…”

Strokes after intravenous gamma globulin: Thrombotic phenomenon in patients with risk factors or just coincidence?

“…Hyperviscosity induced acute ischemia and vasospasm of cerebral arteries [6][7][8]20] as well as the thrombogenic effects of the stabilizing agent used in the IG preparations (glucose, sucrose, maltose, or sorbitol) have the potential to trigger thrombosis [19]. Some IVIG preparations were found to have increased concentrations of factor XI, which may potentially trigger intrinsic coagulation pathway activation and thrombin formation [32]. Moreover, a thrombogenic effect of IVIG preparations may occur through activation of the serum complement.…”

Induction of an inhibitor antibody to factor XI in a patient with severe inherited factor XI deficiency by Rh immune globulin

“…4 The patient is exceptional among previously described patients with inherited FXI deficiency and an inhibitor because she has never been exposed to blood products. Since FXI copurifies with immunoglobulins, 5 and FXI and FXIa are present in immunoglobulin concentrates, 6,7 we hypothesized that the Rh immune globulin that the patient received contained FXI. This was indeed the case.…”