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Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products.
Vox Sang. 2012 Jan; 102(1):40-6.VS

Abstract

BACKGROUND AND OBJECTIVES

The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events.

MATERIAL AND METHODS

The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively.

RESULTS

Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S-2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT.

CONCLUSIONS

Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs.

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Authors+Show Affiliations

Etscheid M
Department of Haematology/Transfusion Medicine, Paul Ehrlich Institute, Langen, Germany. etsmi@pei.de
Breitner-Ruddock S
No affiliation info available
Gross S
No affiliation info available
Hunfeld A
No affiliation info available
Seitz R
No affiliation info available
Dodt J
No affiliation info available

MeSH

Blood CoagulationDose-Response Relationship, DrugDrug ContaminationDrug-Related Side Effects and Adverse ReactionsEnzyme-Linked Immunosorbent AssayFactor XIIaFactor XIaFibrinolysinHumansImmunoglobulinsImmunoglobulins, IntravenousKallikreinsPartial Thromboplastin TimePrekallikreinThrombinThromboembolism

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21545600

Citation

Etscheid, M, et al. "Identification of Kallikrein and FXIa as Impurities in Therapeutic Immunoglobulins: Implications for the Safety and Control of Intravenous Blood Products." Vox Sanguinis, vol. 102, no. 1, 2012, pp. 40-6.
Etscheid M, Breitner-Ruddock S, Gross S, et al. Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. Vox Sang. 2012;102(1):40-6.
Etscheid, M., Breitner-Ruddock, S., Gross, S., Hunfeld, A., Seitz, R., & Dodt, J. (2012). Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. Vox Sanguinis, 102(1), 40-6. https://doi.org/10.1111/j.1423-0410.2011.01502.x
Etscheid M, et al. Identification of Kallikrein and FXIa as Impurities in Therapeutic Immunoglobulins: Implications for the Safety and Control of Intravenous Blood Products. Vox Sang. 2012;102(1):40-6. PubMed PMID: 21545600.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. AU - Etscheid,M, AU - Breitner-Ruddock,S, AU - Gross,S, AU - Hunfeld,A, AU - Seitz,R, AU - Dodt,J, Y1 - 2011/05/05/ PY - 2011/5/7/entrez PY - 2011/5/7/pubmed PY - 2012/5/9/medline SP - 40 EP - 6 JF - Vox sanguinis JO - Vox Sang VL - 102 IS - 1 N2 - BACKGROUND AND OBJECTIVES: The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events. MATERIAL AND METHODS: The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively. RESULTS: Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S-2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT. CONCLUSIONS: Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs. SN - 1423-0410 UR - https://www.unboundmedicine.com/medline/citation/21545600/Identification_of_kallikrein_and_FXIa_as_impurities_in_therapeutic_immunoglobulins:_implications_for_the_safety_and_control_of_intravenous_blood_products_ L2 - https://doi.org/10.1111/j.1423-0410.2011.01502.x DB - PRIME DP - Unbound Medicine ER -