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Evaluating the thrombin generation profiles of four different rFVIII products in FVIII-deficient plasma using FIXa and FXIa activation.
Haemophilia. 2018 Sep; 24(5):815-822.H

Abstract

INTRODUCTION

The thrombin generation assay (TGA) can be used to monitor factor replacement therapy in patients with haemophilia. The TGA assay is typically performed using tissue factor as the reaction activator; however, activating with FIXa or FXIa can enhance assay sensitivity when FVIII < 1%.

AIMS

To evaluate the sensitivity of the TGA when FIXa (5 nmol/L) and FXIa (0.22 nmol/L) are used to activate the assay in platelet-poor plasma and to compare these data to the one-stage and chromogenic assays.

METHODS

Plasma from 10 severe FVIII-deficient subjects was supplemented with FVIII (0%, 0.1%, 0.4%, 1.2%, 4%, 11% and 33%), using either Novo Eight® , Advate® , Eloctate® , turoctocog alfa pegol or a control standard. The one-stage and chromogenic assays quantified the FVIII levels. The TGA assay was activated using either FIXa or FXIa.

RESULTS

Both FIXa- and FXIa-activated TGA were sensitive across FVIII concentrations, with intra-assay coefficient of variation (CV) < 10%. The FXIa-activated assay had 25% CV at the lowest level of FVIII compared to 10% CV with FIXa activation. There were strong correlations between the FIXa- and FXIa-activated TGA tests (R2 = 0.9912) and between the one-stage and chromogenic assays (R2 = 0.9469). However, there were poor relationships between the TGA tests and one-stage and chromogenic assays.

CONCLUSIONS

Both FIXa- and FXIa activation results in similar TGA profiles across a FVIII range of 0.1%-33%; however, FIXa activation was more robust at the lowest levels of FVIII compared with FXIa activation.

Authors+Show Affiliations

Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, Virginia.Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, Virginia.Novo Nordisk A/S, Bagsvaerd, Denmark.Coagulation Advancement Laboratory, Department of Pharmacotherapy & Outcomes Science, Virginia Commonwealth University (VCU), Richmond, Virginia. Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.Internal Medicine/Division of Haematology/Oncology, VCU, Richmond, Virginia.Internal Medicine/Division of Haematology/Oncology, VCU, Richmond, Virginia.Internal Medicine/Division of Haematology/Oncology, VCU, Richmond, Virginia.Novo Nordisk A/S, Bagsvaerd, Denmark.Novo Nordisk A/S, Bagsvaerd, Denmark.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30112856

Citation

Brophy, Donald F., et al. "Evaluating the Thrombin Generation Profiles of Four Different rFVIII Products in FVIII-deficient Plasma Using FIXa and FXIa Activation." Haemophilia : the Official Journal of the World Federation of Hemophilia, vol. 24, no. 5, 2018, pp. 815-822.
Brophy DF, Martin EJ, Ninivaggi M, et al. Evaluating the thrombin generation profiles of four different rFVIII products in FVIII-deficient plasma using FIXa and FXIa activation. Haemophilia. 2018;24(5):815-822.
Brophy, D. F., Martin, E. J., Ninivaggi, M., Mohammed, B. M., Barrett, J. C., Kuhn, J., Nolte, M. E., Waters, E. K., & Ezban, M. (2018). Evaluating the thrombin generation profiles of four different rFVIII products in FVIII-deficient plasma using FIXa and FXIa activation. Haemophilia : the Official Journal of the World Federation of Hemophilia, 24(5), 815-822. https://doi.org/10.1111/hae.13597
Brophy DF, et al. Evaluating the Thrombin Generation Profiles of Four Different rFVIII Products in FVIII-deficient Plasma Using FIXa and FXIa Activation. Haemophilia. 2018;24(5):815-822. PubMed PMID: 30112856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluating the thrombin generation profiles of four different rFVIII products in FVIII-deficient plasma using FIXa and FXIa activation. AU - Brophy,Donald F, AU - Martin,Erika J, AU - Ninivaggi,Marisa, AU - Mohammed,Bassem M, AU - Barrett,John C, AU - Kuhn,Janice, AU - Nolte,Melinda E, AU - Waters,Emily K, AU - Ezban,Mirella, Y1 - 2018/08/16/ PY - 2018/04/26/received PY - 2018/07/11/revised PY - 2018/07/11/accepted PY - 2018/8/17/pubmed PY - 2019/1/5/medline PY - 2018/8/17/entrez KW - factor IXa KW - factor VIII KW - factor XIa KW - haemophilia KW - one-stage assay KW - thrombin generation assay SP - 815 EP - 822 JF - Haemophilia : the official journal of the World Federation of Hemophilia JO - Haemophilia VL - 24 IS - 5 N2 - INTRODUCTION: The thrombin generation assay (TGA) can be used to monitor factor replacement therapy in patients with haemophilia. The TGA assay is typically performed using tissue factor as the reaction activator; however, activating with FIXa or FXIa can enhance assay sensitivity when FVIII < 1%. AIMS: To evaluate the sensitivity of the TGA when FIXa (5 nmol/L) and FXIa (0.22 nmol/L) are used to activate the assay in platelet-poor plasma and to compare these data to the one-stage and chromogenic assays. METHODS: Plasma from 10 severe FVIII-deficient subjects was supplemented with FVIII (0%, 0.1%, 0.4%, 1.2%, 4%, 11% and 33%), using either Novo Eight® , Advate® , Eloctate® , turoctocog alfa pegol or a control standard. The one-stage and chromogenic assays quantified the FVIII levels. The TGA assay was activated using either FIXa or FXIa. RESULTS: Both FIXa- and FXIa-activated TGA were sensitive across FVIII concentrations, with intra-assay coefficient of variation (CV) < 10%. The FXIa-activated assay had 25% CV at the lowest level of FVIII compared to 10% CV with FIXa activation. There were strong correlations between the FIXa- and FXIa-activated TGA tests (R2 = 0.9912) and between the one-stage and chromogenic assays (R2 = 0.9469). However, there were poor relationships between the TGA tests and one-stage and chromogenic assays. CONCLUSIONS: Both FIXa- and FXIa activation results in similar TGA profiles across a FVIII range of 0.1%-33%; however, FIXa activation was more robust at the lowest levels of FVIII compared with FXIa activation. SN - 1365-2516 UR - https://www.unboundmedicine.com/medline/citation/30112856/Evaluating_the_thrombin_generation_profiles_of_four_different_rFVIII_products_in_FVIII_deficient_plasma_using_FIXa_and_FXIa_activation_ L2 - https://doi.org/10.1111/hae.13597 DB - PRIME DP - Unbound Medicine ER -