Research and practice in thrombosis and haemostasis · 2026
Intrinsic activated thrombin generation for treatment efficacy and monitoring of octocog alfa and emicizumab in severe hemophilia A.
СтатьяСравнительное исследованиеНазвание и аннотация: Перевод в очереди
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Urlings Emma H, Heubel-Moenen Floor C J I, van Oerle René, Hellenbrand Dave L S, van der Meijden Paola E J, Hackeng Tilman M, Cate Hugo Ten, Nagy Magdolna, Henskens Yvonne M C, Spronk Henri M H
Аннотация
BACKGROUND: Monitoring patients with severe hemophilia A (SHA) receiving nonfactor replacement therapies such as emicizumab presents significant challenges, because conventional activated partial thromboplastin time-based assays are subject to interference from these treatments. Therefore, we hypothesized that an intrinsic activated thrombin generation assay (TGA) could be an improved alternative.
OBJECTIVES: To investigate the sensitivity and applicability of intrinsic activated TGA compared with extrinsic activated assays for monitoring SHA patients on factor (F)VIII (FVIII) and non-FVIII replacement products.
METHODS: We developed a novel intrinsic trigger reagent (platelet-poor plasma [PPP] Reagent INT) and compared it with tissue factor (TF) reagents, as well as an FXIa-based reagent, using the Calibrated Automated Thrombography method. Thrombin generation was measured in deficient plasmas, healthy volunteers (n = 103), FVIII-deficient plasma spiked with octocog alfa or emicizumab, and plasma from SHA patients on emicizumab (n = 22).
RESULTS: PPP Reagent INT specifically activated the intrinsic pathway, showing minimal thrombin generation in FXII- and FXI-deficient plasma, and no thrombin generation in FIX- and FVIII-deficient plasma, whereas activation occurred independently of prekallikrein. Linear regression analysis showed superior sensitivity for PPP Reagent INT triggered thrombin generation in FVIII-deficient plasma spiked with octocog alfa or emicizumab. In plasma from SHA patients, PPP Reagent INT demonstrated sixfold and fourfold greater sensitivity to emicizumab level changes compared with TF-based reagents.
CONCLUSION: Intrinsic activated TGA using PPP Reagent INT provides enhanced sensitivity for monitoring SHA patients on both FVIII and non-FVIII replacement products compared with TF-based triggers, representing a promising tool for personalized monitoring.
OBJECTIVES: To investigate the sensitivity and applicability of intrinsic activated TGA compared with extrinsic activated assays for monitoring SHA patients on factor (F)VIII (FVIII) and non-FVIII replacement products.
METHODS: We developed a novel intrinsic trigger reagent (platelet-poor plasma [PPP] Reagent INT) and compared it with tissue factor (TF) reagents, as well as an FXIa-based reagent, using the Calibrated Automated Thrombography method. Thrombin generation was measured in deficient plasmas, healthy volunteers (n = 103), FVIII-deficient plasma spiked with octocog alfa or emicizumab, and plasma from SHA patients on emicizumab (n = 22).
RESULTS: PPP Reagent INT specifically activated the intrinsic pathway, showing minimal thrombin generation in FXII- and FXI-deficient plasma, and no thrombin generation in FIX- and FVIII-deficient plasma, whereas activation occurred independently of prekallikrein. Linear regression analysis showed superior sensitivity for PPP Reagent INT triggered thrombin generation in FVIII-deficient plasma spiked with octocog alfa or emicizumab. In plasma from SHA patients, PPP Reagent INT demonstrated sixfold and fourfold greater sensitivity to emicizumab level changes compared with TF-based reagents.
CONCLUSION: Intrinsic activated TGA using PPP Reagent INT provides enhanced sensitivity for monitoring SHA patients on both FVIII and non-FVIII replacement products compared with TF-based triggers, representing a promising tool for personalized monitoring.