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Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation

BACKGROUND: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmege...

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Autores principales: Valke, Lars L.F.G., Bukkems, Laura H., Barteling, Wideke, Laros‐van Gorkom, Britta A.P., Blijlevens, Nicole M.A., Mathôt, Ron A.A., van Heerde, Waander L., Schols, Saskia E.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756259/
https://www.ncbi.nlm.nih.gov/pubmed/32979031
http://dx.doi.org/10.1111/jth.15106
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author Valke, Lars L.F.G.
Bukkems, Laura H.
Barteling, Wideke
Laros‐van Gorkom, Britta A.P.
Blijlevens, Nicole M.A.
Mathôt, Ron A.A.
van Heerde, Waander L.
Schols, Saskia E.M.
author_facet Valke, Lars L.F.G.
Bukkems, Laura H.
Barteling, Wideke
Laros‐van Gorkom, Britta A.P.
Blijlevens, Nicole M.A.
Mathôt, Ron A.A.
van Heerde, Waander L.
Schols, Saskia E.M.
author_sort Valke, Lars L.F.G.
collection PubMed
description BACKGROUND: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG). OBJECTIVE: To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model. METHODS: Twenty‐five HA patients (baseline FVIII < 1‐9 IU/dL) underwent a pharmacokinetic study with a single dose of 25‐50 IU/kg standard half‐life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA. RESULTS: FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0‐6.0) to 71 IU/dL (62‐82) 15 minutes after administration and decreased to 15 IU/dL (10‐26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15‐35) to 222nM (159‐255), and thrombin potential (TP) from 404nM/min (undetectable‐876) to 1834nM/min (1546‐2353). Twenty‐four hours after infusion, TG parameters remained high (TPH 73nM [58.5‐126.3]; TP 1394nM/min [1066‐1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation. CONCLUSION: HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients.
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spelling pubmed-77562592020-12-28 Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation Valke, Lars L.F.G. Bukkems, Laura H. Barteling, Wideke Laros‐van Gorkom, Britta A.P. Blijlevens, Nicole M.A. Mathôt, Ron A.A. van Heerde, Waander L. Schols, Saskia E.M. J Thromb Haemost HAEMOSTASIS BACKGROUND: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG). OBJECTIVE: To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model. METHODS: Twenty‐five HA patients (baseline FVIII < 1‐9 IU/dL) underwent a pharmacokinetic study with a single dose of 25‐50 IU/kg standard half‐life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA. RESULTS: FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0‐6.0) to 71 IU/dL (62‐82) 15 minutes after administration and decreased to 15 IU/dL (10‐26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15‐35) to 222nM (159‐255), and thrombin potential (TP) from 404nM/min (undetectable‐876) to 1834nM/min (1546‐2353). Twenty‐four hours after infusion, TG parameters remained high (TPH 73nM [58.5‐126.3]; TP 1394nM/min [1066‐1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation. CONCLUSION: HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients. John Wiley and Sons Inc. 2020-10-21 2020-12 /pmc/articles/PMC7756259/ /pubmed/32979031 http://dx.doi.org/10.1111/jth.15106 Text en © 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle HAEMOSTASIS
Valke, Lars L.F.G.
Bukkems, Laura H.
Barteling, Wideke
Laros‐van Gorkom, Britta A.P.
Blijlevens, Nicole M.A.
Mathôt, Ron A.A.
van Heerde, Waander L.
Schols, Saskia E.M.
Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title_full Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title_fullStr Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title_full_unstemmed Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title_short Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation
title_sort pharmacodynamic monitoring of factor viii replacement therapy in hemophilia a: combining thrombin and plasmin generation
topic HAEMOSTASIS
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756259/
https://www.ncbi.nlm.nih.gov/pubmed/32979031
http://dx.doi.org/10.1111/jth.15106
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