In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype

Marieke J A Verhagen, Waander L van Heerde, Johanna G van der Bom, Erik A M Beckers, Nicole M A Blijlevens, Michiel Coppens, Samantha C Gouw, Joop H Jansen, Frank W G Leebeek, Lize F D van Vulpen, Daniëlle Meijer, Saskia E M Schols*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Heterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding. Objectives: The objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia. Methods: The Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis. Results: In total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively. Conclusion: A decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity.

Original languageEnglish
Article number100062
Number of pages12
JournalResearch and practice in thrombosis and haemostasis
Issue number2
Publication statusPublished - Feb 2023


  • phenotype
  • hemophilia A
  • thrombin
  • hemophilia B
  • factor VIII


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