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Decreased thrombin generation profile is associated with severe bleeding phenotype in hemophilia: data from the Hemophilia in the Netherlands study

1Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands; Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands , Nijmegen, Gelderland, Netherlands, 2Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands; Enzyre BV, Novio Tech Campus, Nijmegen, the Netherlands, Nijmegen, Gelderland, Netherlands, 3Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; Center for Clinical Transfusion Research, Sanquin-Leiden University Medical Center, Leiden, the Netherlands, Leiden, Zuid-Holland, Netherlands, 4Department of Hematology, Maastricht University Medical Center, Maastricht University, Maastricht, the Netherlands, Maastricht, Limburg, Netherlands, 5Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands, Nijmegen, Gelderland, Netherlands, 6Amsterdam University Medical Centers, Amsterdam, the Netherlands, Amsterdam, Noord-Holland, Netherlands, 7Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Amsterdam, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands, Amsterdam, Noord-Holland, Netherlands, 8Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands, Nijmegen, Gelderland, Netherlands, 9Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands, Rotterdam, Zuid-Holland, Netherlands, 10Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands, Utrecht, Utrecht, Netherlands, 11Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, the Netherlands, Nijmegen, Gelderland, Netherlands

Abstract Number: OC 63.1

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Heterogeneity in clinical bleeding phenotype is observed in hemophilia patients with similar factor VIII or factor IX activity levels. Thrombin generation (TG) as a global hemostasis assay may contribute to better predict which patients are at increased risk of bleeding.

Aims: To quantify the association between clinical bleeding phenotype and TG profile in hemophilia patients.

Methods: The Nijmegen Hemostasis Assay (NHA), which simultaneously measures TG and plasmin generation, was performed in 863 hemophilia patients (adults and children) originating from the sixth Hemophilia in the Netherlands study. Patients using prophylaxis underwent a washout period. Ethical approval and written informed consent were obtained. Severe clinical bleeding phenotype was defined as an annual bleeding rate (ABR) ≥5 or an annual joint bleeding rate (AJBR) ≥3. Correlations were determined using Spearman’s correlation test.

Results: TG parameters significantly differed between hemophilia patients and healthy controls (thrombin peak height (TPH) in severe 1.0nM [IQR 1.0-1.0], moderate 25.5nM [1.0-46.5], mild hemophilia A 47.4nM [27.9-71.1], and controls 266.5nM [252.8-280.6]; thrombin potential in severe 1.0nM·min [1.0-1.0], moderate 607.6nM·min [1.0-1083.0], mild hemophilia A 1034.0nM·min [668.4-1398.0], and controls 2088.0nM·min [1988.0-2175.0]). Weak but significant correlations were found between clinical bleeding phenotype and TPH (ABR r=-0.2571; AJBR r=-0.2776) or thrombin potential (ABR r=-0.2752; AJBR r=-0.3084) (Figure 1). A severe clinical bleeding phenotype was observed in patients with a TPH < 35% and a thrombin potential < 70%, independent of hemophilia severity. Median TPH and thrombin potential were significantly lower in patients with a severe clinical bleeding phenotype versus a mild clinical bleeding phenotype (TPH: 0.4% vs 17%; thrombin potential 0.05% vs 46%) (Figure 2).

Conclusion(s): A decreased TG profile is associated with severe clinical bleeding phenotype in hemophilia patients. TG parameters in combination with clinical bleeding severity may be better tools to personalize prophylactic replacement therapy, irrespective of hemophilia severity.

To cite this abstract in AMA style:

Verhagen M, van Heerde W, van der Bom J, Beckers E, Blijlevens N, Coppens M, Gouw S, Jansen J, Leebeek F, van Vulpen L, Meijer D, Schols S. Decreased thrombin generation profile is associated with severe bleeding phenotype in hemophilia: data from the Hemophilia in the Netherlands study [abstract]. https://abstracts.isth.org/abstract/decreased-thrombin-generation-profile-is-associated-with-severe-bleeding-phenotype-in-hemophilia-data-from-the-hemophilia-in-the-netherlands-study/. Accessed October 1, 2023.

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