Verhagen Marieke J A, van Heerde Waander L, van der Bom Johanna G, Beckers Erik A M, Blijlevens Nicole M A, Coppens Michiel, Gouw Samantha C, Jansen Joop H, Leebeek Frank W G, van Vulpen Lize F D, Meijer Daniëlle, Schols Saskia E M
Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, The Netherlands.
Res Pract Thromb Haemost. 2023 Feb 1;7(2):100062. doi: 10.1016/j.rpth.2023.100062. eCollection 2023 Feb.
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.
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.
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.
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.
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.
在FVIII或FIX活性水平相似的血友病患者中观察到临床出血表型的异质性。凝血酶生成和纤溶酶生成作为一种全面的止血检测方法，可能有助于更好地预测哪些患者出血风险增加。
本研究的目的是描述血友病患者临床出血表型与凝血酶生成及纤溶酶生成特征之间的关联。
在参与荷兰第六次血友病研究（HiN6）的血友病患者血浆样本中进行奈梅亨止血检测，该检测可同时测量凝血酶和纤溶酶生成。接受预防性治疗的患者经历了洗脱期。严重临床出血表型定义为自我报告的年出血率≥5、自我报告的年关节出血率≥3或使用二级/三级预防性治疗。
本亚研究共纳入446例患者，中位年龄44岁。血友病患者与健康个体之间的凝血酶生成和纤溶酶生成参数不同。重度、中度和轻度血友病患者及健康个体的凝血酶峰值高度中位数分别为1.0 nM、25.9 nM、47.1 nM和143.9 nM。与健康个体相比，凝血酶峰值高度<49%且凝血酶潜力<72%的患者出现严重出血表型，且与血友病严重程度无关。严重临床出血表型患者的凝血酶峰值高度中位数为0.70%，轻度临床出血表型患者为30.3%。这些患者的凝血酶潜力中位数分别为0.06%和59.3%。
血友病患者凝血酶生成减少与严重临床出血表型相关。凝血酶生成结合出血严重程度可能是一种更好的工具，可用于根据个体情况制定预防性替代治疗方案，而不考虑血友病严重程度。
