Haisma Bauke, Rijpma Sanna R, Cnossen Marjon H, den Exter Paul L, Kruis Ilmar C, Meijer Karina, Nieuwenhuizen Laurens, van Es Nick, Saes Joline L, Blijlevens Nicole M A, van Heerde Waander L, Schols Saskia E M
Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands.
Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands; Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands.
Thromb Res. 2025 May;249:109317. doi: 10.1016/j.thromres.2025.109317. Epub 2025 Apr 4.
Congenital fibrinogen disorders (CFDs), encompassing quantitative (hypo-/afibrinogenemia) and qualitative (dysfibrinogenemia) defects, can result in bleeding or thrombotic events. This study aimed to enhance understanding of the clinical and genetic characteristics of CFD patients.
The Dutch cross-sectional RBiN study included 47 CFD patients (median age 38, 55 % women), categorized into (hypo)dysfibrinogenemia, severe (<500 mg/L), moderate (500-1000 mg/L) and mild hypofibrinogenemia (1000-1800 mg/L) as well as carriers with pathogenic variants but normal fibrinogen levels (>1800 mg/L). Clinical assessments included bleeding phenotype, thrombosis history, fibrinogen activity and antigen levels, thrombin and plasmin generation assays and genotypic analysis.
Patients with severe hypofibrinogenemia displayed the highest median ISTH-BAT score (16), followed by moderate hypofibrinogenemia (11), (hypo)dysfibrinogenemia (6), mild hypofibrinogenemia (4) and carriers (0). Female-specific bleeding (postpartum hemorrhage, heavy menstrual bleeding) was prevalent across all CFD subtypes, with moderate hypofibrinogenemia showing high average scores on these ISTH-BAT items (3.0 and 2.3). Postoperative bleeding was common in moderate and severe hypofibrinogenemia (average ISTH-BAT item scores of 2.5 and 2.8, respectively). Patients with biallelic variants had lower fibrinogen activity levels (median 200 mg/L) than those with monoallelic variants (935 mg/L, p < 0.001). Fibrinogen activity levels correlated positively with plasmin peak height (R = 0.74, p < 0.001) and inversely with thrombin potential (R = -0.55, p = 0.002). Thrombin potential was 1.77-fold higher in patients with a venous thrombosis history (n = 5, p = 0.03) than in healthy controls.
In patients with CFDs, postoperative bleeding correlates with fibrinogen activity, while female-specific bleeding affects all CFD subtypes. Elevated thrombin generation might explain thrombosis risk in these patients.
先天性纤维蛋白原疾病（CFDs）包括数量缺陷（低纤维蛋白原血症/无纤维蛋白原血症）和质量缺陷（异常纤维蛋白原血症），可导致出血或血栓形成事件。本研究旨在加深对CFD患者临床和遗传特征的理解。
荷兰的横断面RBiN研究纳入了47例CFD患者（中位年龄38岁，55%为女性），分为（低）异常纤维蛋白原血症、严重（<500mg/L）、中度（500 - 1000mg/L）和轻度低纤维蛋白原血症（1000 - 1800mg/L），以及携带致病变异但纤维蛋白原水平正常（>1800mg/L）的携带者。临床评估包括出血表型、血栓形成病史、纤维蛋白原活性和抗原水平、凝血酶和纤溶酶生成试验以及基因分型分析。
严重低纤维蛋白原血症患者的中位ISTH - BAT评分最高（16分），其次是中度低纤维蛋白原血症（11分）、（低）异常纤维蛋白原血症（6分）、轻度低纤维蛋白原血症（4分）和携带者（0分）。女性特异性出血（产后出血、月经过多）在所有CFD亚型中都很常见，中度低纤维蛋白原血症在这些ISTH - BAT项目上的平均得分较高（3.0分和2.3分）。术后出血在中度和严重低纤维蛋白原血症中很常见（ISTH - BAT项目平均得分分别为2.5分和2.8分）。双等位基因变异患者的纤维蛋白原活性水平（中位值200mg/L）低于单等位基因变异患者（935mg/L，p < 0.001）。纤维蛋白原活性水平与纤溶酶峰值高度呈正相关（R = 0.74，p < 0.001），与凝血酶潜力呈负相关（R = -0.55，p = 0.002）。有静脉血栓形成病史的患者（n = 5，p = 0.03）的凝血酶潜力比健康对照高1.77倍。
在CFD患者中，术后出血与纤维蛋白原活性相关，而女性特异性出血影响所有CFD亚型。凝血酶生成增加可能解释了这些患者的血栓形成风险。
