From the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Germany.
Circ Res. 2019 Aug 16;125(5):523-534. doi: 10.1161/CIRCRESAHA.119.315037. Epub 2019 Jul 17.
Carriers of the most common prothrombotic mutations FVL (factor V Leiden) and FII (prothrombin) 20210G>A show a highly variable clinical phenotype. Using standardized in vivo coagulation activation followed by activity pattern analysis we have recently shown, that the FVL mutation accelerates thrombin and APC (activated protein C) formation in carriers without a history of venous thromboembolism (VTE).
The aim of this prospective cohort study was to investigate, if the FII 20210G>A mutation induces a similar reaction pattern, and if the response rates differ in FVL and FII 20210G>A mutation carriers with prior VTE (VTE+).
We comparatively analyzed 30 FVL carriers, 28 FII 20210G>A carriers (thereof 13 VTE+ each) and 15 healthy controls. Changes in plasma levels of thrombin, prothrombin activation fragment 1+2 (F1+2), TAT (thrombin-antithrombin complex), APC, and D-dimer were monitored over 8 hours after infusion of recombinant factor VIIa (15 µg/kg). An increase of F1+2 and TAT levels was observed, that did neither differ between FVL and FII 20210G>A carriers nor between asymptomatic and VTE+ carriers of these mutations. Median plasma levels of APC increased more (P=0.008) in FVL carriers (from 1.39 to 7.79 pmol/L) than in FII 20210G>A carriers (from 1.03 to 5.79 pmol/L), and more in FII 20210G>A carriers (P=2×10) than in healthy controls (from 0.86 to 3.00 pmol/L). Most importantly, however, the APC response was greater (P=0.015) in asymptomatic (n=13) than in VTE+ (n=12) heterozygous FVL carriers, with an increase of APC levels from 1.44 to 8.11 pmol/L versus 1.27 to 5.62 pmol/L.
These in vivo data demonstrate that the FII 20210G>A and FVL mutations share an intermediate phenotype that is characterized by increased thrombin formation after coagulation activation. Furthermore, our data support the conclusion that the APC activating capacity of FVL carriers modifies the thrombotic risk of this common prothrombotic mutation.
携带最常见的促血栓形成突变 FVL（因子 V Leiden）和 FII（凝血酶原）20210G>A 的患者表现出高度可变的临床表型。我们最近使用标准化的体内凝血激活，随后进行活性模式分析，表明 FVL 突变可加速无静脉血栓栓塞（VTE）病史的携带者中凝血酶和 APC（活化蛋白 C）的形成。
本前瞻性队列研究的目的是研究 FII 20210G>A 突变是否诱导类似的反应模式，以及在有或无 VTE（VTE+）既往史的 FVL 和 FII 20210G>A 突变携带者中，反应率是否存在差异。
我们比较分析了 30 名 FVL 携带者、28 名 FII 20210G>A 携带者（其中 13 名 VTE+）和 15 名健康对照者。在输注重组 VIIa 因子（15 µg/kg）后 8 小时内监测血浆中凝血酶、凝血酶原激活片段 1+2（F1+2）、TAT（凝血酶-抗凝血酶复合物）、APC 和 D-二聚体的变化。观察到 F1+2 和 TAT 水平的升高，但 FVL 和 FII 20210G>A 携带者之间以及这些突变的无症状和 VTE+携带者之间均无差异。FVL 携带者的 APC 水平升高更为明显（P=0.008）（从 1.39 增加到 7.79 pmol/L），高于 FII 20210G>A 携带者（从 1.03 增加到 5.79 pmol/L），且高于健康对照组（从 0.86 增加到 3.00 pmol/L）。然而，更重要的是，无 VTE+（n=12）的杂合 FVL 携带者（n=13）的 APC 反应更大（P=0.015），APC 水平从 1.44 增加到 8.11 pmol/L，而有 VTE+（n=12）的杂合 FVL 携带者的 APC 水平从 1.27 增加到 5.62 pmol/L。
这些体内数据表明，FII 20210G>A 和 FVL 突变具有共同的中间表型，其特征是凝血激活后凝血酶形成增加。此外，我们的数据支持这样的结论，即 FVL 携带者的 APC 激活能力改变了这种常见促血栓形成突变的血栓形成风险。
