Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Clinic of Hematology, University Clinical Center, Belgrade, Serbia.
J Thromb Haemost. 2017 Apr;15(4):670-677. doi: 10.1111/jth.13618. Epub 2017 Feb 24.
Essentials Prothrombin Belgrade mutation leads to antithrombin resistance. Clinical and biochemical phenotypes in a large family with this mutation were investigated. In carriers, we detected decreased factor II activity and increased endogenous thrombin potential. Prothrombin Belgrade mutation represents a strong prothrombotic risk factor.
Background The recently reported c.1787G>A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods Nineteen family members were investigated, among whom 10 were carriers of the c.1787G>A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.
研究携带 prothrombin Belgrade 突变的大型塞尔维亚家族中与抗凝血酶抵抗相关的血栓形成的临床和生化表型。
对 19 名家族成员进行了调查，其中 10 名携带 c.1787G>A 突变。在所有受试者中确定了临床表型，并进行了止血参数的实验室检查。
在 10 名突变携带者中，有 6 名发生了血栓栓塞事件，主要是深静脉和肠系膜静脉血栓形成。首次血栓事件的中位年龄为 26.5（12-41）岁，而首次血栓形成的发生率为每年 2.2%。与非携带者相比，所有突变携带者的凝血酶原活性均显著降低，明显区分了两组。然而，突变的存在并未影响血浆中凝血酶原抗原水平。与非携带者相比，所有携带者的内源性凝血酶潜力均显著增加，表明血液存在高凝状态。有趣的是，两组的 D-二聚体和 F1+2 片段水平相似。
尽管罕见，但 prothrombin Belgrade 突变代表了强烈的血栓形成倾向，在研究的家族中，血栓形成的发病年龄较早。根据我们的结果，凝血酶原活性降低可能是血栓形成患者检测这种突变的简单筛查试验。
