Antithrombin deficiency, the most severe thrombophilia, might be underestimated, since it is only investigated in cases with consistent functional deficiency or family history. We have analyzed 444 consecutive, unrelated cases, from 1998 to 2021, with functional results supporting antithrombin deficiency in at least one sample. Plasma antithrombin was evaluated by functional and biochemical methods in at least two samples. SERPINC1 gene was analyzed by sequencing and MPLA. Hypoglycosylation was studied by electrophoresis and high-performance liquid chromatography (HPLC). In 260 of 305 cases (85.2%) with constitutive deficiency (activity < 80% in all samples), a SERPINC1 (N = 250), or N-glycosylation defect (N = 10) was observed, while 45 remained undetermined. The other 139 cases had normal antithrombin activity (≥ 80%) in at least one sample, what we called transient deficiency. Sixty-one of these cases (43.9%) had molecular defects: 48 had SERPINC1 variants, with two recurrent mutations (p.Ala416Ser[Cambridge II], N = 15; p.Val30Glu[Dublin], N = 12), and 13 hypoglycosylation. Thrombotic complications occurred in transient deficiency, but were less frequent, latter-onset, and had a higher proportion of arterial events than in constitutive deficiency. Two mechanisms explained transient deficiency: The limitation of functional methods to detect some variants and the influence of external factors on the pathogenic consequences of these mutations. Our study reveals a molecular defect in a significant proportion of cases with transient antithrombin deficiency, and changes the paradigm of thrombophilia, as the pathogenic effect of some mutations might depend on external factors and be present only at certain timepoints. Antithrombin deficiency is underestimated, and molecular screening might be appropriate in cases with fluctuating laboratory findings.

中文翻译：

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一过性抗凝血酶缺乏症的分子和临床特征：先天性血栓形成倾向的新概念

抗凝血酶缺乏症是最严重的血栓形成倾向，可能被低估了，因为它只在具有持续功能缺陷或家族史的病例中进行调查。从 1998 年到 2021 年，我们分析了 444 例连续的无关病例，功能结果支持至少一个样本中的抗凝血酶缺乏症。在至少两个样品中通过功能和生化方法评估血浆抗凝血酶。通过测序和 MPLA 分析SERPINC1基因。通过电泳和高效液相色谱 (HPLC) 研究低糖基化。在 305 例 (85.2%) 中，有 260 例 (85.2%) 存在组成性缺陷（所​​有样品中活性 < 80%）、SERPINC1（N  = 250）或 N-糖基化缺陷（N = 10) 被观察到，而 45 仍未确定。其他 139 例在至少一个样本中具有正常的抗凝血酶活性（≥ 80%），我们称之为暂时性缺乏。其中 61 例（43.9%）有分子缺陷：48 例有SERPINC1变体，有两个复发突变（p.Ala416Ser[Cambridge II]，N  = 15；p.Val30Glu[Dublin]，N = 12) 和 13 低糖基化。血栓并发症发生在短暂性缺乏症中，但发生频率较低，发病较晚，动脉事件的比例高于构成性缺乏症。两种机制解释了短暂的缺陷：检测某些变异的功能方法的局限性以及外部因素对这些突变的致病后果的影响。我们的研究揭示了在很大一部分短暂性抗凝血酶缺乏的病例中存在分子缺陷，并改变了血栓形成倾向的范式，因为某些突变的致病作用可能取决于外部因素并且仅在某些时间点出现。抗凝血酶缺乏症被低估了，分子筛查可能适用于实验室检查结果波动的情况。