Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis

Abstract

The antithrombin A384S mutation has a relatively high frequency in the British population but has not been identified in other populations. This variant has been associated with cases of thrombotic disease, but its clinical relevance in venous thrombosis remained unclear. We have conducted a secondary analysis of the prevalence of the mutation in a large case-control study, including 1018 consecutive Spanish patients with venous thromboembolism. In addition, we evaluated its functional consequences in 20 carriers (4 homozygous). This mutation, even in the homozygous state, did not affect anti-Xa activity or antigen levels, and it only slightly impaired anti-IIa activity. Thus, routine clinical methods cannot detect this anomaly, and, accordingly, this alteration could have been underestimated. We identified this mutation in 0.2% of Spanish controls. Among patients, this variant represented the first cause of antithrombin anomalies. Indeed, 1.7% patients carried the A384S mutation, but 0.6% had any other antithrombin deficiency. The mutated allele was associated with an increased risk of venous thrombosis with an adjusted OR of 9.75 (95% CI, 2.2-42.5). This is the first study supporting that antithrombin A384S mutation is a prevalent genetic risk factor for venous thrombosis and is the most frequent cause of antithrombin deficiency in white populations. (Blood. 2007;109: [4258][4259][4260][4261][4262][4263]

Disease-causing mutations in the serpin antithrombin reveal a key domain critical for inhibiting protease activities

“…The identification and analysis of natural mutations in patients with antithrombin deficiency have assisted the description of key functional domains or residues of this anticoagulant (15)(16)(17)(18)22). Thus, mutations at the RCL, HBS, and the C-sheet are responsible for the three subtypes of antithrombin type II deficiency.…”

Influence of natural SERPINC1 mutations on ex vivo thrombin generation

“…For the diagnosis of a RDVT, different CUS criteria are established. [2][3][4]. Previous studies have validated these criteria for the diagnosis of RDVT by CUS, but there is a lack of data in the literature reporting the daily practise of diagnosing clinically suspected ipsilateral RDVT [2][3][4].…”

“…Moreover, whether the AT Cambridge II mutation increases the risk of VT remains doubtful. Initially, this mutation was described in asymptomatic subjects from the UK [2,3]; in contrast, subsequent findings from a large Spanish case-control study [4] suggested that the mutation may be a VT risk factor and the most frequent cause of AT deficiency in Caucasian populations. However, results obtained in three independent large French cohorts [5,6] are not in agreement with this hypothesis.…”

Antithrombin deficiency and its laboratory diagnosis

“…As the reactive site of thrombin and FXa differs somewhat, one would expect that AT deficiencies caused by certain mutations around the reactive site are detected by the two types of assays with different sensitivity. Indeed, the Ala384Ser mutation (AT Cambridge II) which is a relatively prevalent variant in the general population, is not detected by the anti-FXa assay, but anti-thrombin activity is mildly, but significantly, reduced (63,64). However, this mutation causes only a relatively mild thrombophilia, and even elderly homozygous individuals might lack the history of VTE.…”

“…However, there is at least one notable exception. The heterozygous p.Ala384Ser mutation (AT Cambridge II) causes type II RS deficiency with a mild phenotype, and this mutation can also exist in homozygous form (63,64). Type II HBS deficiency confers a lower risk of thrombosis compared with the other subtypes (65,66).…”