Article

Inherited antithrombin deficiency: A review

Department of Internal Medicine, University of Minnesota School of Medicine, Minneapolis, MN, USA.
Haemophilia (Impact Factor: 2.47). 12/2008; 14(6):1229-39. DOI: 10.1111/j.1365-2516.2008.01830.x
Source: PubMed

ABSTRACT Antithrombin (AT) is a potent inactivator of thrombin and factor Xa and the major inhibitor of blood coagulation. Inherited AT deficiencies are uncommon, with prevalences in the general population between 1 in 500 and 1 in 5000. They are either quantitative (type I) or qualitative (type II). Type II is subdivided into the more common, but less thrombogenic, type IIb deficiency caused by a defect in the heparin-binding region of AT and the less common, but more thrombophilic, type IIa variant caused by mutations in the thrombin-binding site. A pleiotropic type IIc deficiency also exists. In the evaluation of a thrombophilic individual, a functional AT assay (AT activity) should be used and the diagnosis of AT deficiency only established after acquired causes have been ruled out and repeat AT testing on an additional sample has been performed. A subsequent antigenic AT assay result leads to differentiation between type I and type II deficiency. Further specialized tests help subclassify the type II deficiencies, but this is typically not carried out for clinical purposes, even though it might be helpful to assess thrombosis risk. AT deficiency is associated with an increased risk for venous thromboembolism (VTE) and pregnancy loss. The association with arterial thrombosis is only weak. VTE prophylaxis and treatment management will be discussed in this article and existing treatment guidelines presented. The lack of data surrounding the use of AT concentrates and the resulting ambiguity as to when to use such concentrates will be discussed.

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Available from: Mrinal M Patnaik, Aug 17, 2015
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    • "The prevalence of this mutation in Europe is about 2–3% for heterozygous carriers and VTE risk is increased 2–4 fold [10]. On the other hand, deficiency of naturally existing anticoagulants like antithrombin, protein C or protein S can be caused by heritable genetic defects [11] [12]. Heritable thrombophilia is also discussed for patients with klinefelter syndrome and chronic leg ulcers. "
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    • "Moreover, two of the patients with a type IIb mutation also presented with normal AT activity levels using the FXa inhibition-activity assay (Table 1) suggesting that this method may be affected also by other type II mutations. Altogether, this supports previous findings indicating that there is a risk of not detecting all type II deficiencies when using FXa inhibition-based methods alone [14] [15]. "
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    ABSTRACT: Objectives: In hereditary antithrombin (AT) deficiency it is important to determine the underlying mutation since the future risk of thromboembolism varies considerably between mutations. DNA investigations are in general thought of as flawless and irrevocable, but the diagnostic approach can be critical. We therefore investigated mutation results in the AT gene, SERPINC1, with two different approaches. Design and methods: Sixteen patients referred to the Centre for Thrombosis and Haemostasis, Odense University Hospital, with biochemical indications of AT deficiency, but with a negative denaturing high-performance liquid chromatography (DHPLC) mutation screening (routine approach until recently) were included. As an alternative mutation analysis, direct sequencing of all exons and exon-intron boundaries without pre-selection by DHPLC was performed. Results: Out of sixteen patients with a negative DHPLC mutation screening, discordant results were found in ten patients (62.5%) when using direct sequencing: Eight had the Basel mutation (c.218C>T), while two had the Cambridge II mutation (c.1246G>T). For seven of the ten patients this meant an altered clinical risk-assessment for future thromboses. Conclusions: Awareness must be drawn to the possibility of differences in DNA diagnostics in general and advances when using newer techniques in particular. One should consider re-analysis of results obtained by earlier sequencing strategies, as clinically important information can be overlooked.
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    • "Also, decreased control over thrombin in cases with AT deficiency may have a positive effect on an inhibitor of fibrinolysis called thrombin-activatable fibrinolysis inhibitor (TAFI), which may add to the hypercoagulable status in these patients, as will be explained later. Hereditary AT deficiency has been found in 1-5 % of thrombotic cases, with a prevalence of one in 500-5000 in different populations (Tait et al., 1991; Koster et al., 1995a; Koeleman et al., 1997; Bertina, 1997; Laffan & Manning, 2002b; Ehsan & Plumbley, 2002; Dahlbäck, 2008; Patnaik & Moll, 2008). It has an autosomal dominant mode of inheritance, and it accounts for a 10-fold increased risk of developing VTE (Dahlbäck, 2008). "
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