Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene

Picard, Véronique; Nowak‐Göttl, Ulrike; Biron‐Andréani, Christine; Fouassier, Marc; Frère, Corinne; Goualt-Heilman, Michèle; Maistre, Emmanuel de; Régina, Sandra; Rugeri, Lucia; Ternisien, Catherine; Trichet, Catherine; Vergnes, C.; Aiach, Martine; Alhenc‐Gelas, Martine

doi:10.1002/humu.9425

Cited by 54 publications

(42 citation statements)

References 16 publications

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“…However, in proband 8, AT heparin cofactor activity was much lower than AT antigen level (20 and 56%, respectively), suggesting the presence of 2 mutations, one responsible for a type I and the other responsible for a type II HBS deficiency. This is consistent with the observation that proband 8 is a compound heterozygote who carries both the c.440C[T substitution changing an amino acid located in the heparin binding site (p.147Thr[Ile), and a three exon-deletion (Picard et al 2006). We noticed that three other probands are also compound heterozygotes, although they had a typical type I deficiency AT phenotype.…”

Section: Serpinc1 Analysis In 86 Probands With Type I At Deficiencysupporting

confidence: 91%

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency

et al. 2009

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Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.

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Section: Serpinc1 Analysis In 86 Probands With Type I At Deficiencysupporting

confidence: 91%

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency

et al. 2009

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“…The homozygous state is almost universally fatal in utero. Functional antithrombin levels in heterozygous individual ranges 35-70% [4, 8, 48, 49]. Besides presenting as DVT or PE, VTE from antithrombin deficiency can occur in unusual sites, such as cerebral sinuses and the mesenteric, portal, and renal veins.…”

Section: Specific Hypercoagulable Disorders and Laboratory Studiesmentioning

confidence: 99%

“…Type II deficiencies are further classified by antithrombin mutation site. However, subclassification is generally not clinically necessary because anticoagulant therapy does not differ between types [41, 46, 47, 49]. …”

Section: Specific Hypercoagulable Disorders and Laboratory Studiesmentioning

confidence: 99%

Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants

Nakashima

Rogers

2014

Blood Res

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Hypercoagulability can result from a variety of inherited and, more commonly, acquired conditions. Testing for the underlying cause of thrombosis in a patient is complicated both by the number and variety of clinical conditions that can cause hypercoagulability as well as the many potential assay interferences. Using an algorithmic approach to hypercoagulability testing provides the ability to tailor assay selection to the clinical scenario. It also reduces the number of unnecessary tests performed, saving cost and time, and preventing potential false results. New oral anticoagulants are powerful tools for managing hypercoagulable patients; however, their use introduces new challenges in terms of test interpretation and therapeutic monitoring. The coagulation laboratory plays an essential role in testing for and treating hypercoagulable states. The input of laboratory professionals is necessary to guide appropriate testing and synthesize interpretation of results.

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“…However, an immunochemical assay for PC is often employed in the second diagnostic step in case of reduced functional activity as a useful additional step by comparison with functional PC levels (108). In contrast, type II deficiency for AT is divided into three subtypes on the basis of the nature of the functional defect that can affect the heparin binding site (HBS mutation), reactive site (RS mutation) or can have pleiotropic effects (PE mutation) (109). Among the three subtypes, only the HBS mutation is considered to have a low risk of thrombosis, thus increasing the clinical relevance of differentiating the subtypes of AT deficiencies (107,110,111).…”

Section: Deficiencies Of Physiological Anticoagulantsmentioning

confidence: 99%

Laboratory Investigation of Thrombophilia / LABORATORIJSKO ISPITIVANJE TROMBOFILIJA

Margetić¹

2014

Journal of Medical Biochemistry

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Summary: Laboratory investigation of thrombophilia is aimed at detecting the well-established hereditary and acquired causes of venous thromboembolism, including activated protein C resistance/factor V Leiden mutation, prothrombin G20210A mutation, deficiencies of the physiological anticoagulants antithrombin, protein C and protein S, the presence of antiphospholipid antibodies and increased plasma levels of homocysteine and coagulation factor VIII. In contrast, investigation of dysfibrinogenemia, a very rare thrombophilic risk factor, should only be considered in a patient with evidence of familial or recurrent thrombosis in the absence of all evaluated risk factors mentioned above. At this time, thrombophilia investigation is not recommended for other potential hereditary or acquired risk factors whose association with increased risk for thrombosis has not been proven sufficiently to date. In order to ensure clinical relevance of testing and to avoid any misinterpretation of results, laboratory investigation of thrombophilia should always be performed in accordance with the recommended guidelines on testing regarding the careful selection of patients, time of testing and assays and assay methods used. The aim of this review is to summarize the most important aspects on thrombophilia testing, including whom and when to test, what assays and assay methods to use and all other variables that should be considered when performing laboratory investigation of thrombophilia.Keywords: acquired risk factors, hereditary risk factors, laboratory investigation of thrombophilia, venous thromboembolism Sa`etak: Cilj laboratorijskog ispitivanja trombofilije je otkrivanje ve} ustanovljenih naslednih i ste~enih uzroka venskog tromboembolizma, me|u kojima su aktivirana rezistencija na protein C/mutacija faktora V Leiden, mutacija protrombina G20210A, deficijencija fiziolo{kih antikoagulanasa antitrombina, proteina C i proteina S, prisustvo antifosfolipidnih antitela i povi{enih nivoa homocisteina i faktora koagulacije VIII u plazmi. Nasuprot tome, ispitivanje disfibrinogenemije, veoma retkog faktora rizika za trombofiliju, treba uzeti u razmatranje samo kod pacijenata kod kojih postoje dokazi o porodi~noj ili rekurentnoj trombozi uz odsustvo svih navedenih faktora rizika. U ovom trenutku, ispitivanje trombofilije se ne preporu~uje za ostale potencijalne nasledne ili ste~ene faktore rizika, ~ija povezanost sa pove}anim rizikom za trombozu jo{ nije nedvosmisleno dokazana. Kako bi se obezbedila klini~ka relevantnost testiranja i izbeglo pogre{no tuma~enje rezultata, laboratorijsko ispitivanje trombofilije trebalo bi uvek vr{iti u skladu s preporukama za testiranje koje se odnose na pa`ljiv odabir pacijenata, vreme testiranja i testove i metode koji se koriste. Cilj ovog preglednog ~lanka je da se ukratko predstave najva`niji aspekti testiranja trombofilije, izme|u ostalog, koga i kada testirati, koje testove i metode upotrebiti i koje sve varijable treba uzeti u obzir prilikom laboratorijskog ispitivanja trombofilije.Klju~ne rije~i...

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Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene

Cited by 54 publications

References 16 publications

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency

Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulants

Laboratory Investigation of Thrombophilia / LABORATORIJSKO ISPITIVANJE TROMBOFILIJA

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