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Thromb Haemost 2017; 117(06): 1040-1051
DOI: 10.1160/TH16-08-0635
Coagulation and Fibrinolysis
Schattauer GmbH

Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency

Martine Alhenc-Gelas
1   Hématologie biologique, AP-HP Hôpital Européen G Pompidou, Hôpitaux Universitaires Paris Ouest, Paris, France
,
Genevieve Plu-Bureau
2   Unité d’hémostase, AP-HP, Hôpital Cochin, Hôpitaux universitaires Paris Centre, Faculté de Médecine Paris Descartes, Paris, France
,
Justine Hugon-Rodin
3   Unité de Gynécologie endocrinienne, AP-HP, Hôpital Cochin, Hôpitaux universitaires Paris Centre, Faculté de Médecine Paris Descartes, Paris, France
,
Veronique Picard
4   Laboratoire d’Hématologie, AP-HP Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France
,
Marie-Helene Horellou
5   Laboratoire d’Hématologie, AP-HP Hôpital Cochin, Hôpitaux universitaires Paris Centre Faculté de Médecine Paris Descartes, Paris, France
,
GFHT study group on Genetic Thrombophilia › Author Affiliations Financial support: This study was supported in part by a DHOS program „Soutien financier en faveur des laboratoires pratiquant le diagnostic par génétique moléculaire des maladies rares”.
Further Information

Publication History

Received: 17 August 2016

Accepted after major revision: 23 February 2017

Publication Date:
07 November 2017 (online)

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Summary

Inherited quantitative (type I) or qualitative (type II) antithrombin deficiency (ATD) due to mutations in the SERPINC1 gene is a well-known risk factor for venous thromboembolism. ATD may also increase risk for arterial thrombosis. Few studies have investigated risk for thrombosis according to mutations. We addressed this topic in a large retrospective cohort study of 540 heterozygous carriers of SERPINC1 mutations and compared risk for first venous or arterial thrombosis associated with carrying of different type II or type I mutations. No clear difference in risk for first venous thrombotic event was observed among type I (missense or null), type IIRS or type IIPE mutation carriers except for a few variants that displayed lower risk [all events, adjusted relative risk: Cambridge II: 0.42 (95%CI 0.25–0.70), Dublin: 0.35 (95%CI 0.13–0.99)]. IIHBS mutation carrying was associated with a clearly lower risk than type I mutation carrying [0.28 (95%CI 0.20–0.40)]. These differences in risk were observed for both all venous thrombotic events and pulmonary embolism associated with deep venous thrombosis. The HBS group was also heterogeneous, with AT Budapest 3 carriers displaying a non-significantly different risk [0.61 (95%CI 0.31–1.20)] compared to type I mutation carriers. We also studied risk for arterial thrombosis and found no significant influence of mutation type. Altogether, our findings suggest a place for SERPINC1 genotyping in the diagnosis of ATD.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Coagulation inhibitor - antithrombin - SERPINC1 - thrombophilia - thrombosis

 

  • References

  • 1 Harper PL, Carrell RW. The serpins. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EG, editors. Haemostasis and Thrombosis New York: Churchill-Livingstone; 1994: 641-653.
    Google Scholar
  • 2 Patnak NM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008; 14: 1229-1239.
    CrossrefPubMedGoogle Scholar
  • 3 Lane DA, Bayston T, Olds RJ. et al. Antithrombin mutation Database: 2nd (1997) Update. Thromb Haemost 1997; 77: 197-211.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Di Mino MND, Ambrosino P, Ageno W. et al. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 2015; 135: 923-932.
    CrossrefPubMedGoogle Scholar
  • 5 Finazzi G, Caccia R, Barbui T. Different prevalences of thromboembolism in the subtypes of congenital antithrombin III deficiency: review of 404 cases. Thromb Haemost 1987; 58: 1094.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Luxembourg B, Pavlova A, Geisen C. et al. Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype on hereditary antithrombin deficiency. Thromb Haemost 2014; 111: 249-257.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Puurunen M, Salo P, Engelbarth S. et al. Type II antithrombin deficiency caused by a founder mutation Pro73Leu in the Finnish population: clinical picture. J Thromb Haemost 2013; 11: 1844-1849.
    CrossrefPubMedGoogle Scholar
  • 8 Gindele R, Olah Z, Iloncza P. et al. Founder effect is responsible for the p.Leu131Phe heparin-binding-site antithrombin mutation common in Hungary: phenotype analysis in a large cohort. J Thromb Haemost 2016; 14: 704-715.
    CrossrefPubMedGoogle Scholar
  • 9 Corral J, Hernandez-Espinosa D, Soria JM. et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis. Blood 2007; 109: 4258-4263.
    CrossrefPubMedGoogle Scholar
  • 10 Navarro-Fernandez J, De la Morena-Barrio ME, Padilla J. et al. Antithrombin Dublin (p.Val30Glu): a relatively common variant with moderate thrombosis risk of causing transient antithrombin deficiency. Thromb Haemost 2016; 116: 146-154.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Soare AM, Popa C. Deficiencies of protein C, S and Antithrombin and Activated Protein C resistance – their involvement in the occurrence of arterial thrombosis. J Med Life 2010; 3: 412-415.
    PubMedGoogle Scholar
  • 12 Roldan V, Ordonez A, Marin F. et al. Antithrombin Cambridge II (A384S) supports a role for antithrombin deficiency in arterial thrombosis. Thromb Haemost 2009; 101: 483-486.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Kuhle S, Lane DA, Jochmanns K. et al. Homozygous antithrombin deficiency type II (99 Leu to Phe mutation) and childhood thromboembolism. Thromb Haemost 2001; 86: 1007-1011.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Orlando C, Heylen O, Lissens W, Jochmans K. Antithrombin heparin bindig site deficiency: a challenging diagnosis of a not so benign thrombophilia. Thromb Res 2015; 135: 1179-1185.
    CrossrefPubMedGoogle Scholar
  • 15 Picard V, Dautzenberg MD, Villoutreix BO. et al. Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerisation in vivo associated with severe childhood thrombosis. Blood 2003; 102: 919-925.
    CrossrefPubMedGoogle Scholar
  • 16 Ng p PC, Henikoff S. SIFT: Predicting amino-acid changes that affect protein function. Nucleic Acids Res 2003; 30: 3812-3814.
    PubMedGoogle Scholar
  • 17 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nature Methods 2010; 7: 248-249.
    CrossrefPubMedGoogle Scholar
  • 18 Houdayer C. In silico prediction of splice-affecting nucleotide variants. In silico tools for gene discovery. Methods Mol Biol 2011; 760: 269-281.
    PubMedGoogle Scholar
  • 19 Luxembourg B, D’Souza M, Körber S. et al. Prediction of the pathogenicity of anti-thrombin sequence variations by in silico methods. Thromb Res 2015; 135: 404-409.
    CrossrefPubMedGoogle Scholar
  • 20 Alhenc-Gelas M, Canonico M, Picard V. Influence of natural SERPINC1 mutations on ex vivo thrombin generation. J Thromb Haemost 2010; 8: 2718-2726.
    CrossrefPubMedGoogle Scholar
  • 21 Jin L, Abrahams JP, Skinner R. et al. The anticoagulant activation of antithrombin by heparin. Proc Natl Acad Sci USA 1997; 94: 14683-14638.
    CrossrefPubMedGoogle Scholar
  • 22 Beauchamp NJ, Pike RN, Daly M, Butler R. et al. Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis and heparin activation. Blood 1998; 92: 2696-2706.
    CrossrefPubMedGoogle Scholar
  • 23 Picard V, Dautzenberg MD, Villoutreix B. et al. Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerisation in vivo associated with severe childhood thrombosis. Blood 2003; 102: 919-925.
    CrossrefPubMedGoogle Scholar
  • 24 Lane DA, Olds RJ, Conard J. et al. Pleiotropic effects of antithrombin strand 1C substitution mutations. J Clin Invest 1992; 90: 2422-2433.
    CrossrefPubMedGoogle Scholar
  • 25 Ni H, Blajchman MA, Ananthanarayanan VS. et al. Mutation of any site of N-glycosylation accelerates the in vivo clearance of recombinant rabbit anti-thrombin. Thromb Res 2000; 99: 407-415.
    CrossrefPubMedGoogle Scholar
  • 26 Picard V, Chen JM, Tardy B. et al. Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency. Hum Genet 2010; 127: 45-53.
    CrossrefPubMedGoogle Scholar
  • 27 Picard V, Présot I, Scarabin PY. et al. Antithrombin Cambridge II (A384S): prevalence in patients of the Paris Thrombosis Study (PATHROS). Blood 2007; 110: 2777-2778.
    CrossrefPubMedGoogle Scholar
  • 28 Sanchez C, Alessi MC, Saut N. et al. Relation between the antithrombin Cambridge II mutation, the risk of venous thrombosis, and the endogenous thrombin generation. J Thromb Haemost 2008; 6: 1975-1977.
    CrossrefPubMedGoogle Scholar