Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency

Beate Luxembourg; Anna Pavlova; Christof Geisen; Michael Spannagl; Frauke Bergmann; Manuela Krause; Sonja Alesci; Erhard Seifried; Edelgard Lindhoff-Last

doi:10.1160/TH13-05-0402

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2014; 111(02): 249-257
DOI: 10.1160/TH13-05-0402

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency

Authors

Beate Luxembourg

¹Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostaseology, University Hospital Frankfurt, DRK Blood Donor Service Baden-Württemberg – Hessen, Frankfurt, Germany

²Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, Frankfurt, Germany
Anna Pavlova

³Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
Christof Geisen

¹Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostaseology, University Hospital Frankfurt, DRK Blood Donor Service Baden-Württemberg – Hessen, Frankfurt, Germany
Michael Spannagl

⁴Medical Department, Division of Haemostaseology, Ludwig-Maximillian-University Munich, Munich, Germany
Frauke Bergmann

⁵MVZ Wagnerstibbe, Hannover, Germany
Manuela Krause

⁶Haemostaseology and Angiology, Stiftung Deutsche Klinik für Diagnostik GmbH, Wiesbaden, Germany
Sonja Alesci

⁷IMD Gerinnungspraxis Mannheim, Mannheim, Germany
Erhard Seifried

¹Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostaseology, University Hospital Frankfurt, DRK Blood Donor Service Baden-Württemberg – Hessen, Frankfurt, Germany
Edelgard Lindhoff-Last

²Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, Frankfurt, Germany

Abstract

Summary

Mutations in the antithrombin (AT) gene can impair the capacity of AT to bind heparin (AT deficiency type IIHBS), its target proteases such as thrombin (type IIRS), or both (type IIPE). Type II AT deficiencies are almost exclusively caused by missense mutations, whereas type I AT deficiency can originate from missense or null mutations. In a retrospective cohort study, we investigated the impact of the type of mutation and type of AT deficiency on the manifestation of thromboembolic events in 377 patients with hereditary AT deficiencies (133 from our own cohort, 244 reported in the literature). Carriers of missense mutations showed a lower risk of venous thromboembolism (VTE) than those of null mutations (adjusted hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.27–0.58, p<0.001), and the risk of VTE was significantly decreased among patients with type IIHBS AT deficiency compared to patients with other types of AT deficiency (HR 0.23, 95%CI 0.13–0.41, p<0.001). The risk of pulmonary embolism complicating deep-vein thrombosis was lower in all type II AT deficiencies compared to type I AT deficiency (relative risk 0.69, 95%CI 0.56–0.84). By contrast, the risk of arterial thromboembolism tended to be higher in carriers of missense mutations than in those with null mutations (HR 6.08-fold, 95%CI 0.74–49.81, p=0.093) and was 5.9-fold increased (95%CI 1.22–28.62, p=0.028) in type IIHBS versus other types of AT deficiency. Our data indicate that the type of inherited AT defect modulates not only the risk of thromboembolism but also the localisation and encourage further studies to unravel this phenomenon.

Keywords

Antithrombin deficiency - SERPINC1 - mutation - venous thromboembolism - arterial thromboembolism

Volltext

Referenzen

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