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Thromb Haemost 2012; 108(02): 247-257
DOI: 10.1160/TH11-12-0875
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Deficiencies of antithrombin, protein C and protein S – Practical experience in genetic analysis of a large patient cohort

Michael Caspers
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Anna Pavlova
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Julia Driesen
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Ursula Harbrecht
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Robert Klamroth
2   Vivantes – Klinikum in Friedrichhain, Department of Angiology and Clotting Disorders, Haemophilia Treatment Center, Berlin, Germany
,
Janos Kadar
3   Laboratory and Medical practice for Transfusion Medicine, Köln, Germany
,
Ronald Fischer
4   Department of Internal Medicine, Justus Liebig University Giessen, Giessen, Germany
,
Bettina Kemkes- Matthes
4   Department of Internal Medicine, Justus Liebig University Giessen, Giessen, Germany
,
Johannes Oldenburg
1   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
› Author Affiliations
Further Information

Publication History

Received: 20 December 2011

Accepted after major revision: 22 April 2012

Publication Date:
25 November 2017 (online)

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Summary

Deficiencies of natural anticoagulant proteins including antithrombin (AT), protein C (PC) and protein S (PS) are important causes of inherited thrombophilia. This study aimed to report on the practical experience gained in performing genetic analyses of a large cohort of patients with AT, PC and PS deficiencies and to relate this knowledge to clinical application. We genotyped a large cohort of 709 unrelated patients with AT (231), PC (234) and PS (244) deficiencies referred to us by physicians throughout Germany. Mutations were detected by direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The highest mutation detection rate (MDR) was found for the SERPINC1 gene (83.5%), followed by the PROC (69%) and PROS1 (43%) genes. Even at AT activities close to the normal range (75%), the MDR was 70%. Contrastingly, for PC and PS deficiencies, the MDR dropped significantly and mildly lowered to subnormal values. At PS activities >55% for PS no mutations were detected. Mutation profiles of all three genes were similar with the highest prevalence for missense mutations (63–78%), followed by nonsense (7–11%), splice-site mutations (7–13%), small deletions (1–8%), small insertions/duplications (1–4%) and large deletions (3–6%). In conclusion, genetic testing is a useful diagnostic tool for diagnosing thrombophilia. Based on our data, genetic analysis for patients with AT deficiency is indicated for all subnormal activities. In contrast, genotyping is not advisable for PC activities >70% and for PS activities >55%.

Keywords

Protein C - protein S - antithrombin - thrombophilia - genetic analysis
 

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