European Journal of Pediatrics

, Volume 178, Issue 10, pp 1471–1478 | Cite as

Genotype phenotype correlation in a pediatric population with antithrombin deficiency

  • Mirjana KovacEmail author
  • Gorana Mitic
  • Iva Djilas
  • Milos Kuzmanovic
  • Olivera Serbic
  • Danijela Lekovic
  • Branko Tomic
  • Zsuzsanna Bereczky
Original Article


Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the AT gene (SERPINC1). Considering that the genotype phenotype relationship in AT deficiency patients remains unclear, especially in pediatric patients, the aim of our study was to evaluate genotype phenotype correlation in a Serbian pediatric population. A retrospective cohort study included 19 children younger than 18 years, from 15 Serbian families, with newly diagnosed AT deficiency. In 21% of the recruited families, mutations affecting exon 4, 5, and 6 of the SERPINC1 gene that causes type I AT deficiency were detected. In the remaining families, the mutation in exon 2 causing type II HBS (AT Budapest 3) was found. Thrombosis events were observed in 1 (33%) of those with type I, 11 (85%) of those with AT Budapest 3 in the homozygous respectively, and 1(33%) in the heterozygous form. Recurrent thrombosis was observed only in AT Budapest 3 in the homozygous form, in 27% during initial treatment of the first thrombotic event. Abdominal venous thrombosis and arterial ischemic stroke, observed in almost half of the children from the group with AT Budapest 3 in the homozygous form, were unprovoked in all cases.

Conclusion: Type II HBS (AT Budapest 3) in the homozygous form is a strong risk factor for arterial and venous thrombosis in pediatric patients.

What is Known:

Inherited AT deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1gene.

The genotype phenotype correlation in AT deficiency patients remains unclear, especially in pediatric patients.

What is New:

The genetic results for our paediatric population predominantly showed the presence of a single specific mutation in exon 2, that causes type II HBS deficiency (AT Budapest 3).

In this group thrombosis mostly occurred as unprovoked, in almost half of them as abdominal thrombosis or stroke with high incidence of recurrent thrombosis, in 27% during initial treatment.


Antithrombin deficiency SERPINC1 mutations Pediatric population 





Deep venous thrombosis


Heparin-binding site


Human genome mutation database


Low molecular weight heparin


Multiplex ligation-dependent probe amplification


Pulmonary embolism


Serine protease inhibitors


Tissue factor pathway inhibitor


Venous thromboembolism


Unfractionated heparin


Vitamin K antagonist


Authors’ contributions

Mirjana Kovac: designed the study, provided funding of the study, analyzed the data, drafted this manuscript, and agreed on the final version of this manuscript.

Gorana Mitic: participated on the design of this study, analyzed the data, revised the manuscript critically, and agreed on the final version of this manuscript.

Branko Tomic: run statistical analysis of the study data together with Iva Djilas and agreed on the final version of this manuscript.

Milos Kuzmanovic, Olivera Serbic and Danijela Lekovic participated on the design of this study, revised the manuscript critically, and agreed on the final version of this manuscript.

Zsuzsanna Bereczky: provided funding of the study, revised the manuscript critically and agreed on the final version of this manuscript.


This study was supported by grant 173008 from the Ministry of Education, Science and Technological Development, Serbia and from the Hungarian National Research Fund (OTKA K116228) and by the Ministry of National Economy, Hungary (GINOP-2.3.2-15-2016-00039).

Compliance with ethical statements

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Institutional approval for the study was granted by the Local Research Ethics Committee (EK-number 2471/1) in accordance with internationally accepted ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculty of MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Blood Transfusion Institute of SerbiaHemostasis DepartmentBelgradeSerbia
  3. 3.Institute of Laboratory Medicine, Clinical Center of Vojvodina, Faculty of Medicine Novi SadUniversity of Novi SadNovi SadSerbia
  4. 4.Institute for Health Care of Mother and Child of Serbia Dr Vukan CupicBelgradeSerbia
  5. 5.Clinic of HematologyClinical Center of SerbiaBelgradeSerbia
  6. 6.Institute of Molecular Genetics and Genetic EngineeringUniversity of BelgradeBelgradeSerbia
  7. 7.Division of Clinical Laboratory Research, Department of Laboratory Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary

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