Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center

Réka Gindele, Anna Selmeczi, Zsolt Oláh, Péter Ilonczai, György Pfliegler, Erzsébet Marján, L. Nemes, Ágnes Nagy, Hajna Losonczy, Gorana Mitic, Mirjana Kovac, Gábor Balogh, I. Komáromi, Ágota Schlammadinger, Katalin Rázsó, Z. Boda, L. Muszbek, Z. Bereczky

Research output: Article

2 Citations (Scopus)

Abstract

Introduction Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. Patients and methods Non-related AT deficient patients (n = 156) and their family members (total n = 246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. Results Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH 7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. Conclusion Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

Original languageEnglish
Pages (from-to)119-128
Number of pages10
JournalThrombosis Research
Volume160
DOIs
Publication statusPublished - dec. 1 2017

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Antithrombins
Cohort Studies
Heparin
Mutation
Thrombosis
Phenotype
Pregnancy Complications
Homozygote
Genetic Association Studies
Mutation Rate
Binding Sites

ASJC Scopus subject areas

  • Hematology

Cite this

Clinical and laboratory characteristics of antithrombin deficiencies : A large cohort study from a single diagnostic center. / Gindele, Réka; Selmeczi, Anna; Oláh, Zsolt; Ilonczai, Péter; Pfliegler, György; Marján, Erzsébet; Nemes, L.; Nagy, Ágnes; Losonczy, Hajna; Mitic, Gorana; Kovac, Mirjana; Balogh, Gábor; Komáromi, I.; Schlammadinger, Ágota; Rázsó, Katalin; Boda, Z.; Muszbek, L.; Bereczky, Z.

In: Thrombosis Research, Vol. 160, 01.12.2017, p. 119-128.

Research output: Article

Gindele, R, Selmeczi, A, Oláh, Z, Ilonczai, P, Pfliegler, G, Marján, E, Nemes, L, Nagy, Á, Losonczy, H, Mitic, G, Kovac, M, Balogh, G, Komáromi, I, Schlammadinger, Á, Rázsó, K, Boda, Z, Muszbek, L & Bereczky, Z 2017, 'Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center', Thrombosis Research, vol. 160, pp. 119-128. https://doi.org/10.1016/j.thromres.2017.10.023
Gindele, Réka ; Selmeczi, Anna ; Oláh, Zsolt ; Ilonczai, Péter ; Pfliegler, György ; Marján, Erzsébet ; Nemes, L. ; Nagy, Ágnes ; Losonczy, Hajna ; Mitic, Gorana ; Kovac, Mirjana ; Balogh, Gábor ; Komáromi, I. ; Schlammadinger, Ágota ; Rázsó, Katalin ; Boda, Z. ; Muszbek, L. ; Bereczky, Z. / Clinical and laboratory characteristics of antithrombin deficiencies : A large cohort study from a single diagnostic center. In: Thrombosis Research. 2017 ; Vol. 160. pp. 119-128.
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abstract = "Introduction Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. Patients and methods Non-related AT deficient patients (n = 156) and their family members (total n = 246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. Results Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98{\%}) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6{\%}) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86{\%}, 9{\%} and 4{\%} of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH 7.4 as assay conditions had low (44{\%}) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. Conclusion Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.",
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author = "R{\'e}ka Gindele and Anna Selmeczi and Zsolt Ol{\'a}h and P{\'e}ter Ilonczai and Gy{\"o}rgy Pfliegler and Erzs{\'e}bet Marj{\'a}n and L. Nemes and {\'A}gnes Nagy and Hajna Losonczy and Gorana Mitic and Mirjana Kovac and G{\'a}bor Balogh and I. Kom{\'a}romi and {\'A}gota Schlammadinger and Katalin R{\'a}zs{\'o} and Z. Boda and L. Muszbek and Z. Bereczky",
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TY - JOUR

T1 - Clinical and laboratory characteristics of antithrombin deficiencies

T2 - A large cohort study from a single diagnostic center

AU - Gindele, Réka

AU - Selmeczi, Anna

AU - Oláh, Zsolt

AU - Ilonczai, Péter

AU - Pfliegler, György

AU - Marján, Erzsébet

AU - Nemes, L.

AU - Nagy, Ágnes

AU - Losonczy, Hajna

AU - Mitic, Gorana

AU - Kovac, Mirjana

AU - Balogh, Gábor

AU - Komáromi, I.

AU - Schlammadinger, Ágota

AU - Rázsó, Katalin

AU - Boda, Z.

AU - Muszbek, L.

AU - Bereczky, Z.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Introduction Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. Patients and methods Non-related AT deficient patients (n = 156) and their family members (total n = 246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. Results Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH 7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. Conclusion Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

AB - Introduction Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. Patients and methods Non-related AT deficient patients (n = 156) and their family members (total n = 246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. Results Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH 7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. Conclusion Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

KW - Antithrombin activity

KW - Antithrombin deficiency

KW - Assay sensitivity

KW - Genotype-phenotype association

KW - Mutation spectrum

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