Genotype phenotype correlation in a pediatric population with antithrombin deficiency

Kovač, Mirjana; Mitić, Gorana; Djilas, Iva; Kuzmanović, Miloš; Serbic, Olivera; Leković, Danijela; Tomic, Branko; Bereczky, Zsuzsanna

doi:10.1007/s00431-019-03433-5

Cited by 6 publications

(11 citation statements)

References 31 publications

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“…In conclusion, the estimated age of the SERPINC1 c.391C>T mutation, the geographic distribution of families with ATBp3, and the history of the modern Hungarian population are consistent with the hypothesis that the mutation originated (or was originally introduced) and expanded in the later Ottoman period and Royal Hungary. Almost all patients with ATBp3 mutation have been reported so far are of Central Eastern European origin, and this is consistent with the proposed origin of the founder effect (8,(59)(60)(61)(62). The considerable carrier frequency (around 3%) in such a rare disease that was found in the Roma general population and the confirmation of the founder effect of the ATBp3 mutation further strengthens the hypothesis that the mutation is of Roma origin, or at least became more prevalent in that population due to high frequency of consanguinity and inbreeding (63).…”

Section: Discussionsupporting

confidence: 85%

“…ATBp3 heterozygous state is less severe; however, its association with VTE is also significant. Recently, reports on association of ATBp3 and other type IIHBS AT deficiencies with ATE have been published; however, as hereditary AT belongs to the group of rare diseases, well-designed, large clinical studies with high statistical power cannot be carried out (6,10,11,61). Multicenter studies may overcome this problem; however, they are likely to be subjected to bias due to heterogeneous ethnicity.…”

Section: Discussionmentioning

confidence: 99%

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Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases

Bereczky

Gindele

Fiatal

et al. 2021

Front. Cardiovasc. Med.

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Background: Antithrombin (AT) is one of the most important regulator of hemostasis. AT Budapest 3 (ATBp3) is a prevalent type II heparin-binding site (IIHBS) deficiency due to founder effect. Thrombosis is a complex disease including arterial (ATE) and venous thrombotic events (VTE) and the Roma population, the largest ethnic minority in Europe has increased susceptibility to these diseases partly due to their unfavorable genetic load. We aimed to calculate the age and origin of ATBp3 and to explore whether the frequency of it is higher in the Roma population as compared with the general population from the corresponding geographical area. We investigated the association of ATBp3 with thrombotic events in well-defined patients' populations in order to refine the recommendation when testing for ATBp3 is useful.Methods and Results: Prevalence of ATBp3, investigated in large samples (n = 1,000 and 1,185 for general Hungarian and Roma populations, respectively) was considerably high, almost 3%, among Roma and the founder effect was confirmed in their samples, while it was absent in the Hungarian general population. Age of ATBp3—as calculated by analysis of 8 short tandem repeat sequences surrounding SERPINC1—was dated back to XVII Century, when Roma migration in Central and Eastern Europe occurred. In our IIHBS cohort (n = 230), VTE was registered in almost all ATBp3 homozygotes (93%) and in 44% of heterozygotes. ATE occurred with lower frequency in ATBp3 (around 6%); it was rather associated with AT Basel (44%). All patients with ATE were young at the time of diagnosis. Upon investigating consecutive young (<40 years) patients with ATE (n = 92) and VTE (n = 110), the presence of ATBp3 was remarkable.Conclusions: ATBp3, a 400-year-old founder mutation is prevalent in Roma population and its Roma origin can reasonably be assumed. By the demonstration of the presence of ATBp3 in ATE patients, we draw the attention to consider type IIHBS AT deficiency in the background of not only VTE but also ATE, especially in selected populations as young patients without advanced atherosclerosis. We recommend including the investigation of ATBp3 as part of thrombosis risk assessment and stratification in Roma individuals.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases

Bereczky

Gindele

Fiatal

et al. 2021

Front. Cardiovasc. Med.

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“…In our experience and according to data from the literature, AT levels of patients with AT deficiency are usually clearly below the normal range (ie, ,80%; most have levels ,70%) 17,41 ; however, patients with type 1 defects can also have levels up to 72% or even 78%. 17,42 AT activity ,70% is highly suggestive of AT deficiency, and a single measurement is sufficient to guide further treatment of VTE patients in the acute phase, particularly if the family history is positive. A confirmatory AT measurement should be performed a few weeks after the first measurement.…”

Section: Comments On Casementioning

confidence: 99%

How I treat patients with hereditary antithrombin deficiency

Pabinger

Thaler

2019

Blood

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“…Recently, we identified the first compound antithrombin deficiency in a human dead embryo 24 . Antithrombin deficiency is also prevalent in perinatal thrombosis, and pediatric thromboses are relatively common among patients homozygous for the Budapest 3 variant 16,25,26 . Particularly interesting to this study was the extensive thrombosis involving the IVC and the renal vein described by our group in a newborn homozygous for the Budapest 3 variant 27 .…”

Section: Discussionmentioning

confidence: 75%

“…24 Antithrombin deficiency is also prevalent in perinatal thrombosis, and pediatric thromboses are relatively common among patients homozygous for the Budapest 3 variant. 16,25,26 Particularly interesting to this study was the extensive thrombosis involving the IVC and the renal vein described by our group in a newborn homozygous for the Budapest 3 variant. 27 Thus, severe antithrombin deficiency states might also be involved in intrauterine or perinatal thrombosis.…”

Section: Discussionmentioning

confidence: 84%

High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: Description of a new syndrome

et al. 2021

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Atresia of inferior vena cava (IVC) is a rare congenital malformation associated with high risk of venous thrombosis that still has unknown etiology, although intrauterine IVC thrombosis has been suggested to be involved. The identification of IVC atresia in a case with early idiopathic venous thrombosis and antithrombin deficiency caused by the homozygous SERPINC1 c.391C > T variant (p.Leu131Phe; antithrombin Budapest 3) encouraged us to evaluate the role of this severe thrombophilia in this vascular abnormality. We have done a cross‐sectional study in previously identified cohorts of patients homozygous for the Budapest 3 variant (N = 61) selected from 1118 patients with congenital antithrombin deficiency identified in two different populations: Spain (N = 692) and Hungary (N = 426). Image analysis included computed tomography and phlebography. Atresia of the IVC system was observed in 17/24 cases (70.8%, 95% confidence interval [CI]: 48.9%–87.3%) homozygous for antithrombin Budapest 3 with available computed tomography (5/8 and 12/16 in the Spanish and Hungarian cohorts, respectively), 16 had an absence of infrarenal IVC and one had atresia of the left common iliac vein. All cases with vascular defects had compensatory mechanisms, azygos‐hemiazygos continuation or double IVC, and seven also had other congenital anomalies. Short tandem repeat analysis supported the specific association of the IVC system atresia with SERPINC1. We show the first evidence of the association of a severe thrombophilia with IVC system atresia, supporting the possibility that a thrombosis in the developing fetal vessels is the reason for this anomaly. Our hypothesis‐generating results encourage further studies to investigate severe thrombophilic states in patients with atresia of IVC.

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Genotype phenotype correlation in a pediatric population with antithrombin deficiency

Cited by 6 publications

References 31 publications

Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases

Age and Origin of the Founder Antithrombin Budapest 3 (p.Leu131Phe) Mutation; Its High Prevalence in the Roma Population and Its Association With Cardiovascular Diseases

How I treat patients with hereditary antithrombin deficiency

High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: Description of a new syndrome

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