Antithrombin heparin binding site deficiency: A challenging diagnosis of a not so benign thrombophilia

Orlando, Christelle; Heylen, Olivier; Lissens, Willy; Jochmans, Kristin

doi:10.1016/j.thromres.2015.03.013

Cited by 31 publications

(40 citation statements)

References 31 publications

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“…From a clinical point of view, HBS mutations have mild thrombotic consequences but they have relatively high representation in the general population [8]. Interestingly, the study of Orlando and coworkers reveals that only one method, which is the only one that uses human FXa as target protease, longer incubation times and lower heparin concentration, showed 100% sensitivity for all HBS mutations [7]. This result is important to answer the first question we raised.…”

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confidence: 90%

“…Moreover, the descriptions of patients carrying SERPINC1 mutations that develop thrombotic events in the arterial territory is growing. Orlando and coworkers observed that the p.Pro73Leu and p.Arg79His mutations were associated with a high prevalence of arterial thrombosis [7]. The high incidence of arterial thrombosis in patients with type II deficiency, particularly with HBS mutations, compared with the incidence of these thrombotic events in patients with otherwise more severe type I deficiency, deserve further studies.…”

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confidence: 94%

“…[5] Moreover, if thrombin and FXa are critical not only for venous but also for arterial thrombosis (they also play a pro-inflammatory role, and thrombin is the main platelet agonist), and these procoagulant proteases are targets of anticoagulant drugs efficiently used in arterial thromboembolic disorders, why is antithrombin deficiency only relevant in venous thrombosis? [6] The paper of Orlando and coworkers published in this issue of Thrombosis Research deals with these two questions [7]. First, this study has evaluated the ability of four commercial activity assays to diagnose antithrombin deficiency in 35 patients carrying 5 different mutations affecting the heparin binding site (HBS): p.Pro73Leu; p.Asn77His, p.Arg79Cys, p.Arg79His, p.Leu131Phe, and p.Gln150Pro.…”

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confidence: 99%

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Puzzling questions on antithrombin: Diagnostic limitations and real incidence in venous and arterial thrombosis

Corral

Vicente

2015

Thrombosis Research

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confidence: 90%

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confidence: 94%

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confidence: 99%

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Puzzling questions on antithrombin: Diagnostic limitations and real incidence in venous and arterial thrombosis

Corral

Vicente

2015

Thrombosis Research

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“…AT deficiency is a strong risk factor of VTE; according to the results of the large prospective (the European Prospective Cohort on Thrombophilia) study, among inherited thrombophilia risk factors, the annual incidence of first VTE was the highest in AT deficiency [9]. Beside venous thrombotic symptoms, occasionally arterial thrombotic events were also described in the presence of AT deficiency [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Heparin cofactor (hc) AT assays are based on the inhibition of FIIa or FXa in the presence of heparin. Most recent results suggest that the anti-FXa test is the method of choice to detect II HBS deficiencies [15,20].…”

Section: Introductionmentioning

confidence: 99%

Founder effect is responsible for the p.Leu131Phe heparin‐binding‐site antithrombin mutation common in Hungary: phenotype analysis in a large cohort

Gindele

Oláh

Ilonczai

et al. 2016

Journal of Thrombosis and Haemostasis

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EssentialsAntithrombin Budapest3 (ATBp3; p.Leu131Phe) causing heparin-binding-site defect is common. We studied the clinical and laboratory phenotype of a large Hungarian ATBp3 cohort (n = 102). Founder effect of ATBp3 was confirmed by 12 genetic markers; anti-FXa AT assay was 100% sensitive. The spectrum of thrombotic symptoms was wide in ATBp3 patients including arterial thrombosis.Summary. Background: Antithrombin (AT) is a key regulator of the coagulation. In type II deficiency, the heparinbinding-site defect (type II HBS) is considered to be relatively low thrombosis risk. Objectives: Our aims were to search for SERPINC1 mutation(s) and to describe the clinical and laboratory phenotype of a large number of AT Budapest3 (ATBp3, p.Leu131Phe) carriers and confirm the presence of a founder effect. Patients/Methods: AT-deficient patients were recruited and carriers of ATBp3, n = 102 (63 families) were selected. To investigate the founder effect, eight intragenic single nucleotide polymorphisms, a 5 0 -length dimorphism, and five microsatellite markers were detected. Clinical and laboratory data of the patients were collected and analyzed. Results: In AT deficiency, 16 different causative mutations were found, and the great majority of patients were of type II HBS subtype. Most of them (n = 102/118, 86.5%) carried the ATBp3 mutation. The ATBp3 mutant allele was associated with one single haplotype, while different haplotypes were detected in the case of normal allele. The anti-factor Xabased AT activity assay that we used could detect all ATBp3 patients with high sensitivity in our cohort. ATBp3 homozygosity (n = 26) was associated with thrombosis at a young age and conferred a high thrombotic risk. Half of the heterozygotes (n = 41/76, 53.9%) also had venous and/ or arterial thrombosis, and pregnancy complications were also recorded. Conclusion: In Hungary, the founder mutation, ATBp3, is the most common AT deficiency. Our study is the first in which the clinical characterization of ATBp3 mutation was executed in a large population.

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Causative genetic mutations for antithrombin deficiency and their clinical background among Japanese patients

et al. 2016

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We summarize causative genetic mutations for antithrombin (AT) deficiency and their clinical background in Japanese patients. A total of 19 mutations, including seven novel mutations, were identified. We also summarize clinical symptoms of thrombosis, age at onset, family history, and contributing factors for thrombosis, and review the use of prophylactic anticoagulation in pregnant women with heterozygous type II heparin binding site defects (HBS) AT deficiency. The prevalence of thrombosis in probands with type I AT deficiency (88%) was double that observed in those with type II AT deficiency (50%). The prevalence of thrombotic episodes among family members was also higher for type I AT deficiency subjects (82%) than for those with type II AT deficiency (0%). The most common contributing factor for thrombosis among women with type I AT deficiency was pregnancy. Forty-five percent of women with type I AT deficiency developed thrombotic events before the 20th week of gestation. In contrast, women with type II (HBS) AT deficiency appear to be at a lower risk of thrombosis during pregnancy. In conclusion, thrombotic risk varies among different subtypes. Risk assessments based on genetic/clinical backgrounds may contribute to appropriate diagnosis, treatment, and prophylaxis for patients with AT deficiency.

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Antithrombin heparin binding site deficiency: A challenging diagnosis of a not so benign thrombophilia

Cited by 31 publications

References 31 publications

Puzzling questions on antithrombin: Diagnostic limitations and real incidence in venous and arterial thrombosis

Puzzling questions on antithrombin: Diagnostic limitations and real incidence in venous and arterial thrombosis

Founder effect is responsible for the p.Leu131Phe heparin‐binding‐site antithrombin mutation common in Hungary: phenotype analysis in a large cohort

Causative genetic mutations for antithrombin deficiency and their clinical background among Japanese patients

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