Heerlen polymorphism associated with type III protein S deficiency and factor V Leiden mutation in a Polish patient with deep vein thrombosis

Wypasek, Ewa; Potaczek, Daniel P.; Alhenc‐Gelas, Martine; Undas, Anetta

doi:10.1097/mbc.0b013e328365032c

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…This low frequency is likely due to the fact that homozygous carriers are considered to be protein S deficient, a condition with high morbidity. There is one PS Heerlen homozygous patient documented in the literature, with very low levels of free protein S (34%)13. In the MARTHA study, even if FPS deficiency was excluded by design, plasma FPS levels were significantly lower in individuals with PS Heerlen compared to those without.…”

Section: Discussionmentioning

confidence: 97%

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Suchon

Germain

Delluc

et al. 2017

Sci Rep

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Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10−14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10−6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.

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Section: Discussionmentioning

confidence: 97%

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Suchon

Germain

Delluc

et al. 2017

Sci Rep

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“…74 Unusual Protein S Variants PS Heerlen (p.Ser501Pro) is a frequently encountered missense mutation in the Caucasian population (0.5%) causing a type III deficiency. 118 Originally considered to be a neutral variant with little or no pathogenicity, 144 subsequent reports have suggested that it may be significant when associated with other acquired or genetic VTE risk factors [145][146][147] or have demonstrated an association with VTE risk. 148 Heterozygotes exhibit mildly reduced FPS antigen levels, 145,148 but they may also be normal, 145,148 whereas homozygotes have lower FPS levels and may have reduced TPS, thereby presenting as a type I deficiency.…”

Section: Total Protein S Antigen Assaysmentioning

confidence: 99%

Thrombophilia Screening: Not So Straightforward

Moore

2024

Semin Thromb Hemost

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Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays.

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“…The Polish patients with this thrombophilia genetically characterized have been described recently [29][30][31]32]. There is a 10-fold increased risk of VTE in PS deficient subjects [14,21].…”

Section: Protein S Deficiencymentioning

confidence: 99%

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment

Undas

Góralczyk

2016

Adv Clin Exp Med

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Heerlen polymorphism associated with type III protein S deficiency and factor V Leiden mutation in a Polish patient with deep vein thrombosis

Cited by 6 publications

References 9 publications

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Thrombophilia Screening: Not So Straightforward

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment

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