Racial differences in protein S Tokushima and two protein C variants as genetic risk factors for venous thromboembolism

Tsuda, Hiroko; Noguchi, Kenta; Oh, Doyeun; Bereczky, Zsuzsanna; Lee, Lai H.; Kang, Dongchon; Dusse, Luci Maria S.; Carvalho, Maria das Graças; Morishita, Eriko

doi:10.1002/rth2.12440

Cited by 12 publications

(14 citation statements)

References 16 publications

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“…18,19 The main reason for that is thought to be the PS gene (PROS1) variant, PS p.K196E, which is exclusive to Japanese. 20 Mutant allele of PS p.K196E is seen in 1 of about 55 people (about 2%) in the general population. 21 The carriers show type II PS deficiency with mild to moderate decreases in PS activity and have a threefold to eightfold elevated relative risk of VTE.…”

Section: Antithrombin Deficiencymentioning

confidence: 99%

“…21 The carriers show type II PS deficiency with mild to moderate decreases in PS activity and have a threefold to eightfold elevated relative risk of VTE. 20,22 Not only is this mutation not detected in Caucasians, it is also not detected in Chinese or Koreans; it is a form of thrombophilia exclusive to Japanese. 23 In diagnosing PS deficiency, measurements are made of plasma PS activity (APC cofactor activity), free PS antigen level, and total PS antigen level (sum of free PS and PS-C4BP complex).…”

Section: Antithrombin Deficiencymentioning

confidence: 99%

“…The frequency of AT deficiency and PC deficiency is very nearly the same in Caucasians and Japanese, 7,8 but PS deficiency has a higher frequency in Japanese. Specifically, there are many heterozygous carriers of PS p. K196E, or type II deficiency, [18][19][20][21][22] and there are racial differences in thrombophilia (Table 4). 62 The DVT risks in women who are not pregnant are shown in Table 5, 7,19,21,28 but in carriers of PS p.K196E the odds ratio was shown to be 4.72, not that high when compared with AT deficiency and PC deficiency.…”

Section: Commentarymentioning

confidence: 99%

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Clinical guidance for peripartum management of patients with hereditary thrombophilia

Kobayashi

Morishita

Tsuda

et al. 2021

J of Obstet and Gynaecol

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Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due to a hereditary deficiency in anticoagulant factors, antithrombin (AT), protein C (PC), or protein S (PS). Many Japanese thrombophilia patients have PS deficiency, especially PS p.K196E (also called as PS Tokushima), which is exclusive to the Japanese population, and thrombosis sometimes occurs during pregnancy. At present, no management guidelines for pregnancy and delivery in thrombophilia patients have been developed. The Study Group for Hereditary Thrombophilia, one of the research groups of blood coagulation abnormalities in the Research Program on Rare and Intractable Diseases supported with the Research Grants of the Ministry of Health, Labour and Welfare Science, has therefore developed this clinical guidance to provide healthcare workers with necessary information on safe pregnancy, parturition and neonatal management, adopting a format of responses to seven clinical questions (CQ). At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

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Section: Antithrombin Deficiencymentioning

confidence: 99%

Section: Antithrombin Deficiencymentioning

confidence: 99%

Section: Commentarymentioning

confidence: 99%

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Clinical guidance for peripartum management of patients with hereditary thrombophilia

Kobayashi

Morishita

Tsuda

et al. 2021

J of Obstet and Gynaecol

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“…Thus, the assays that measure the levels of PS, AT, and PC activities are essential screening tests. In Japan, inherited PS deficiency is the most common inherited thrombophilia, with an incidence of 1%-2% in the Japanese population, approximately 5-10 times higher than that (0.16%-0.21%) in Europe and the United States [9][10][11][12] . This higher incidence in Japan is associated with the presence of the PS Tokushima variant (PS p.Lys196Glu: PS K196E).…”

Section: Introductionmentioning

confidence: 99%

“…This higher incidence in Japan is associated with the presence of the PS Tokushima variant (PS p.Lys196Glu: PS K196E). The reported frequency of the PS K196E allele in the Japanese population is 0.9% [9][10][11] , and PS K196E is considered a pathogenic variant in the Japanese population 13,14) .…”

Section: Introductionmentioning

confidence: 99%

Effect on Plasma Protein S Activity in Patients Receiving the Factor Xa Inhibitors

Terakami

Nagaya

Hayashi

et al. 2022

JAT

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Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan. Methods:The study enrolled 152 patients (82 males and 70 females; the average age: 68.5 14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays.Results: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. Conclusion:In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.and their frequency of use continues to increase yearly [1][2][3][4][5] . DOACs are classified as thrombin inhibitor (dabigatran) or factor Xa (FXa) inhibitors (rivaroxaban, edoxaban, and apixaban) based on the target of inhibition. Compared with vitamin K antagonists such as warfarin, DOACs exhibit more

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The clinical and genetic landscape of early‐onset thrombophilia in Japan

Egami,

Ishimura,

Ochiai

et al. 2023

Pediatric Blood & Cancer

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ObjectivesTo determine the optimal management for early‐onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)‐, protein S (PS)‐, or antithrombin (AT)‐deficient patients of ≤20 years of age were studied in Japan.Methods/resultsClinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One‐hundred‐one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC‐ and PS‐monoallelic variant. Fifty‐five PC‐deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS‐deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT‐biallelic variants. The frequent low‐risk allele p.K193del (PC‐Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low‐risk allele p.K196E (PS‐Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother–newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication‐free survivors. Neurological complications were more frequently found in patients with PC‐biallelic variants than those with PC‐, PS‐, or AT‐monoallelic variants (73% vs. 24%, p = .019).ConclusionsWe demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother–infant pairs may prevent perinatal thrombosis in them.

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Racial differences in protein S Tokushima and two protein C variants as genetic risk factors for venous thromboembolism

Cited by 12 publications

References 16 publications

Clinical guidance for peripartum management of patients with hereditary thrombophilia

Clinical guidance for peripartum management of patients with hereditary thrombophilia

Effect on Plasma Protein S Activity in Patients Receiving the Factor Xa Inhibitors

The clinical and genetic landscape of early‐onset thrombophilia in Japan

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