Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis

Miyata, Toshiyuki; Sato, Yukiko; Ishikawa, Junko; Okada, Hiromi; Takeshita, Satoshi; Sakata, Toshiyuki; Kokame, Koichi; Kimura, Ryota; Honda, Susumu; Kawasaki, Tomio; Suehisa, Etsuji; Tsuji, Hajime; Madoiwa, Seiji; Sakata, Yoichi; Kojima, Tetsuhito; Murata, Mitsuru; Ikeda, Yasuo

doi:10.1016/j.thromres.2008.08.020

Cited by 102 publications

(95 citation statements)

References 24 publications

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“…28 In addition to the presence of prevalent Lys196Glu of PROS1 in Japan, it was suggested that this high frequency could have been due to a selection bias in patient recruitment which had possibly enriched the study population with patients with natural anticoagulant deficiency. Likewise, the 14.4% frequency in the present study was lower than the frequency of 24.1% in our previous study on selected patients with (idiopathic) pulmonary embolism.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…As for the population-specific prevalent mutations, frequent Lys196Glu (K196E) of PROS1 in Japan results in PS deficiency being most frequent in both VTE patients and the general population (Table 3). [26][27][28] Although the sensitivity of coagulation tests for detecting heterozygous Lys196Glu mutation is limited, 27,29,30 earlier studies involving only coagulation tests also demonstrated a high frequency of PS deficiency in the Japan population.…”

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Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nIn this regard, we investigated the molecular genetic defects of natural anticoagulant deficiencies (PC, PS, and AT) in a large number of consecutive VTE patients and in the general population in Korea screened by coagulation tests. The results revealed unique frequencies and mutation spectrums of natural anticoagulant deficiencies in the group of VTE patients and in the general population. These frequencies and the mutation spectrums in Korea were not only distinct from those in Caucasian populations but also from those in other Asian countries. Methods Patients and populationThe group of patients consisted of consecutive VTE patients screened for thrombophilia including PC, PS, and AT deficiencies at Samsung Medical Center, Seoul, Korea, from January 2005 to December 2012. For the population group, at least 3,000 individuals visiting the institution for routine check-ups were screened from September 2005 to January 2006 using the same coagulation tests for natural anticoagulant deficiency as those used in the patients. In each group, those suspected of having a natural anticoagulant deficiency underwent molecular genetic tests to confirm the deficiency. In both groups, we excluded those with low levels of multiple (2 or more) natural anticoagulants, especially in association with underlying liver disease or other extrinsic factors. Written informed consent was obtained from the patients in the study, which was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. Coagulation testsThe thrombophilia profile tests for VTE patients included screening for genetic thrombophilia: PC activity (Stachrom ® Protein C, Diagnostica Stago, Asnieres-Sur-Seine, France), PS free antigen (Liatest ® Free Protein S, Diagnostica Stago), and AT activity (Stachrom ® ATIII, Diagnostica Stago). All coagulation tests were performed on the STA ® coagulation analyzer (Diagnostica Stago). The local reference intervals were determined according to the guidelines from the Clinical and Laboratory Standards Institute (http://www.clsi.org/) as the 2.5-97.5 percentiles (PC activity, PS free antigen,.2% for males and 56.0-132.6% for females; and AT activity, 81.5-119.3%). 10 Tests for PC antigen, PS total antigen and activity, and AT antigen were additionally performed when indicated. Natural anticoagulant deficiency was suspected in VTE patients when the result was below the lower limit of the reference interval (2.5 percentile). Screening for natural anticoagulant deficiency in the population group was performed using the same coagulation tests as those used in the VTE patients. Individuals with levels of PC, PS, or AT below the 1 st percentile were selected for molecular genetic tests. Molecular genetic analysesGenomic DNA was extracted from peripheral blood leukocytes using the Wizard Genomic DNA Purification kit following the standard protocols (Promega, Madison, WI, USA). Molecular genetic diagnosis of natural anticoagulant deficiency was performed by...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

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confidence: 99%

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

et al. 2013

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“…Individuals with less-severe ProS deficiencies due to heterozygous mutations or polymorphisms, of which more than 200 forms have been documented, are at elevated risk for deep vein thrombosis (DVT) and other life-threatening thrombotic events (7,8). These same risks appear in the many SLE patients who display ProS deficiency (9).…”

Section: Introductionmentioning

confidence: 99%

Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis

Burstyn‐Cohen¹,

Heeb²,

Lemke³

2009

J. Clin. Invest.

148

170

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Protein S (ProS) is a blood anticoagulant encoded by the Pros1 gene, and ProS deficiencies are associated with venous thrombosis, stroke, and autoimmunity. These associations notwithstanding, the relative risk that reduced ProS expression confers in different disease settings has been difficult to assess without an animal model. We have now described a mouse model of ProS deficiency and shown that all Pros1 -/-mice die in utero, from a fulminant coagulopathy and associated hemorrhages. Although ProS is known to act as a cofactor for activated Protein C (aPC), plasma from Pros1 +/-heterozygous mice exhibited accelerated thrombin generation independent of aPC, and Pros1 mutants displayed defects in vessel development and function not seen in mice lacking protein C. Similar vascular defects appeared in mice in which Pros1 was conditionally deleted in vascular smooth muscle cells. Mutants in which Pros1 was deleted specifically in hepatocytes, which are thought to be the major source of ProS in the blood, were viable as adults and displayed less-severe coagulopathy without vascular dysgenesis. Finally, analysis of mutants in which Pros1 was deleted in endothelial cells indicated that these cells make a substantial contribution to circulating ProS. These results demonstrate that ProS is a pleiotropic anticoagulant with aPC-independent activities and highlight new roles for ProS in vascular development and homeostasis.

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“…Heterozygous carriers for PS K196E mutation showed reduced anticoagulant activity within normal limits of antigen levels, indicating type II deficiency [13,16,[19][20][21]. We reported that the PS anticoagulant activities in individuals with the heterozygous (KE) genotype in a Japanese general population were substantially overlapped with those in individuals with the wild-type (KK) genotype; the mean difference of PS anticoagulant activity was only 16% [22].…”

Section: Introductionmentioning

confidence: 99%

“…This finding suggests that PS anticoagulant activity is not a useful marker for the PS K196E mutation. PS K196E carriers have been identified thus far by genetic analyses such as direct sequencing, genotyping (e.g., TaqMan), and restriction fragment length polymorphism analysis [19][20][21][22]. These analyses are accurate but expensive and time-consuming.…”

Section: Introductionmentioning

confidence: 99%

ELISA-based detection system for Protein S K196E mutation, a genetic risk factor for venous thromboembolism

慶子¹

2016

Nihon Kessen Shiketsu Gakkaishi

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Protein S (PS) acts as a cofactor for activated protein C in the plasma anticoagulant system. PS Lys196-to-Glu (K196E) mutation is a genetic risk factor for venous thromboembolism in Japanese individuals. Because of the substantial overlap in PS anticoagulant activity between KK (wild-type) and KE (heterozygous) genotypes, it is difficult to identify PS K196E carriers by measuring PS activity. Here, we generated monoclonal antibodies specific to the PS K196E mutant and developed a simple and reliable method for the identification of PS K196E carriers. We immunized mice with a keyhole limpet hemocyanin-conjugated synthetic peptide with Glu196. The hybridoma cells were screened for the binding ability of the produced antibodies to recombinant mutant EGF-like domains of PS (Ile117-Glu283). We obtained three hybridoma cell lines producing PS K196E mutation-specific antibodies. We established a sandwich enzyme-linked immunosorbent assay (ELISA) system in which the PS K196E mutation-specific monoclonal antibody was used as a detection antibody. We measured human plasma samples by using this system and successfully discriminated 11 individuals with the KE genotype from 122 individuals with the KK genotype. The ELISA system using the PS K196E mutation-specific antibody is a useful tool for the rapid identification of PS K196E carriers, who are at a higher risk for venous thromboembolism.

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Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis

Cited by 102 publications

References 24 publications

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

Distinct frequencies and mutation spectrums of genetic thrombophilia in Korea in comparison with other Asian countries both in patients with thromboembolism and in the general population

Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis

ELISA-based detection system for Protein S K196E mutation, a genetic risk factor for venous thromboembolism

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