Thrombomodulin Gene Mutations Associated With Myocardial Infarction

Ireland, H; Kunz, G; Kyriakoulis, Konstantinos G; Stubbs, P J; Lane, David A.

doi:10.1161/01.cir.96.1.15

Cited by 125 publications

(100 citation statements)

References 16 publications

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“…They found 6 of 208 individuals harboring one of these polymorphisms. Interestingly, 5 of them were of Asian origin, even though only 38 Asians were included in their study population (6). This observation suggested that these polymorphisms were more common in the Asian population than in Caucasians.…”

Section: Discussionmentioning

confidence: 97%

“…The TM-thrombin complex can activate protein C, which then acts as a potent anticoagulant (1). Studies on mice without functional TM (2) as well as on rare mutations in the TM gene reported in patients of myocardial infarction (MI) (3,4) have suggested that dysfunction of TM plays an important role in the pathorisk for MI (6). According to the latter study, the three SNPs may be more common in Asians than Caucasians, although the authors did not provide precise frequencies of the polymorphisms in clearly defined ethnic populations.…”

Section: Introductionmentioning

confidence: 99%

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Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans.

et al. 2002

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Thrombomodulin (TM), a thrombin receptor expressed on the endothelial surface, is known to play an important role in the anti-thrombogenic system in vivo. In this study, we examined the effects of 3 single-nucleotide polymorphisms (SNPs) in the TM gene (G 33A, C1418T and C1922T) on the development of myocardial infarction (MI) in Koreans. We found that G 33A was a common SNP (the minor allele frequency was 0.09) in Koreans. Eighty-five MI patients who had received coronary angiography were enrolled and were di-

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans.

et al. 2002

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“…21 In addition, it has been reported that levels of TM are associated with an increased risk of myocardial infarction and cerebral infarction. 22, 23 Thus, the level of TM may be regarded as a biomarker of endothelial function. In the present study, there was a positive correlation between the levels of TM and those of F1+2 and D-dimer, which means that activation of coagulation might originate from vascular endothelial disorders.…”

Section: Discussionmentioning

confidence: 99%

Effects of Aging on the Coagulation Fibrinolytic System in Outpatients of the Cardiovascular Department

Ochi

Adachi

Inokuchi

et al. 2016

Circ J

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Background:Although clinical trials demonstrate that the elderly with atrial fibrillation have risks of thrombosis and bleeding, the relationship between aging and coagulation fibrinolytic system in "real-world" cardiology outpatients is uncertain. Methods and Results:We retrospectively evaluated 773 patients (mean age: 58 years; 52% men; Asian ethnicity). To thoroughly investigate markers of coagulation and fibrinolysis, we simultaneously measured levels of D-dimer, prothrombin-fragment1+2 (F1+2), plasmin-α2 plasmin inhibitor complex (PIC), and thrombomodulin (TM). There were correlations between aging and levels of F1+2, D-dimer, PIC, and TM (R=0.61, 0.57, 0.49, and 0.30, respectively). We compared 3 age groups, which were defined as the Y group (<64 years), M group (65-74 years), and the O group (>75 years). Levels of markers were higher in older individuals (D-dimer: 1.0±0.8 vs. 0.8±0.8 vs. 0.6±0.4 μg/ml, F1+2: 281.8±151.3 vs. 224.6±107.1 vs. 155.5±90.0 pmol/L, PIC: 0.9±0.3 vs. 0.8±0.3 vs. 0.6±0.5 μg/ml, and TM: 2.9±0.8 vs. 2.7±0.7 vs. 2.5±0.7FU/ml). We performed logistic regression analysis to determine F1+2 and PIC levels. Multivariate analysis revealed that aging was the most important determinant of high F1+2 and PIC levels.Conclusions: Hypercoagulable states develop with advancing age in "real-world" cardiology outpatients. (Circ J 2016; 80: 2133 -2140

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“…17 Protein C deficiency, traditionally associated with venous thrombosis, has been reported in association with peripheral arterial thrombosis, 18,19 and recently, variations in the thrombomodulin gene have been associated with coronary artery thrombosis. 20 In cultured cells, the thrombomodulin-protein C pathway has been shown to regulate the thrombogenic properties of endothelium under shearing conditions simulating both the venous and arterial circulation. 21 Thrombomodulin is only 1 component of the antithrombogenic system of vascular endothelium: Other components include heparan sulfates, plasminogen activator, tissue factor inhibitor, and the endothelium-derived vasodilators nitric oxide and prostacyclin, many of which are regulated by shear stress.…”

Section: Discussionmentioning

confidence: 99%

Arterial Flow Conditions Downregulate Thrombomodulin on Saphenous Vein Endothelium

et al. 1999

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Background —The antithrombogenic properties of venous endothelium may be attenuated when vein is implanted in the arterial circulation. Such changes may facilitate thrombosis, which is the final common pathway for saphenous vein arterial bypass graft occlusion. Methods and Results —Using human saphenous vein in a validated ex vivo flow circuit, we investigated (1) the possibility that arterial flow conditions (mean pressure, 100 mm Hg, 90 cpm, ≈200 mL/min) alter the concentration of proteins involved in regulating thrombosis at the vessel wall and (2) the influence of ion channel blockade on such effects. Concentrations of thrombomodulin and tissue factor were quantified by Western blotting (ratio of von Willebrand factor staining) and immunohistochemistry (as a percentage of CD31-staining area). Thrombomodulin concentrations after 90 minutes of venous and arterial flow conditions were quantified by immunostaining (68.9±4.8% and 41.0±3.0% CD31, respectively; P <0.01) and by Western blotting (1.35±0.20 and 0.15±0.03 ratio of von Willebrand factor, respectively; P <0.01). The ability of endothelial cells to generate activated protein C also decreased from 62±14 to 19±10 ng · min −1 · 1000 cells −1 ( P =0.01). The significant reduction in thrombomodulin was attenuated if calcium was removed from the perfusate but not by external vein stenting. Inclusion in the vein perfusate of drugs that reduce calcium entry (including Gd 3+ , to block stretch-activated ion channels, and nifedipine) abolished the reduction in thrombomodulin concentration observed after arterial flow conditions. In freshly excised vein, negligible concentrations of tissue factor were detected on the endothelium and concentrations did not increase after 90 minutes of arterial flow conditions, although the inclusion of nifedipine caused the immunostaining to increase from 3.0±0.4% to 8.5±0.7% CD31 ( P <0.02). Conclusions —In saphenous vein endothelium exposed to arterial flow conditions, there is rapid downregulation of thrombomodulin, sufficient to limit protein C activation, by a calcium-dependent mechanism.

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Thrombomodulin Gene Mutations Associated With Myocardial Infarction

Abstract: The findings suggest that mutations in the promoter region of the thrombomodulin gene may constitute a risk for arterial thrombosis.

Cited by 125 publications

References 16 publications

Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans.

Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans.

Effects of Aging on the Coagulation Fibrinolytic System in Outpatients of the Cardiovascular Department

Arterial Flow Conditions Downregulate Thrombomodulin on Saphenous Vein Endothelium

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