Studies on the Hemostatic and Genetic Risk Factors for Atherothrombotic Diseases

• Main Authors: Yi-Heng Li, 李貽恒
• Other Authors: Jyh-Hong Chen
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/00076512183725336315

博士 === 國立成功大學 === 基礎醫學研究所 === 88 === 英文摘要 Atherosclerosis and its complications, including acute myocardial infarction and ischemic stroke, have become the major causes of death and disability in Taiwan. Previous studies have demonstrated that occlusive thrombus formation at the site of a ruptured atherosclerotic plaque in coronary artery is the most important pathogenetic mechanism in acute myocardial infarction. In the first part of this thesis, we used several hemostatic markers to monitor the activities of coagulation system and thrombus formation in the early stage of acute myocardial infarction. These hemostatic markers, including fibrinopeptide A, prothrombin fragment 1+2 and thrombin-antithrombin complex, are the byproducts of coagulation system activation. We found that these hemostatic markers were significantly increased in acute myocardial infarction. Their elevation in the early phase of myocardial infarction also identified patients with increased risk for subsequent cardiac mortality. These results indicate that activation of coagulation cascade with the formation a hypercoagulable state is not only the cause of myocardial infarction but also associated with patients’ prognosis. Although it is well established that the risk for myocardial infarction is influenced by hypertension, diabetes mellitus and smoking, there is also an increasing body of evidence suggesting that hypercoagulability caused by genetic mutations may contribute to the disease development. Thrombomodulin is an endothelial cell membrane-bound anticoagulant glycoprotein. Protein C pathway is initiated when thrombin binds to thrombomodulin. Protein C proteolytically inactivates factor Va and VIIIa, and inhibits the propagation of coagulation cascade. Thrombomodulin itself also decreases the physiological effects of thrombin, including blood coagulation and cellular proliferation. Thrombomodulin gene mutation may be related to the pathogenesis of myocardial infarction. We therefore studied the association of thrombomodulin G-33A promoter mutation with myocardial infarction and coronary atherosclerosis. The mutation was detected by polymerase chain reaction and single-strand conformation polymorphism. Thrombomodulin G-33A mutation was found to be a common genetic variant in our population and there was a significant association of the mutation with coronary artery disease and myocardial infarction. The association is even more significant in young patients with myocardial infarction. We also evaluated the functional effect of G-33A mutation on thrombomodulin gene transcriptional efficiency. Luciferase reporter gene assays demonstrated that cultured endothelial cells transfected with the constructs containing thrombomodulin promoter with G-33A mutation decreased reporter gene products by 36% when compared with the transfects of the wild type promoter. Furthermore, the soluble thrombomodulin level increased only in coronary artery disease patients with normal GG genotype, but not in patients with G-33A mutation. These experimental results suggested that thrombomodulin G-33A mutation was a functional genetic variant. It influenced both the gene transcription and protein production. Finally, with the similar methods used in myocardial infarction study, we evaluated the influence of thrombomodulin G-33A mutation on the occurrence of ischemic stroke and carotid atherosclerosis in Taiwan. We found that the mutation was associated with carotid atherosclerosis in young subjects. However, there was no significant association of the mutation with ischemic stroke. In conclusion, coagulation cascade activation with the formation of a hypercoagulable state is not only an important cause of acute myocardial infarction but also may influence the patients’ prognosis. Thrombomodulin G-33A mutation is a functional genetic variant. It is also a common genetic cause of hypercoagulability in our population. Thrombomodulin G-33A mutation contributes to acute myocardial infarction and atherosclerosis. It is a genetic risk factor for acute myocardial infarction and atherosclerosis in this area.