Effects Of Thrombosis Related Factors On Coronary Heart Disease

Chapter 1Study of Relationship Between Gene Polymorphism of VWF andCoronary Heart DiseaseBackground: Single nucleotide polymorphism of promoter region of vonWillebrand factor(vWF) is associated with coronary heart disease (CHD).vWF-1793C/G is a novel genetic mutation with increased plasma level ofvWF, which was epidemiologically and clinically manifested by increasedrisk for CHD and worsening prognosis of acute coronary syndromes(ACS).Therefore, vWF-1793C/G is considered as a genetic basis for CHD.Objective: To investigate the correlation between genetic mutation inVWF-1793 and CHD.Methods: A Case-control study enrolled 190 patients with CHD and 180control subjects with no overt evidences of CHD and cerebravascular disease(CVD). Polymerase chain reaction-restricted fragment length polymorphismwas used to determine genetype of VWF-1793.Results:1. The distribution of vWF-1793C/G genetype in this study population wasCC 26.6%, CG 58.5% and GG14.9%, respectively. Allele frequencies for C and G were 55.9% and 44.1%, respectively.2. The differcnce of -1793C/G genetype distribution between two groupswas significant (P＜0.01), but allele frequencies for C and G were notsignificant (P＞0.05).3. The differences of the levels of plasma vWF among three genotypes wereinsignificant in case-control cohort, but within control group the levels ofplasma vWF was much higher in subjects with G allele than that in CChomozygous carriers (P＜0.05).4. Linear regression analysis showed plasma levels of vWF is a new riskfactor of CHD. In the meantime, The traditional risk factors keep still theposition of risk factors for CHD.vWF genetype could not enter theregression equatation.Conclusions: The frequency of heterozygous carrier of G in patients withCHD is significantly higer than that in control subjects. No associations werefound between allele G and plasma level of vWF in the patients. Chapter 2Studies about plasma level of VWF:Agand the prognosis of CHDBackground: The von Willebrand factor (vWF) is a plasma glycoprotein thatis mostly synthesized and stored by endothelial cells and about 15～20%synthesized in megakaryocytes and stored in platelets. It enhanceshaemostasis and thrombosis as an important cofactor in platelet adhesion andaggregation,and as the carrier protein for coagulation factorⅧ, namely, itpromotes adhesion of platelets to the sites of vascular injury by forming amolecular bridge between sub-endothelial collagen matrix andplatelet-surface receptor complex GPIb-Ⅸ-Ⅴ. vWF also acts as a chaperonefor coagulation factorⅧ, delivering it to the site of injury, stabilizing itsheterodimeric structure and protecting it from premature clearance fromplasma. Several epidemiological studies have presented evidence that a highcirculating VWF level is an independent risk factor for coronary heart diseasealthough the results are not consistent.Objectives:To investigate the association of plasma vWF level withcoronary heart disease.Methods: A case-control study was designed, including 156 patients withdocumented coronary heart disease and 88 control subjects. Circulating VWF:Ag was measured by an enzyme-linked immunosorbent assay(ELISA).The association between the circulating VWF:Ag and subsquentcadiovascular events of patients with CHD was prospectively examined.Results:1. The difference of plasma level of vWF: Ag between CHD patients and thecontrol subjects was significant (125.3%±74.5% vs 70.2%±66.7%,P＜0.01).2. The plasma level of vWF: Ag is correlated with CHD and the age in lightof the stepwise regression analysis.3. The prognosis of patients with CHD after 1 months was correlated withthe level of blood urea nitrogen (BUN) and the heart rate, respectively,but no independent risk factor for adverse prognosis of CHD patients bythe stepwise regression analysis.4. The prognosis of patients with CHD after 3months was correlated with thefollowing factors such as postprandial blood glucose level of 2hours ,white blood cell count, the levels of serum creatinine, BUN andC-RP, respectively, but no independent risk factor for adverse prognosis ofCHD patients by the stepwise regression analysis.5. The prognosis of patients with CHD either at the first month or at the thirdmonth was not correlated with the circulating level of vWF.Conclusions: The circulating level of vWF: Ag is significantly higher in patients with CHD than in the control subjects. This is the first study inChina to investigate the relationship between the circulating vWF:Ag and theprognosis of patients with CHD within 3 months. No correlation between thecirculating vWF: Ag with recurrent cardiovascular events was found. Theage, log-CRP and CHD per se were correlated with the level of circulatingvWF:Ag. Chapter 3Effects of simvastatin on plasma levels of tissue factor andtissue factor pathway inhibitor in patients with acute coronarysyndromesBackground : Rupture of atherosclerotic plaque and subsequentthrombus formation lead to acute coronary syndromes (ACS) and progressionof atherosclerotic disease. Numerous studies have demonstrated thatdisturbances of coagulation and fibrinolysis contribute to the developmentand progression of atherosclerosis, and that they affect the incidence oftherosclerosis-related clinical events. Tissue factor (TF) triggers acoagulation cascade thrombus formation after plaque ruptures. Tissue factorpathway inhibitor (TFPI) is a leading physiological inhibitor of TF and caninhibit the endothelial proliferation and thrombus embolism of atheroscleroticvessel after vascular damage. The 3-hydroxy-3-methylglutaryl(HMG)-coenzyme A (HMG-CoA) reductase inhibitors (statins) are beneficialboth in the primary and secondary prevention of atherosclerotic vasculardisease and acute events in a broad spectrum of patient subgroups. However,the observed clinical benefit with statin therapy is much greater thanexpected through the reduction of cholesterol levels alone. Clinical andexperimental studies suggested that several antiatherosclerotic effects otherthan lipid lowering also contribute to the observed benefit of statin therapy. These 'pleiotropic effects' include improvement of endothelial function,antithrombotic actions, plaque stabilization, reduction of the vascularinflammatory process and anti-oxidation. There is growing evidence thattreatment with statins can lead to a significant downregulation of the bloodcoagulation cascade, most probably as a result of decreased tissue factorexpression, which leads to reduced thrombin generation.Objectives The aim of this study was to investigate the effects of differentdoses of simvastatin on plasma levels of tissue factor (TF) and tissue factorpathway inhibitor (TFPI) in patients with acute coronary syndromes (ACS).Methods: A cohort of 88 patients with acute coronary syndromes wererandomized to treatment with either none (n=28), 20mg (n=29) or 40mg(n=31) simvastatin per day for the mean hospital-stay period of 8 daysstarting the day after admission. Fasting blood samples were collected onadmission day and after mean 8 days of simvastatin therapy to determineplasma tissue factor (TF) and tissue factor pathway inhibitor (TFPI) by anenzyme -linked immunosorbent assay(ELISA).Results:1. Simvastatin treatment with either 20mg or 40mg per day can significantlydecrease the median level of plasma TF from 12.75 pg/ml to 6.00pg/mland from 10.5 pg/ml to 5.25pg/ml, respectively (P＜0.01).2. Simvastatin treatment with either 20mg or 40mg per day significantly increased the median level of plasma TFPI from 182 ng/ml to 243ng/mland from 175 ng/ml to 318ng/ml, respectively (P＜0.05).3. The median levels of TFPI in 20mg and 40mg simvastatin treatment weresignificantly higher than that in control group, respectively (P＜0.05).4. The differences of the levels of total cholesterol (TC) and low densitylipoprotein chloesterol(LDL-C) between baseline and therapy duration ofsimvastatin with 40mg per day were significant (P＜0.05).5. Either decrease of TF or increase of TFPI during therapy of simvastatinwas not correlated with the plasma levels of TC and LDL-C.6. Baseline level of TF was positively with the baseline level of C-reactiveprotein (r=0.569, p=0.014) .Conclusions Simvastatin can change plasma levels of TF and TFPI. Thedecrease of TF and increase of TFPI during therapy of simvastatin areindependent of lipid-lowering effect.