The Research Of Individualized Anticoagulation For Warfarin After Heart Valve Replacement

Part I The research of correlation between warfarin and demographic factors and pharmacological factors1、The multicenter study of Han population in Yunnan-Guizhou plateau between warfarin dose and demographic factorsObjective To study the correlation between warfarin dose and demographic factors with multicenter data for the Han population after cardiac valve replacement in Yunnan-Guizhou plateau region and to guide the individual anticoagulant therapy. Method We choosed236cases of Chinese Han people in Yunnan-Guizhou plateau region who had finished cardiac valve replacement from the database of " The multi-center clinical research of low intensity anticoagulation therapy for Chinese people after heart valve replacement ".To observe the demographic factors including age, height, weight, BSA, BMI and clinical factors including atrial fibrillation, embolism, cardiac function, and to analyse the correltion between warfarin dose and them, and to obtain individualized anticoagulant equation. Results Atrial fibrillation, embolism and cardiac function were inflent factors in warfarin dose (p<0.05).There was not difference between man and female in warfarin stable dose and INR value(p>0.05).The analysis showed that there was correlation between age, height, weigh, body surface area and warfarin dose (p<0.05). The multiple linear regression equation showed that demographic factors could explain7.1%difference of warfarin dose. Conclusion There wss correlation between warfarin dose and demographic factors for Han population in Yunnan-Guizhou plateau region after the operation.We should consider the influence when we used warfarin. 2、The research of correlation between warfarin dose and amiodarone for Han population in Yunnan-Guizhou plateauObjective To investigate the therapy of reasonable warfarin anticoagulation after heart valve replacement with radiofrequency ablation and study the correlation between warfarin dose and amiodarone. Methods130cases of heart valve disease with atrial fibrillation were divided into2groups. A group for the heart valve replacement with radiofrequency ablation, took amiodarone6month with warfarin together after operation(n=60). B group took only warfarin for anticoagulant therapy after valve replacement surgery(n=70). Two groups were used low intensity anticoagulation standard with INR value1.5-2.5and observed in the anticoagulant effects and warfarin stable dose. Results The two groups showed no statistical difference(p>0.05) in anticoagulant-related mortality, the ratio of anticoagulant-related bleeding, thromboembolism rates and unusually high INR value rates during the time following up. The two groups showed no statistical difference(p>0.05) for the warfarin stable dose in different operation way. The diagram of group A showed that the warfarin dose in mean±standard deviation was2.43±0.58mg/d. Conclusion We choosed the low-intensity anticoagulation standard with INR value1.5-2.5and got satisfied anticoagulant effects for the patients who finished the valve replacement with radiofrequency ablation. Amiodarone might not be the important influent factors for the dose difference of warfarin in Han population of Yunnan-Guizhou plateau. Anticoagulation monitoring should be strengthened in the group A because of taking amiodarone. To avoid bleeding, we should regulate appropriatly the dose of warfarin according to the anticoagulant INR value. Part II The research of warfarin about the individualized anticoagulation forcast modelObjective To study the correlation of the CYP2C9(rs1057910),VKORC1(rs9923231) gene polymorphism and warfarin dose, and verify the relevance between the dose from four kinds of warfarin prediction models and the actual stable warfarin dose, and study the clinical application of all kinds of models. Methods We selected88cases as the research objects and researched gene sequence of CYP2C9and VKORC1with the PCR-ASPE method. To study the correlation of gene polymorphism and warfarin dose, and study the correlation between warfarin dose of four kinds prediction models which were IWPC, WADELIUS, MIAO, HUANG and the actual stable warfarin dose. Results For the Han population in Yunnan-Guizhou plateau after cardiac valve replacement the genotype frequency of VKORC1(rs9923231)AA, AG, GG were78.4%,20.5%,1.1%, A allele frequency was88.6%, the G allele frequency was11.4%. The genotype frequency of CYP2C9(rs1057910)*1/*1,*1/*3were89.8%,10.2%,*1allele frequency was94.9%,*3allele frequency was5.1%, They all met the Hardy-Weinberg genetic equilibrium(p>0.05). The warfarin dose of VKORC1(rs9923231) AA was below GG+AG types(p<0.05). The dose of CYP2C9(rs1057910)*1/*3type was below*1/*1, there was not difference in them(p>0.05). There was a significant difference in warfarin dose of different genotype combinations(p<0.01). There was statistical difference in warfarin dose between four kinds models and actual warfarin (p<0.05). The dose from high to low in all were:WADELIUS model, IWPC model, the actual dose, MIAO model, HUANG model. In three different dose groups of those models also showed a statistically difference(p<0.05).The linear regression analysis revealed that MIAO model, HUANG model, WADELIUS model, IWPC model can explain7.7%,7.2%,5.9%,5.6%for the individual differences of warfarin dose. Conclusion There was not statistical correlation between CYP2C9(rs1057910) gene polymorphism and warfarin stable dose. There was statistical correlation between VKORC1(rs9923231) gene polymorphism and warfarin dose for Han people in Yunnan-Guizhou plateau. And there was significant difference of warfarin stable dose in different genotype combination groups.The four equations were poor accuracy, they were not very good to predict the warfarin dose in Yunnan-Guizhou Han population. Part III The research of correlation between gene polymorphism and warfarin anticoagulation dose for Han population in Yunnan-Guizhou plateauObjective To investigate the genotype and allele frequencies of25sites for Han population in Yunnan-Guizhou plateau and study the correlation between gene polymorphism and the warfarin stable dose in the patient after valve replacement. Methods25sites gene types of the176cases were detected by SnaPshot technology in order to explore the genotype and allele frequencies. The176cases after valve replacement were investigated the correlation between gene polymorphism and the stabe dose of warfarin and studied the individualized prediction model of warfarin dose. Results All genotypes and allele frequencies met with Hardy-winberg genetic balance(p>0.05).There were statistical correlation between warfarin dose and different genotypes in some sites(p<0.05). They were: VKORC1(rs9923231), CYP2C9(rs1057910), CYP2C9(rs4086116), GGCX (rs12714145), GGCX(rs699664), GGCX(rs7568458), GGCX(rs6738645), GGCX (rs762684), CALU(rs339097), CYP2C18(rs7896133), CYP2C19(rs3862009), STX4A(rs10871454), ZNF646(rs11150604). The forecast mode showed that the genetic factors could explain approximately46.8%the difference of warfarin dose, and demographic factors with genetic factors could explain52.0%the difference of warfarin dose for Han population of Yunnan-Guizhou plateau. Conclusion Gene polymorphism of these gene sites for Yunnan-Guizhou plateau Han population were important factors which affected warfarin stable dose in the patients after the operation.