血栓调节蛋白、活化蛋白C抵抗与脑梗死的相关性研究
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摘要
本课题选择60例急性脑梗死患者及33例健康体检者,晨起空腹采取静脉血,进行血浆血栓调节蛋白、活化蛋白C抵抗检测。我们发现实验组血浆血栓调节蛋白(TM)浓度与对照组血浆血栓调节蛋白浓度之间差别显著,有统计学意义;实验组血浆活化蛋白C抵抗(APCR)阳性率与对照组血浆活化蛋白C抵抗阳性率比较有显著差异,在中青年组与中老年组间血浆活化蛋白C抵抗阳性率比较有差别,具有统计学意义;按照脑卒中神经功能缺损程度评分标准(MESSS)将卒中患者分为轻、中、重型脑梗死,各组血浆血栓调节蛋白浓度比较有差别,具有统计学意义。采用多元素直线相关分析,发现血栓调节蛋白与收缩压、舒张压、空腹血糖、总胆固醇、甘油三酯、低密度脂蛋白呈正相关,与高密度脂蛋白呈负相关。最终我们得出如下结论:TM是脑梗死发病的危险因素之一,且与脑梗死的严重程度呈正相关,TM升高对缺血脑组织具有保护作用。APCR阳性亦为脑梗死高发的危险因素之一,且与中青年脑卒中的发病关系更密切。TM水平的降低可产生获得性APCR现象,进而引起凝血功能障碍,导致脑梗死的发生。
Cerebral vascular disease(CVD) refers to brain dysfunction caused by a variety of cerebral vascular lesions.CVD or stroke in the narrow sense(Stroke), refers to the acute onset vascular case of the limitations or diffuse signs of brain function defect.Its high incidence,high mortality,high morbidity of stroke constitutes a huge threat to human health.Acute cerebrovascular disease(ACVD) incidence was higher trend,and tend to have younger because of dietary changes in the structure and the aging of society,this causes an immense burden on family and society.
The risk factors of ischemic cerebrovascular disease(CVD) including atherosclerosis,hypertension,cardiac disease,diabetes,hyperlipemia,smoking and excessive drinking are generally acknowledged in the world.Virchow noted that the vessel wall injury,blood flow changes,blood changes in the nature are of the three elements of thrombosis formation,and prethrombotic state refers to the body imbalance of the procoagulant and natural anticoagulant mechanism, that is,vascular endothelial cells,platelets,coagulation and fibrinolytic system caused by changes in favor of thrombosis pathological status,are of the early stage of thrombosis formation.Protein C system(PCS) is a group of proteins, consist of protein C(PC),protein S(PS),protein C inhibitor(PCI),thrombomodulin (thrombomodulin,TM),plays an important regulatory role in blood coagulation of the body,is important in plasma anti-coagulation system,impacts the dynamic balance of blood coagulation - anticoagulant mechanisms directly, is related to the incidence of ischemic cerebrovascular disease closely.TM as one of the important components of PCS involved in anticoagulation effect.TM are single-chain glycoprotein,synthesized by vascular endothelial cells,together with the surface of endothelial cells.TM and thrombin 1:1 specific binding to change thrombin configuration,form thrombin-Tm complex.At the participation of Ca2+,bind specific to protein C,and activat it,to form thrombin-TM-protein C complex(APC).At the participation of protein S,APC inactivates factor V a and factorⅧa,at the same time inhibiting plasminogen activator inhibitor,to play the role of anticoagulation and promoting fibrinolysis.Combinating with TM,thrombin loss procoagulant activity,Including to prevent platelet aggregation release function,to prevent fibrin formation and activation of factorⅤand factorⅧ,which have important physiological significance in the prevention of thrombosis.TM have biphasic effect in the coagulation process. And activated protein C resistance(APCR) was mainly due to gene mutation of coagulation factorⅤ(ie,FV Leiden) and enable the activated protein C(APC) can not hydrolyzed and inactivated FⅤa,FⅧa effectively,making an increase of thrombin generation,resulting the hypercoagulable state in the body.In the normal population the incidence of APCR was also 5%,APCR-positive population may be considered high-risk groups of thrombosis.
Therefore,the relations of TM,APCR and cerebral infarction were studied systematically to detect the relationship of TM,APCR with cerebral infarction and other stroke risk factors,which can provide a meaningful theoretical basis for prevention and treatment of stroke.
Experimental Methods:select 60 cases of patients with acute cerebral infarction,one of 30 cases of male,female 30 cases,age 28-82 years old,the average age of 54.31±13.85 years old.Consistent with the diagnostic criteria that be revised by 1995 Fourth National Conference on Cerebrovascular Diseases,with the head CT or MRI confirmed,and by TCD(transcranial color Doppler ultrasound) and neck CDFI(neck color Doppler ultrasound) confirmed the exception of blood vessels narrow and harden.Selected 33 cases of healthy persons as a normal control group,one of 17 cases of male,female 16 cases,age 27-78 years old,the average age of 53.70±15.96 years old,and match the experimental group(P＞0.05).All patients except for acute and chronic liver disease,blood system disea,es,recent surgery,nephrotic syndrome and oral contraceptives,such as.Subjects were draw 3.6ml fasting blood into 0.4ml anticoagulant test tube containing 0.109mmol/L sodium citrate,3000r/min centrifugal 10min,check the upper plasma 1000μl,placed in-70℃refrigerator to be preserved seized.Using enzyme-linked immunosorbent assay method (ELISA) for plasma TM assay,sing APTT±APC(Dahlback) measured APCR.
Experimental Results:There was significant differences between Plasma TM concentration(2.82±1.62) and the control group plasma TM concentrations (0.85±0.47),there was statistical significance.Under the modified Edinburgh-candinavian Stroke degree of neurological deficit score(MESSS) is divided into light,medium and heavy cerebral infarction.Inter-group comparison of plasma concentration of TM:The differences has statistical significance between light plasma TM concentration(1.71±0.71),medium-sized group of plasma TM concentration(2.94±0.85) and severe group of plasma TM concentration(4.94±1.46).There is significant difference,and there is statistical significance between experimental group,plasma APCR positive 12(20%) people and the control group plasma APCR positive one person(3.0%).There is significant difference and statistical significance between Youth Group plasma APCR positive rate (33.3%) and middle-aged and old groups of plasma APCR positive rate(11.1%); At the same time,the correlation analysis between plasmaTM concentration and risk factors of cerebral infarction show that there was positively correlated between.plasma TM concentration and systolic blood pressure,diastolic blood pressure,fasting blood glucose,cholesterol,triglycerides,LDL.There was negative correlation between plasma TM concentration and high density lipoprotein.
Experimental conclusions:
1.TM is a risk factor for cerebral infarction,there was positive correlation between TM and the severity of the cerebral infarction,TM increased on ischemic brain tissue has a protective effect.
2.APCR was also one of the risk factors of high incidence of cerebral infarction,and have closer relationship with the incidence of youth stroke.
3.The lower level of TM can produce acquired APCR phenomenon, thereby causing coagulation dysfunction,resulting in the occurrence of cerebral infarction.
Cerebral vascular disease(CVD) refers to brain dysfunction caused by a variety of cerebral vascular lesions.CVD or stroke in the narrow sense(Stroke), refers to the acute onset vascular case of the limitations or diffuse signs of brain function defect.Its high incidence,high mortality,high morbidity of stroke constitutes a huge threat to human health.Acute cerebrovascular disease(ACVD) incidence was higher trend,and tend to have younger because of dietary changes in the structure and the aging of society,this causes an immense burden on family and society.
The risk factors of ischemic cerebrovascular disease(CVD) including atherosclerosis,hypertension,cardiac disease,diabetes,hyperlipemia,smoking and excessive drinking are generally acknowledged in the world.Virchow noted that the vessel wall injury,blood flow changes,blood changes in the nature are of the three elements of thrombosis formation,and prethrombotic state refers to the body imbalance of the procoagulant and natural anticoagulant mechanism, that is,vascular endothelial cells,platelets,coagulation and fibrinolytic system caused by changes in favor of thrombosis pathological status,are of the early stage of thrombosis formation.Protein C system(PCS) is a group of proteins, consist of protein C(PC),protein S(PS),protein C inhibitor(PCI),thrombomodulin (thrombomodulin,TM),plays an important regulatory role in blood coagulation of the body,is important in plasma anti-coagulation system,impacts the dynamic balance of blood coagulation - anticoagulant mechanisms directly, is related to the incidence of ischemic cerebrovascular disease closely.TM as one of the important components of PCS involved in anticoagulation effect.TM are single-chain glycoprotein,synthesized by vascular endothelial cells,together with the surface of endothelial cells.TM and thrombin 1:1 specific binding to change thrombin configuration,form thrombin-Tm complex.At the participation of Ca2+,bind specific to protein C,and activat it,to form thrombin-TM-protein C complex(APC).At the participation of protein S,APC inactivates factor V a and factorⅧa,at the same time inhibiting plasminogen activator inhibitor,to play the role of anticoagulation and promoting fibrinolysis.Combinating with TM,thrombin loss procoagulant activity,Including to prevent platelet aggregation release function,to prevent fibrin formation and activation of factorⅤand factorⅧ,which have important physiological significance in the prevention of thrombosis.TM have biphasic effect in the coagulation process. And activated protein C resistance(APCR) was mainly due to gene mutation of coagulation factorⅤ(ie,FV Leiden) and enable the activated protein C(APC) can not hydrolyzed and inactivated FⅤa,FⅧa effectively,making an increase of thrombin generation,resulting the hypercoagulable state in the body.In the normal population the incidence of APCR was also 5%,APCR-positive population may be considered high-risk groups of thrombosis.
Therefore,the relations of TM,APCR and cerebral infarction were studied systematically to detect the relationship of TM,APCR with cerebral infarction and other stroke risk factors,which can provide a meaningful theoretical basis for prevention and treatment of stroke.
Experimental Methods:select 60 cases of patients with acute cerebral infarction,one of 30 cases of male,female 30 cases,age 28-82 years old,the average age of 54.31±13.85 years old.Consistent with the diagnostic criteria that be revised by 1995 Fourth National Conference on Cerebrovascular Diseases,with the head CT or MRI confirmed,and by TCD(transcranial color Doppler ultrasound) and neck CDFI(neck color Doppler ultrasound) confirmed the exception of blood vessels narrow and harden.Selected 33 cases of healthy persons as a normal control group,one of 17 cases of male,female 16 cases,age 27-78 years old,the average age of 53.70±15.96 years old,and match the experimental group(P＞0.05).All patients except for acute and chronic liver disease,blood system disea,es,recent surgery,nephrotic syndrome and oral contraceptives,such as.Subjects were draw 3.6ml fasting blood into 0.4ml anticoagulant test tube containing 0.109mmol/L sodium citrate,3000r/min centrifugal 10min,check the upper plasma 1000μl,placed in-70℃refrigerator to be preserved seized.Using enzyme-linked immunosorbent assay method (ELISA) for plasma TM assay,sing APTT±APC(Dahlback) measured APCR.
Experimental Results:There was significant differences between Plasma TM concentration(2.82±1.62) and the control group plasma TM concentrations (0.85±0.47),there was statistical significance.Under the modified Edinburgh-candinavian Stroke degree of neurological deficit score(MESSS) is divided into light,medium and heavy cerebral infarction.Inter-group comparison of plasma concentration of TM:The differences has statistical significance between light plasma TM concentration(1.71±0.71),medium-sized group of plasma TM concentration(2.94±0.85) and severe group of plasma TM concentration(4.94±1.46).There is significant difference,and there is statistical significance between experimental group,plasma APCR positive 12(20%) people and the control group plasma APCR positive one person(3.0%).There is significant difference and statistical significance between Youth Group plasma APCR positive rate (33.3%) and middle-aged and old groups of plasma APCR positive rate(11.1%); At the same time,the correlation analysis between plasmaTM concentration and risk factors of cerebral infarction show that there was positively correlated between.plasma TM concentration and systolic blood pressure,diastolic blood pressure,fasting blood glucose,cholesterol,triglycerides,LDL.There was negative correlation between plasma TM concentration and high density lipoprotein.
Experimental conclusions:
1.TM is a risk factor for cerebral infarction,there was positive correlation between TM and the severity of the cerebral infarction,TM increased on ischemic brain tissue has a protective effect.
2.APCR was also one of the risk factors of high incidence of cerebral infarction,and have closer relationship with the incidence of youth stroke.
3.The lower level of TM can produce acquired APCR phenomenon, thereby causing coagulation dysfunction,resulting in the occurrence of cerebral infarction.
引文
[1]王维治,罗祖明.神经病学[M].第4版.北京:人民卫生出版社,2003.122-127
[2]候熙德.神经病学[M].第3版.北京:人民卫生出版社,1996,108-111
[3]饶明俐,中国脑血管病防治指南[M].中风与神经疾病杂志,2006,23(1):5.
[4]王淑娟.关于选择血栓前状态实验诊断指标的建议[J].中华医学检验杂志,1998,21(5):305-307
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[7]Ganesan V,McShane MA,Liesner R.et al.Inherned prothrombotic states and ischemic stroke in childhood[J].J Neurol Neurosurg Psychiatry,1998,65(4):508-511
[8]Douay X,Lucas C,Caron C.et al.Antithrombin,protein C and protein S levels in 127 consecutive young adults with ischemic stroke[J].Acta Neurol Scand,1998,98(2):124-127
[9]Van de Wouwer M,Collen D,Conway EM.Thrombomdulin protein CEPCR system[J].Biology,2004,24:1374-1385
[10]张蕾,孙旦澄,张燕香.脑梗死和心肌梗死患者血栓调节蛋白的检测及临床应用[M].检验医学,2005,20:40-41
[11]周惠,李玲.糖尿病患者血栓调节蛋白测定结果分析[J].广西医学.2003,25:1129-1131
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[16]Bokarwa MI,Bremme K,Falk G,et al.Studies on phospholipids antibodies,APC2 resistance and associated mutation in the coagula tion factor V gene [J].Thromb Res,1995,78(3):193-200
[17]屈晨雪,夏铁安,王建中.血栓病患者凝血、抗凝和纤溶活性改变的研究[J].中国实验诊断学,2001,5(5):222-223
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[21]芦兴国,付国胜,黄连生.等.原发性高血压PTM的水平及其临床意义[J].上海:上海医学检验杂志,1999,14(5):305-306
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[24]周青珍,吴家幂.凝血酶调节蛋白与脑缺血[J].神经疾病与精神卫生,2006,6(2):153-155
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[26]张淑敏,王学谦.凝血酶调节蛋白的研究进展[J].国外医学输血及血液学分册,2001,24(2):159-161
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[29]Mosnier LO,Meijers JC,Bouma BN.Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin [J].Thromb Haemost,2001,85(1):5-11
[30]Olivot JM,Labreuche J,Aiach M.et al.Soluble thrombomodulin and brain infarction[J].Stroke,2004,35(8):1946-1951
[31]Kario K,Matsuo T,Kobayashi H,et al.Silent Cerebral infarction is associated with hypercoagulability endothelial cell damage,and high Lp(a)levels in elderly Japanese[J].Arterioscler Thromb Vase,1996,16:734-741
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[2]候熙德.神经病学[M].第3版.北京:人民卫生出版社,1996,108-111
[3]饶明俐,中国脑血管病防治指南[M].中风与神经疾病杂志,2006,23(1):5.
[4]王淑娟.关于选择血栓前状态实验诊断指标的建议[J].中华医学检验杂志,1998,21(5):305-307
[5]毛焕元,曹林生.心脏病学[M].第2版,北京:人民卫生出版社,2000:1031
[6]王鸿利,王学峰.血栓病临床新技术[M].北京:人民军医出版社,2003,366
[7]Ganesan V,McShane MA,Liesner R.et al.Inherned prothrombotic states and ischemic stroke in childhood[J].J Neurol Neurosurg Psychiatry,1998,65(4):508-511
[8]Douay X,Lucas C,Caron C.et al.Antithrombin,protein C and protein S levels in 127 consecutive young adults with ischemic stroke[J].Acta Neurol Scand,1998,98(2):124-127
[9]Van de Wouwer M,Collen D,Conway EM.Thrombomdulin protein CEPCR system[J].Biology,2004,24:1374-1385
[10]张蕾,孙旦澄,张燕香.脑梗死和心肌梗死患者血栓调节蛋白的检测及临床应用[M].检验医学,2005,20:40-41
[11]周惠,李玲.糖尿病患者血栓调节蛋白测定结果分析[J].广西医学.2003,25:1129-1131
[12]周泉生.综述.血栓栓调节素的研究进展[J].国外医学输血及血液学分册,1990,I3:222
[13]雷惠新,陈名峰,张旭.等.急性脑梗死患者血栓调节蛋白变化研究[J]. 中国临床神经科学,2001,9(1):68-69
[14]Dahlback B,Carlsson M,Svensson PJ.Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein:prediction of a cofactor to activated protein C [J].Proc Nail Acad Sci USA,1993,90(3):1004-1008
[15]Beaina RM,Koeleman BP,Koster T,et al.Mutation in blood coagulate- on factor V associated with resistance to activated protein C[J].Nature,1994,369(6475):64-67
[16]Bokarwa MI,Bremme K,Falk G,et al.Studies on phospholipids antibodies,APC2 resistance and associated mutation in the coagula tion factor V gene [J].Thromb Res,1995,78(3):193-200
[17]屈晨雪,夏铁安,王建中.血栓病患者凝血、抗凝和纤溶活性改变的研究[J].中国实验诊断学,2001,5(5):222-223
[18]丛玉隆,王淑娟.今日临床检验学[M].第1版.北京;中国科学技术出版社,1997,160-173
[19]王吉耀,内科学(供七年制临床医学等专业用).第一版.北京;人民卫生出版社,2002.821
[20]李运刚,潘旭东.蛋白C系统缺血性脑血管疾病[J].国外医学脑血管疾病分册,2001,9(4):212-213
[21]芦兴国,付国胜,黄连生.等.原发性高血压PTM的水平及其临床意义[J].上海:上海医学检验杂志,1999,14(5):305-306
[22]Bjorn Dahlback.The protein C anticoagulant system:inherited defects as basis for venous thrombosis[J].Thromb Res,1995,77(1):1-43
[23]Sadler JE.Thrombomodulin structure and function[J].Thromb Haemost,1997,78(1):392-395
[24]周青珍,吴家幂.凝血酶调节蛋白与脑缺血[J].神经疾病与精神卫生,2006,6(2):153-155
[25]于逢春,翟艳苓,刘艳.等.急性脑梗死患者血浆组织因子及血栓调节蛋白的研究[J].北京医学,2006,28(4):196-198
[26]张淑敏,王学谦.凝血酶调节蛋白的研究进展[J].国外医学输血及血液学分册,2001,24(2):159-161
[27]Dahlback B.Blood coagulation[J],Lancet,2000,355(9215):1627-1632
[28]Alireza R,Rezaie,Likui Yang.Mutagenesis studies toward understand- ing the mechanism of the cofactor function of thrombomodulin[J].Biophys Chem,2005,117(3):255-261
[29]Mosnier LO,Meijers JC,Bouma BN.Regulation of fibrinolysis in plasma by TAFI and protein C is dependent on the concentration of thrombomodulin [J].Thromb Haemost,2001,85(1):5-11
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