重型血友病临床表现异质性与抗凝蛋白及纤溶相关蛋白的关系
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摘要
背景和目的
重型血友病患者存在着相当大的临床表现异质性。大约10-15%的重型血友病患者具有相对较轻的临床表现。基因变异的类型、整个止血系统活性的变化(包括抗凝和纤溶水平)、局部炎症及血管生成因子、凝血因子输注后的药代动力学以及环境因素等都可能对重型血友病的临床表现产生影响。在国外,比较肯定的结论是如果患者合并易栓因素,例如FV Leiden或凝血酶原G20210A突变,将可显著减轻出血表现。但在我国上述突变极其罕见,影响我国重型血友病临床表现异质性的遗传和环境因素尚不明确。
本研究通过分析我国血友病患者的临床特点,检测血友病患者血浆蛋白C(PC)、蛋白S(PS)、抗凝血酶(AT)和凝血酶激活的纤溶抑制物(TAFI)的活性水平以及组织型纤溶酶原活化物(t-PA)、纤溶酶原活化物的抑制物-1(PAI-1)的抗原水平,初步探讨抗凝蛋白和纤溶相关蛋白对重型血友病临床表现异质性的影响。
方法
采集2008年12月至2010年3月在北京协和医院血友病门诊就诊的血友病患者的血液标本,并登记临床信息,采集病历资料。采用一期法检测FVIII活性FVIII或FIX活性(/FIX:C), Bethesda方法检测FVIII抑制物(FVIII:I)或FIX抑制物(FIX:I),发色底物法检测AT、PC、TAFI活性,凝固法检测PS活性,ELISA法检测vWF、t-PA和PAI-1抗原。使用SPSS PASW Statistics18软件对患者的临床资料和检测数据进行统计分析。
结果
1.本组患者病例特点：234名血友病患者中,血友病A患者206例,占88%,血友病B患者28例,占12%。重型215例,占91.9%,中型16例,占6.8%,轻型3例,占1.3%。中位年龄20岁,四分位数范围13.8～30岁。血友病A患者FVIII:I阳性者10名,占4.9%；血友病B患者FIX:I阳性者1名,占3.6%。133名患者进行了HBsAg检测,阳性者4名,占3%。134名患者进行了HCV-Ab检测,阳性者52名,占38.8%。132名患者进行了HIV-Ab检测,均为阴性。
2.重型血友病患者存在很大的临床表现异质性。首次出血年龄中位数为0.92岁,四分位数范围0.5-2岁。年出血频率中位数为18次／年,四分位数范围7.5-36次/年。畸形关节数中位数为2个,四分位数范围1-4个。
3.234名血友病患者的PC、PS、AT缺乏频率分别为6.8%、6.4%、6.0%,与国内正常人群的相应缺乏频率比较(1.1%、1.2%、2.3%)显著升高(P≤0.001)。 t-PA和PAI-1抗原水平分别为13(6～21) ng/ml和35.5(14～56) ng/ml(中位数及四分位数范围),显著高于正常参考值(1～12ng/ml和5-45ng/ml)。TAFI活性水平为114.04(54.82-173.26)%(均值及95%界限值),显著高于正常参考值108(60-156)%(P=0.046)。
4. HCV-Ab阳性血友病患者的t-PA水平为17(10.8～25) ng/ml(中位数及四分位数范围),阴性患者t-PA水平为11(4-15) ng/ml,阳性患者显著高于阴性患者(P=0.005)。PC、PS、AT、PAI-1、TAFI水平与慢性丙肝病毒感染无明显相关。
5.重型血友病患者中,临床表现重度组的AT水平为105(100.3-110)%(中位数及四分位数范围),轻度组的AT水平为114(106-117)%,重度组显著低于轻度组(P=0.010)。未发现PC、PS、t-PA=PAI-1和TAFI水平在两组间的显著差异。
结论
1.本组血友病患者存在明显的临床表现异质性,主要表现在首次出血年龄、出血频率及部位、关节畸形数等方面。
2.本组血友病患者PC、PS、AT活性的缺乏率显著高于正常人群。
3.本组血友病患者血浆t-PA、PAI-1抗原水平显著增加。其中,t-PA水平的升高在一定程度上与血友病患者的高HCV感染率有关。本组血友病患者的血浆TAFI活性显著升高。
4.重型血友病临床表现异质性可能与血浆AT活性相关。重度临床表现的患者血浆AT活性降低。
Background&Purpose
There is considerable clinical heterogeneity among severe hemophilia patients. About10%to15%of these patients with severe hemophilia have relatively mild clinical presentations. Genetic mutations, variations of the global hemostasis system (including antithrombotic and fibrinolytic proteins), local inflammation and angiogenic factors, pharmacokinetics of administered clotting factor concentrates, and environmental factors can affect the clinical heterogeneity of severe hemophilia. In foreign countries, the conclusive opinion is that if the patient has concurrent prothrombotic factors, such as FV Leiden or prothrombin G20210A mutations, the bleeding can be considerably diminished. But such gene mutations are very rare in Chinese population, so the genetic and environmental factors affecting clinical phenotype of severe hemophilia are still unknown.
In this research, by analyzing clinical characteristics of Chinese hemophilia patients and detecting the plasma levels of protein C (PC), protein S (PS), antithrombin (AT), tissue type plasmonogen activator (t-PA), plasminogen activator inhibitor-1(PAI-1) and thromobin activatable fibrinolysis inhibitor (TAFI), we initially investigate the impact of these antithrombotic and fibrinolytic proteins on the clinical heterogeneity of severe hemophilia.
Methods
We collect blood samples of hemophilia patients who came to the hemophilia clinic of Peking Union Medical College Hospital from December2008to March2010and record clinical data of these patients. FVIII Activity (FVIII:C) or FIX Activity (FIX:C) were measured by one-stage coagulation assay; FVIII Inhibitor (FVIII:I) or FIX Inhibitor (FIX:I) measured by the Bethesda assay; AT, PC and TAFI activity measured by chromogenic assay; PS activity measured by clotting assay; the antigen of vWF, t-PA and PAI-1determined by ELISA. The clinical and laboratory data are analyzed by SPSS PASW Statistics18software.
Results
1. Characteristics of hemophilia patients in this research:Among234hemophilia patients,206(88%) were hemophilia A, hemophilia B accounted for12%; Severe, moderate and mild cases were215(91.9%),16(6.8%) and3(1.3%), respectively. The median age was20years (quartile range13.8-30years). Ten hemophilia A patients (4.9%) were FⅧ:Ⅰ positive and one hemophilia B patients (3.6%) were FIX:I positive.3%(4/133) of the patients carried HbsAg and up to38.8%(52/134) of the patients had positive results in HCV-Ab detection. HIV-Ab were measured in132patients and all of them had negative results.
2. There is considerable clinical heterogeneity among severe hemophilia patients. The median age of first bleeding episode was0.92year (0.5-2years). The median annual bleeding were18(7.5-36) episodes. The median number of joint deformities was2with quartile range1-4.
3. The frequencies of the deficiency of PC, PS and AT among234hemophilia patients were6.8%,6.4%and6.0%, respectively, which were significant higher than those from Chinese healthy population (1.1%,1.2%,2.3%, respectively, P≤0.001). The median antigen levels of t-PA and PAI-1were13(6-21) ng/ml and35.5(14～56) ng/ml, respectively, and significantly higher than reference range which were1～12ng/ml and5-45ng/ml respectively. The average level of TAFI activity was114.04%(95%interval54.82～173.26), and significantly higher than reference range which is108(60～156)%(P=0.046).
4. The plasma level of t-PA in HCV-Ab positive hemophilia patients was17(10.8～25) ng/ml, and significantly higher than the negative ones which was11(4-15) ng/ml (P=0.005). It appeared that the plasma level of PC, PS, AT, PAI-1and TAFI were not related to chronic HCV infection.
5. Among severe hemophilia patients, the plasma level of AT in clinically severe group was105(100.3～110)%, and significantly lower than clinically mild group which was114(106-117)%(P=0.010). It had not been found that there were differences of PC, PS, t-PA, PAI-1and TAFI levels between the two groups.
Conclusions
1. There were considerable clinical heterogeneity among severe hemophilia patients in this research, which was mainly represented by the variations in the age of first bleeding episode, bleeding frequency, bleeding sites and joint deformities.
2. The deficiency frequencies of the activities of PC, PS and AT in this group of hemophilia patients were significantly higher than those in the healthy population.
3. The plasma antigen levels of t-PA and PAI-1in this group of hemophilia patients increased significantly. The elevation of t-PA level was partially related to the high rate of HCV infection among those patients. The TAFI activity of hemophilia patients in this research also significantly elevated.
4. The clinical heterogeneity in severe hemophilia was probably related to the plasma activity of AT, since the plasma activity of AT remarkably descended in clinically severe patients.
重型血友病患者存在着相当大的临床表现异质性。大约10-15%的重型血友病患者具有相对较轻的临床表现。基因变异的类型、整个止血系统活性的变化(包括抗凝和纤溶水平)、局部炎症及血管生成因子、凝血因子输注后的药代动力学以及环境因素等都可能对重型血友病的临床表现产生影响。在国外,比较肯定的结论是如果患者合并易栓因素,例如FV Leiden或凝血酶原G20210A突变,将可显著减轻出血表现。但在我国上述突变极其罕见,影响我国重型血友病临床表现异质性的遗传和环境因素尚不明确。
本研究通过分析我国血友病患者的临床特点,检测血友病患者血浆蛋白C(PC)、蛋白S(PS)、抗凝血酶(AT)和凝血酶激活的纤溶抑制物(TAFI)的活性水平以及组织型纤溶酶原活化物(t-PA)、纤溶酶原活化物的抑制物-1(PAI-1)的抗原水平,初步探讨抗凝蛋白和纤溶相关蛋白对重型血友病临床表现异质性的影响。
方法
采集2008年12月至2010年3月在北京协和医院血友病门诊就诊的血友病患者的血液标本,并登记临床信息,采集病历资料。采用一期法检测FVIII活性FVIII或FIX活性(/FIX:C), Bethesda方法检测FVIII抑制物(FVIII:I)或FIX抑制物(FIX:I),发色底物法检测AT、PC、TAFI活性,凝固法检测PS活性,ELISA法检测vWF、t-PA和PAI-1抗原。使用SPSS PASW Statistics18软件对患者的临床资料和检测数据进行统计分析。
结果
1.本组患者病例特点：234名血友病患者中,血友病A患者206例,占88%,血友病B患者28例,占12%。重型215例,占91.9%,中型16例,占6.8%,轻型3例,占1.3%。中位年龄20岁,四分位数范围13.8～30岁。血友病A患者FVIII:I阳性者10名,占4.9%；血友病B患者FIX:I阳性者1名,占3.6%。133名患者进行了HBsAg检测,阳性者4名,占3%。134名患者进行了HCV-Ab检测,阳性者52名,占38.8%。132名患者进行了HIV-Ab检测,均为阴性。
2.重型血友病患者存在很大的临床表现异质性。首次出血年龄中位数为0.92岁,四分位数范围0.5-2岁。年出血频率中位数为18次／年,四分位数范围7.5-36次/年。畸形关节数中位数为2个,四分位数范围1-4个。
3.234名血友病患者的PC、PS、AT缺乏频率分别为6.8%、6.4%、6.0%,与国内正常人群的相应缺乏频率比较(1.1%、1.2%、2.3%)显著升高(P≤0.001)。 t-PA和PAI-1抗原水平分别为13(6～21) ng/ml和35.5(14～56) ng/ml(中位数及四分位数范围),显著高于正常参考值(1～12ng/ml和5-45ng/ml)。TAFI活性水平为114.04(54.82-173.26)%(均值及95%界限值),显著高于正常参考值108(60-156)%(P=0.046)。
4. HCV-Ab阳性血友病患者的t-PA水平为17(10.8～25) ng/ml(中位数及四分位数范围),阴性患者t-PA水平为11(4-15) ng/ml,阳性患者显著高于阴性患者(P=0.005)。PC、PS、AT、PAI-1、TAFI水平与慢性丙肝病毒感染无明显相关。
5.重型血友病患者中,临床表现重度组的AT水平为105(100.3-110)%(中位数及四分位数范围),轻度组的AT水平为114(106-117)%,重度组显著低于轻度组(P=0.010)。未发现PC、PS、t-PA=PAI-1和TAFI水平在两组间的显著差异。
结论
1.本组血友病患者存在明显的临床表现异质性,主要表现在首次出血年龄、出血频率及部位、关节畸形数等方面。
2.本组血友病患者PC、PS、AT活性的缺乏率显著高于正常人群。
3.本组血友病患者血浆t-PA、PAI-1抗原水平显著增加。其中,t-PA水平的升高在一定程度上与血友病患者的高HCV感染率有关。本组血友病患者的血浆TAFI活性显著升高。
4.重型血友病临床表现异质性可能与血浆AT活性相关。重度临床表现的患者血浆AT活性降低。
Background&Purpose
There is considerable clinical heterogeneity among severe hemophilia patients. About10%to15%of these patients with severe hemophilia have relatively mild clinical presentations. Genetic mutations, variations of the global hemostasis system (including antithrombotic and fibrinolytic proteins), local inflammation and angiogenic factors, pharmacokinetics of administered clotting factor concentrates, and environmental factors can affect the clinical heterogeneity of severe hemophilia. In foreign countries, the conclusive opinion is that if the patient has concurrent prothrombotic factors, such as FV Leiden or prothrombin G20210A mutations, the bleeding can be considerably diminished. But such gene mutations are very rare in Chinese population, so the genetic and environmental factors affecting clinical phenotype of severe hemophilia are still unknown.
In this research, by analyzing clinical characteristics of Chinese hemophilia patients and detecting the plasma levels of protein C (PC), protein S (PS), antithrombin (AT), tissue type plasmonogen activator (t-PA), plasminogen activator inhibitor-1(PAI-1) and thromobin activatable fibrinolysis inhibitor (TAFI), we initially investigate the impact of these antithrombotic and fibrinolytic proteins on the clinical heterogeneity of severe hemophilia.
Methods
We collect blood samples of hemophilia patients who came to the hemophilia clinic of Peking Union Medical College Hospital from December2008to March2010and record clinical data of these patients. FVIII Activity (FVIII:C) or FIX Activity (FIX:C) were measured by one-stage coagulation assay; FVIII Inhibitor (FVIII:I) or FIX Inhibitor (FIX:I) measured by the Bethesda assay; AT, PC and TAFI activity measured by chromogenic assay; PS activity measured by clotting assay; the antigen of vWF, t-PA and PAI-1determined by ELISA. The clinical and laboratory data are analyzed by SPSS PASW Statistics18software.
Results
1. Characteristics of hemophilia patients in this research:Among234hemophilia patients,206(88%) were hemophilia A, hemophilia B accounted for12%; Severe, moderate and mild cases were215(91.9%),16(6.8%) and3(1.3%), respectively. The median age was20years (quartile range13.8-30years). Ten hemophilia A patients (4.9%) were FⅧ:Ⅰ positive and one hemophilia B patients (3.6%) were FIX:I positive.3%(4/133) of the patients carried HbsAg and up to38.8%(52/134) of the patients had positive results in HCV-Ab detection. HIV-Ab were measured in132patients and all of them had negative results.
2. There is considerable clinical heterogeneity among severe hemophilia patients. The median age of first bleeding episode was0.92year (0.5-2years). The median annual bleeding were18(7.5-36) episodes. The median number of joint deformities was2with quartile range1-4.
3. The frequencies of the deficiency of PC, PS and AT among234hemophilia patients were6.8%,6.4%and6.0%, respectively, which were significant higher than those from Chinese healthy population (1.1%,1.2%,2.3%, respectively, P≤0.001). The median antigen levels of t-PA and PAI-1were13(6-21) ng/ml and35.5(14～56) ng/ml, respectively, and significantly higher than reference range which were1～12ng/ml and5-45ng/ml respectively. The average level of TAFI activity was114.04%(95%interval54.82～173.26), and significantly higher than reference range which is108(60～156)%(P=0.046).
4. The plasma level of t-PA in HCV-Ab positive hemophilia patients was17(10.8～25) ng/ml, and significantly higher than the negative ones which was11(4-15) ng/ml (P=0.005). It appeared that the plasma level of PC, PS, AT, PAI-1and TAFI were not related to chronic HCV infection.
5. Among severe hemophilia patients, the plasma level of AT in clinically severe group was105(100.3～110)%, and significantly lower than clinically mild group which was114(106-117)%(P=0.010). It had not been found that there were differences of PC, PS, t-PA, PAI-1and TAFI levels between the two groups.
Conclusions
1. There were considerable clinical heterogeneity among severe hemophilia patients in this research, which was mainly represented by the variations in the age of first bleeding episode, bleeding frequency, bleeding sites and joint deformities.
2. The deficiency frequencies of the activities of PC, PS and AT in this group of hemophilia patients were significantly higher than those in the healthy population.
3. The plasma antigen levels of t-PA and PAI-1in this group of hemophilia patients increased significantly. The elevation of t-PA level was partially related to the high rate of HCV infection among those patients. The TAFI activity of hemophilia patients in this research also significantly elevated.
4. The clinical heterogeneity in severe hemophilia was probably related to the plasma activity of AT, since the plasma activity of AT remarkably descended in clinically severe patients.
引文
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[33]Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of haemophilia A with severe deficiency of factor Ⅷ as measured by one-stage assay. Haemophilia,2001; 7: 9-12.
[34]Schulman S, Eflde A, Blomback M, et al. The plasma concentration of activated protein C appears normal in patients with haemophilia. Haemophilia 2009; 15:566-570.
[35]David DB. Significance of raised plasma concentrations ofbtissue-type plasminogen activator and plasminogen activator inhibitor in patients at risk from ischaemic heart disease. Br Heart J,1994; 71:504-507.
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[37]Charles WF. Plasminogen activator inhibitor-1 levels and polymorphisms association with venous thromboembolism, Arch Pathol Lab Med,2002; 126: 1401-1404.
[38]Mosnier LO, Lisman T, Van Den Berg HM, et al. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost,2001; 86(4):1035-1039.
[39]Foley JH, Nesheim ME. Soluble thrombomodulin partially corrects the premature lysis defect in FⅧ-deficient plasma by stimulating the activation of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost,2009; 7:453-459.
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[33]Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of haemophilia A with severe deficiency of factor Ⅷ as measured by one-stage assay. Haemophilia,2001; 7: 9-12.
[34]Schulman S, Eflde A, Blomback M, et al. The plasma concentration of activated protein C appears normal in patients with haemophilia. Haemophilia 2009; 15:566-570.
[35]David DB. Significance of raised plasma concentrations ofbtissue-type plasminogen activator and plasminogen activator inhibitor in patients at risk from ischaemic heart disease. Br Heart J,1994; 71:504-507.
[36]John TB. Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease. Arch Pathol Lab Med,2002; 126:1376-1381.
[37]Charles WF. Plasminogen activator inhibitor-1 levels and polymorphisms association with venous thromboembolism, Arch Pathol Lab Med,2002; 126: 1401-1404.
[38]Mosnier LO, Lisman T, Van Den Berg HM, et al. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost,2001; 86(4):1035-1039.
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[1]Molho P, Rolland N, Lebrun T, et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. Haemophilia 2000; 6(1):23-32.
[2]Giridhara RJ, Alok S. The Phenotypic Heterogeneity of Severe Hemophilia. Seminars in Thrombosis and Hemostasis 2008; 34(1):128-141.
[3]van Dijk K, van der Bom JG, Fischer K, et al. Do prothrombotic factors influence clinical phenotype of severe haemophilia? A review of the literature. Thromb Haemost 2004; 92(2):305-310.
[4]Pollmann H, Richter H, Ringkamp H, et al. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr 1999; 158(Suppl 3):166-170.
[5]Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361:1801-1809.
[6]van Dijk K, Fischer K, van der Bom JG, et al. Variability in clinical phenotype of severe haemophilia:the role of the first joint bleed. Haemophilia 2005; 11:438-443.
[7]Blanchette P, Rivard G, Israels S, et al. A survey of factor prophylaxis in the Canadian haemophilia A population. Haemophilia 2004; 10:679-683.
[8]Grunewald M, Siegemund A, Grunewald A, et al. Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia. Haemophilia 2002; 8:768-775.
[9]Kubisz P, Stasko J, Dobrotova M, et al. Severe hemophilia and physiologic inhibitors of coagulation. Clin Appl Thromb Hemost 2005; 11:331-334.
[10]Shetty S, Vora S, Kulkarni B, et al. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of haemophilia patients. Br J Haematol 2007; 138:541-544.
[11]Arbini AA, Mannucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among "severe" hemophiliacs with a "milder" bleeding diathesis. Thromb Haemost 1995; 74:1255-1258.
[12]Schulman S, Eflde A, Homstrom M, et al. Validation of a composite score for clinical severity of Hemophilia. J Thromb Haemost 2008; 6:1113-1121.
[13]Malhotra R, Singh Gulati M, Bhan S. Elbow arthropathy in hemophilia. Arch Orthop Trauma Surg 2001; 121:152-157.
[14]Nowak-Gottl U, Escuriola C, Kurnik K, et al. Haemophilia and thrombophilia. What do we learn about combined inheritance of both genetic variations? Hamostaseologie 2003; 23:36-40.
[15]Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83:387-391.
[16]Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of haemophilia A with severe deficiency of factor VIII as measured by one-stage assay. Haemophilia 2001; 7: 9-12.
[17]van Dijk K, van der Bom JG, Fischer K, et al. Phenotype of severe hemophilia A and plasma levels of risk factors for thrombosis. J Thromb Haemost 2007; 5:1062-1064.
[18]Schulman S, Eflde A, Blomback M, et al. The plasma concentration of activated protein C appears normal in patients with haemophilia. Haemophilia 2009; 15:566-570.
[19]Antovic JP, Schulman S, An S, et al. Does an enzyme other than thrombin contribute to unexpected changes in the levels of the different forms of thrombin activatable fibrinolysis inhibitor in patients with hemophilia A, hemophilia B and von Willebrahd disease? Scandinavian Journal of Clinical & Laboratory Investigation 2004; 64(8): 745-752.
[20]Mosnier LO, Lisman T, Van Den Berg HM, Nieuwenhuis HK, et al. The defective down regulation of fibrinolysis in haemophilia A can be restored by increasing the TAFI plasma concentration. Thromb Haemost 2001; 86(4):1035-1039.
[21]Foley JH, Nesheim ME. Soluble thrombomodulin partially corrects the premature lysis defect in FVIII-deficient plasma by stimulating the activation of thrombin activatable fibrinolysis inhibitor. J Thromb Haemost 2008; 7:453-459.
[22]Hvas AM, SOrensen HT, Norengaard L, et al. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A. J Thromb Haemost 2007; 5:2408-2414.
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