我国部分地区血友病A患者临床特点分析、凝血因子VIII抑制物筛查及方法学比较
|
摘要
背景:
血友病A(HA)是一种X连锁隐性遗传病。患者不能合成或合成的凝血因子Ⅷ(FⅧ)有功能缺陷,临床上主要表现为自幼反复发生异常出血,其中以关节、肌肉出血最具特点,也可发生致死性出血。在发达国家,由于积极的诊断和治疗,HA患者不管是从预期寿命还是生活质量,都与普通正常人相似。同时发达国家对HA患者临床表现异质性和替代治疗中所产生针对FⅧ的抑制物都有深入的研究。我国作为发展中国家,不管是血友病临床诊治工作还是相关科研都与发达国家有很大差距。本课题通过总结我国部分地区HA患者临床特点,并对HA患者临床表现异质性、替代治疗中抑制物的产生和危险因素以及抑制物的检测方法等进行初步分析,以期能提高我国HA临床与科研水平。
目的:
1.总结我国HA患者的临床特点并对其临床表现异质性进行分析。
2.探讨HA患者FⅧ抑制物的阳性率检出率及抑制物产生的危险因素。
3.比较Bethesda和Nijmegen两种检测FⅧ抑制物的方法。
方法:
1.赴北京、河南、河北、山西、陕西、新疆等地采集遗传性HA患者的临床资料及血样。
2.用一期法检测FⅧ活性(FⅧ:C),ELISA法检测血管性血友病因子(vWF)抗原,Bethesda和Nijmegen方法检测FⅧ抑制物,发色底物法检测抗凝血酶Ⅲ(ATⅢ)活性和蛋白C(PC)活性,凝固法检测蛋白S(PS)活性和活化蛋白C抵抗(APC-R)。感染指标(HCV、HBV和HIV)统一送上海瑞金医院检测。
3.使用SPSS16.0统计软件对患者临床信息和实验室检查结果进行统计学分析。P＜0.05认为有统计学差异。
结果:
1.HA患者的临床特点:共收集无关家系遗传性HA患者388例,中位年龄19岁;以中型为主,占83.5%。在登记诊断时间的355例患者中,有18.3%从首次出血到诊断血友病间隔长达2年以上。在登记家族史的367例患者中,有54.2%无家族史。在登记关节畸形的362例患者中,10岁以内关节畸形率已达38.5%,20岁以上关节畸形率高达90%。在登记替代治疗的305位患者中,88.8%患者使用过FⅧ制剂,起始使用FⅧ制剂的中位年龄为11岁。213例患者检测了HCV,阳性率为47.9%;164例患者检测了HBV,阳性率为1.8%;164例患者检测了HIV,无一例阳性。
2.HA患者临床异质性的原因分析:选取50例FⅧ:C为1-2%患者按出血频率分成轻度出血组(年出血＜6次)和重度出血组(年出血＞12次),进行临床异质性的原因分析。测PC活性、ATⅢ活性和APC-R均正常,两组中各有3例PS活性低于正常值。
3.FⅧ抑制物的阳性率及危险因素分析:以Nijmegen方法检测FⅧ抑制物,阳性率为6.2%,以低反应型(＜5BU/ml)为主(占83.3%),产生抑制物的患者中位年龄为24岁。分析病情严重度与抑制物产生的关系:32例轻型HA患者无抑制物产生,324例中型中有19例产生抑制物(5.9%),32例重型中有5例产生抑制物(15.6%),使用Fisher检验3组患者抑制物的阳性率,P=0.042,结果具有统计学差异。分析高强度暴露(连续超过5天输注FⅧ)于FⅧ制剂与抑制物产生的关系:在260例HA患者中,76例有高强度暴露史,其中13例抑制物阳性(17.1%),而184例无高强度暴露史的患者仅9例阳性(4.9%),经Chi-Square检验,P=0.001,存在统计学差异。分析HCV感染与抑制物产生的关系:在213例HA患者中,102例HCV阳性患者中11例抑制物阳性(10.8%),而111例HCV阴性患者中仅2例抑制物阳性(1.8%),经Chi-Square检验,P=0.006,存在统计学差异。
4.两种检测方法的比较:使用两种方法分别检测237例患者抑制物水平,Bethesda方法抑制物的阳性率为5.5%,Nijmegen方法为8.4%,两种方法阳性结果不同的抑制物水平均在0.6-0.7Bu/ml,而阳性结果一致的抑制物水平均在0.7Bu/ml以上。经McNemar精确检验,P=0.065,无统计学显著差异。
结论:
1.我国HA患者的临床特征与国外发达国家存在差异,主要为家族史阴性的比例高,关节畸形者多,误诊率、漏诊率和HCV感染率高,替代治疗多元化,但很不充分。
2.HA患者的临床表型具有明显异质性,初步研究未发现抗凝蛋白缺乏和APC-R与之相关。
3.我国HA患者FⅧ抑制物的阳性率较低,以低反应型为主,患者年龄偏大。病情严重程度、高强度暴露于FⅧ制剂和HCV感染可能与FⅧ抑制物的产生相关。
4.使用Bethesda法和Nijmegen法检测抑制物的阳性率无显著差别。但Nijmegen法可能有利于低滴度抑制物的检出。
Background:
Hemophilia A(HA) is a recessive,X chromosome-linked hereditary bleeding disorder.The patients have unusual bleeding symptoms early in life related to deficiency of factorⅧ(FⅧ).The clinical hallmarks of HA are joint and muscle hemorrhages,and potentially fatal hemorrhages.In developed countries hemophiliacs are allowed to have a quality and expectancy of life very similar to those seen in the general population due to accurate diagnosis and sustained replacement therapy. Recently,the phenotypic heterogeneity and FⅧinhibitor development in the patients with HA have been well investigated in the developed countries.China is a developing country,and more efforts are needed to diminish the gap between our country and developed countries in hemophiliac diagnosis,clinical care and scientific research.In this study,we have analyzed the clinical features and phenotypic heterogeneity,investigated the frequency of FⅧinhibitors and related risk factors and explored concordance between two FⅧinhibitor assays among the patients with HA from the Northern China.
Objective:
1.To analyze clinical features of HA and the reasons for phenotypic heterogeneity.
2.To study the positive rate of FⅧinhibitors and the risk factors for the development of the inhibitors.
3.To compare the Bethesda assay and the Nijmegen assay in the inhibitor detection.
Methods:
1.Clinical data and blood samples were collected from the HA patients in Beijing, Henan,Hebei,Shanxi,Shaanxi and Xinjiang.
2.FⅧ:concentration(FⅧ:C) was measured using one-stage coagulation assay; the antigen of von Willbrand Factor(vWF:Ag) determined by ELISA;FⅧinhibitors titred by the Bethesda assay and the Nijmegen assay;AntithrombinⅢ(ATⅢ) activity and Protein C(PC) activity detected by colorimetric assay;Protein S (PS) activity and Activated Protein C Resistance(APC-R) detected by clotting assay. The samples for detection of HCV,HBV and HIV were sent to and measured by Shanghai Ruijin Hospital.
3.Clinical and laboratory data was analyzed by SPSS16.0 software,and P＜0.05 was considered to indicate statistical significance.
Results:
1.Clinical features of HA patients:388 hereditary HA patients were recruited.The median age of patients was 19 years,with 83.5%with moderate disease.18.3%of 355 patients were diagnosed after two years of their first episode of bleeding,and 54.2% of 367 patients had no family history of a bleeding disorder.Among 362 patients, 38.5%had developed joint deformities within ten years old,and more than 90% patients had joint deformities after the second decade.88.8%of 305 patients had received replacement therapy including FⅧconcentrates.The median age of patients first exposed to FⅧproducts was 11 years.47.9%of 213 patients had HCV infection,1.8%of 164 patients had HBV infection,and none of 164 patients had HIV infection.
2.The reasons for phenotypic heterogeneity in HA:50 patients(FⅧ:C 1-2%) were divided into mild bleeding group(＜6 bleeds per year) and severe bleeding group(＞12 bleeds per year).No deficient PC and ATⅢactivity and positive APC-R were found.There were 3 patients with lower PS activity in each group.
3.The positive rate and the risk factors for development of FⅧinhibitors:6.2% patients had FⅧinhibitors using the Nijmegen assay,and 83.3%were low responders(titers less than 5BU).The median age was 24 years.No patients had the inhibitors among 32 with mild HA,and 19 patients had the inhibitors among 324 with moderate HA(5.9%),and 5 patients had the inhibitors among 32 with severe HA (15.6%).There was significant difference among three groups according to the fisher test(P=0.042).Among 76 HA patients with intensive exposure to FⅧ(more than 5 successive exposure days),13(17.1%) had inhibitors.However,only 9 of 184(4.9%) patients without intensive exposure had inhibitors.The positive rate of the inhibitors had significant difference between two groups according to the Chi-Square test (P=0.001).The inhibitor was found in 11 of 102(10.8%) patients with HCV infection and 2 of 111(1.8%) patients without HCV infection,respectively(P=0.006,according to Chi-Square test).
4.Concordance between two FⅧinhibitor assays:Among 237 HA patients,the positive rate of FⅧinhibitor was 5.5%by the Bethesda assay and 8.4%by the Nijmegen assay(P=0.065,according to McNemar exact test).
Conclusions:
1.There are differences in clinical features of HA patients between China and developed countries.The ratio of patients with no family history,the rates of joint deformities and HCV infection in our patients are higher than those in developed countries.More patients have experience of misdiagnosis and inaccurate treatment inclusive of replacement therapy.
2.It seems that the defect anticoagulant proteins and APC-R are not related to the frequency and severity of hemorrhage in HA patients.
3.The positive rate of FⅧinhibitor is lower.Most of the cases are low responders and the ages are older than those reported in developed countries.The HA severity, intensive exposure to FⅧconcentrates and HCV infection are associated with development of the inhibitors.
4.No differences in detecting FⅧinhibitor between the Bethesda assay and the Nijmegen assay.It seems the Nijmegen assay may be sensitive to low titer inhibitors.
血友病A(HA)是一种X连锁隐性遗传病。患者不能合成或合成的凝血因子Ⅷ(FⅧ)有功能缺陷,临床上主要表现为自幼反复发生异常出血,其中以关节、肌肉出血最具特点,也可发生致死性出血。在发达国家,由于积极的诊断和治疗,HA患者不管是从预期寿命还是生活质量,都与普通正常人相似。同时发达国家对HA患者临床表现异质性和替代治疗中所产生针对FⅧ的抑制物都有深入的研究。我国作为发展中国家,不管是血友病临床诊治工作还是相关科研都与发达国家有很大差距。本课题通过总结我国部分地区HA患者临床特点,并对HA患者临床表现异质性、替代治疗中抑制物的产生和危险因素以及抑制物的检测方法等进行初步分析,以期能提高我国HA临床与科研水平。
目的:
1.总结我国HA患者的临床特点并对其临床表现异质性进行分析。
2.探讨HA患者FⅧ抑制物的阳性率检出率及抑制物产生的危险因素。
3.比较Bethesda和Nijmegen两种检测FⅧ抑制物的方法。
方法:
1.赴北京、河南、河北、山西、陕西、新疆等地采集遗传性HA患者的临床资料及血样。
2.用一期法检测FⅧ活性(FⅧ:C),ELISA法检测血管性血友病因子(vWF)抗原,Bethesda和Nijmegen方法检测FⅧ抑制物,发色底物法检测抗凝血酶Ⅲ(ATⅢ)活性和蛋白C(PC)活性,凝固法检测蛋白S(PS)活性和活化蛋白C抵抗(APC-R)。感染指标(HCV、HBV和HIV)统一送上海瑞金医院检测。
3.使用SPSS16.0统计软件对患者临床信息和实验室检查结果进行统计学分析。P＜0.05认为有统计学差异。
结果:
1.HA患者的临床特点:共收集无关家系遗传性HA患者388例,中位年龄19岁;以中型为主,占83.5%。在登记诊断时间的355例患者中,有18.3%从首次出血到诊断血友病间隔长达2年以上。在登记家族史的367例患者中,有54.2%无家族史。在登记关节畸形的362例患者中,10岁以内关节畸形率已达38.5%,20岁以上关节畸形率高达90%。在登记替代治疗的305位患者中,88.8%患者使用过FⅧ制剂,起始使用FⅧ制剂的中位年龄为11岁。213例患者检测了HCV,阳性率为47.9%;164例患者检测了HBV,阳性率为1.8%;164例患者检测了HIV,无一例阳性。
2.HA患者临床异质性的原因分析:选取50例FⅧ:C为1-2%患者按出血频率分成轻度出血组(年出血＜6次)和重度出血组(年出血＞12次),进行临床异质性的原因分析。测PC活性、ATⅢ活性和APC-R均正常,两组中各有3例PS活性低于正常值。
3.FⅧ抑制物的阳性率及危险因素分析:以Nijmegen方法检测FⅧ抑制物,阳性率为6.2%,以低反应型(＜5BU/ml)为主(占83.3%),产生抑制物的患者中位年龄为24岁。分析病情严重度与抑制物产生的关系:32例轻型HA患者无抑制物产生,324例中型中有19例产生抑制物(5.9%),32例重型中有5例产生抑制物(15.6%),使用Fisher检验3组患者抑制物的阳性率,P=0.042,结果具有统计学差异。分析高强度暴露(连续超过5天输注FⅧ)于FⅧ制剂与抑制物产生的关系:在260例HA患者中,76例有高强度暴露史,其中13例抑制物阳性(17.1%),而184例无高强度暴露史的患者仅9例阳性(4.9%),经Chi-Square检验,P=0.001,存在统计学差异。分析HCV感染与抑制物产生的关系:在213例HA患者中,102例HCV阳性患者中11例抑制物阳性(10.8%),而111例HCV阴性患者中仅2例抑制物阳性(1.8%),经Chi-Square检验,P=0.006,存在统计学差异。
4.两种检测方法的比较:使用两种方法分别检测237例患者抑制物水平,Bethesda方法抑制物的阳性率为5.5%,Nijmegen方法为8.4%,两种方法阳性结果不同的抑制物水平均在0.6-0.7Bu/ml,而阳性结果一致的抑制物水平均在0.7Bu/ml以上。经McNemar精确检验,P=0.065,无统计学显著差异。
结论:
1.我国HA患者的临床特征与国外发达国家存在差异,主要为家族史阴性的比例高,关节畸形者多,误诊率、漏诊率和HCV感染率高,替代治疗多元化,但很不充分。
2.HA患者的临床表型具有明显异质性,初步研究未发现抗凝蛋白缺乏和APC-R与之相关。
3.我国HA患者FⅧ抑制物的阳性率较低,以低反应型为主,患者年龄偏大。病情严重程度、高强度暴露于FⅧ制剂和HCV感染可能与FⅧ抑制物的产生相关。
4.使用Bethesda法和Nijmegen法检测抑制物的阳性率无显著差别。但Nijmegen法可能有利于低滴度抑制物的检出。
Background:
Hemophilia A(HA) is a recessive,X chromosome-linked hereditary bleeding disorder.The patients have unusual bleeding symptoms early in life related to deficiency of factorⅧ(FⅧ).The clinical hallmarks of HA are joint and muscle hemorrhages,and potentially fatal hemorrhages.In developed countries hemophiliacs are allowed to have a quality and expectancy of life very similar to those seen in the general population due to accurate diagnosis and sustained replacement therapy. Recently,the phenotypic heterogeneity and FⅧinhibitor development in the patients with HA have been well investigated in the developed countries.China is a developing country,and more efforts are needed to diminish the gap between our country and developed countries in hemophiliac diagnosis,clinical care and scientific research.In this study,we have analyzed the clinical features and phenotypic heterogeneity,investigated the frequency of FⅧinhibitors and related risk factors and explored concordance between two FⅧinhibitor assays among the patients with HA from the Northern China.
Objective:
1.To analyze clinical features of HA and the reasons for phenotypic heterogeneity.
2.To study the positive rate of FⅧinhibitors and the risk factors for the development of the inhibitors.
3.To compare the Bethesda assay and the Nijmegen assay in the inhibitor detection.
Methods:
1.Clinical data and blood samples were collected from the HA patients in Beijing, Henan,Hebei,Shanxi,Shaanxi and Xinjiang.
2.FⅧ:concentration(FⅧ:C) was measured using one-stage coagulation assay; the antigen of von Willbrand Factor(vWF:Ag) determined by ELISA;FⅧinhibitors titred by the Bethesda assay and the Nijmegen assay;AntithrombinⅢ(ATⅢ) activity and Protein C(PC) activity detected by colorimetric assay;Protein S (PS) activity and Activated Protein C Resistance(APC-R) detected by clotting assay. The samples for detection of HCV,HBV and HIV were sent to and measured by Shanghai Ruijin Hospital.
3.Clinical and laboratory data was analyzed by SPSS16.0 software,and P＜0.05 was considered to indicate statistical significance.
Results:
1.Clinical features of HA patients:388 hereditary HA patients were recruited.The median age of patients was 19 years,with 83.5%with moderate disease.18.3%of 355 patients were diagnosed after two years of their first episode of bleeding,and 54.2% of 367 patients had no family history of a bleeding disorder.Among 362 patients, 38.5%had developed joint deformities within ten years old,and more than 90% patients had joint deformities after the second decade.88.8%of 305 patients had received replacement therapy including FⅧconcentrates.The median age of patients first exposed to FⅧproducts was 11 years.47.9%of 213 patients had HCV infection,1.8%of 164 patients had HBV infection,and none of 164 patients had HIV infection.
2.The reasons for phenotypic heterogeneity in HA:50 patients(FⅧ:C 1-2%) were divided into mild bleeding group(＜6 bleeds per year) and severe bleeding group(＞12 bleeds per year).No deficient PC and ATⅢactivity and positive APC-R were found.There were 3 patients with lower PS activity in each group.
3.The positive rate and the risk factors for development of FⅧinhibitors:6.2% patients had FⅧinhibitors using the Nijmegen assay,and 83.3%were low responders(titers less than 5BU).The median age was 24 years.No patients had the inhibitors among 32 with mild HA,and 19 patients had the inhibitors among 324 with moderate HA(5.9%),and 5 patients had the inhibitors among 32 with severe HA (15.6%).There was significant difference among three groups according to the fisher test(P=0.042).Among 76 HA patients with intensive exposure to FⅧ(more than 5 successive exposure days),13(17.1%) had inhibitors.However,only 9 of 184(4.9%) patients without intensive exposure had inhibitors.The positive rate of the inhibitors had significant difference between two groups according to the Chi-Square test (P=0.001).The inhibitor was found in 11 of 102(10.8%) patients with HCV infection and 2 of 111(1.8%) patients without HCV infection,respectively(P=0.006,according to Chi-Square test).
4.Concordance between two FⅧinhibitor assays:Among 237 HA patients,the positive rate of FⅧinhibitor was 5.5%by the Bethesda assay and 8.4%by the Nijmegen assay(P=0.065,according to McNemar exact test).
Conclusions:
1.There are differences in clinical features of HA patients between China and developed countries.The ratio of patients with no family history,the rates of joint deformities and HCV infection in our patients are higher than those in developed countries.More patients have experience of misdiagnosis and inaccurate treatment inclusive of replacement therapy.
2.It seems that the defect anticoagulant proteins and APC-R are not related to the frequency and severity of hemorrhage in HA patients.
3.The positive rate of FⅧinhibitor is lower.Most of the cases are low responders and the ages are older than those reported in developed countries.The HA severity, intensive exposure to FⅧconcentrates and HCV infection are associated with development of the inhibitors.
4.No differences in detecting FⅧinhibitor between the Bethesda assay and the Nijmegen assay.It seems the Nijmegen assay may be sensitive to low titer inhibitors.
引文
1.Hoyer LW.Hemophilia A.N Engl J Med.1994 Jan 6;330(1):38-47.
2.Levine PH.Clinical manifestations and therapy of hemophilias A and B.In:Colman RW,Hirsh J,Marder VJ,Salzman EW,eds.Hemostasis and thrombosis:basic principles and clinical practice.2nd ed.Philadelphia:J.B.Lippincott,1987:97-111.
3.Prevention and control of haemophilia:memorandum from a joint WHO/WFH meeting(World Federation of Haemophilia).Bull World Health Organ 1991;69:17-26.
4.Rosendaal FR,Smit C,Briet E.Hemophilia treatment in historical perspective:a review of medical and social developments.Ann Hematol 1991;62:5-15.
5.Tuddenham EGD,Cooper DN.The molecular genetics of haemostasis and its inherited disorders.Oxford monographs in medical genetics no.25.Oxford,England:Oxford University Press,1994.
6.Foster PA,Zimmerman TS.Factor Ⅷ structure and function.Blood Rev 1989;3:180-191.
7.S.V.ANTUNES Haemophilia in the developing world:the Brazilian experience Haemophilia 2002;8:199-204.
8.Christine A.Lee et al.Textbook of Hemophilia.Blackwell publishing 2005.
9.Mahony B,Black C.Expanding hemophilia care in developing countries.Semin Thromb Hemost 2005;31:561-8.
10.杨仁池等,血友病,上海科学技术出版社 2007.
11.van den Berg HM,De Groot PH,Fischer K.Phenotypic heterogeneity in severe hemophilia.J Thromb Haemost 2007;5 Suppl 1:151-6.
12.Jayandharan GR,Srivastava A.The phenotypic heterogeneity of severe hemophilia.Semin Thromb Hemost 2008;34:128-41.
13.张之南 沈悌,血液病诊断及疗效标准,2007.
14.张之南等,协和血液病学,2004.
15.Larsson SA,Nilsson IM,Blomback M.Current status of Swedish hemophiliacs.I.A demographic survey.Acta Med Scand 1982;212:195.
16.Koumbarelis E,Rosendaal FR,Gialeraki A et al.Epidemiology of haemophilia in Greece:an overvier.Thromb Haemost 1994;72:808.
17.Ikkala E,Helske T,Myllya G et al.Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930-79.Br J Haematol 1982;52:7.
18.Rasi V,Ikkala E,MYllyla G et al.Low prevalence of antibodies against human immunodeficiency virus in Finnish haemophiliacs.Vox Sang 1991;60:159.
19.Walker I,Pai M,Akabatu B et al.The Canadian Hemophilia Registry as the basis for a national system for monitoring the use of factor concentrates.Transfusion 1995;35:548.
20.J.TUSELL.Prophylaxis in developed and in emerging countries.Haemophilia 2002;8:183-188.
21.J.S.STONEBRAKER,R.E.AMAND and A.J.NAGLE.A country-by-country comparison of FⅧ concentrate consumption and economic capacity for the global haemophilia community.Haemophilia 2003;9:245-250.
22.K.GHOSH.Management of haemophilia and its complications in developing countries.Clin Lab Haem 2004;26:243-251.
23.Roosendaal G,Lafeber FP.Blood-induced joint damage in hemophilia.Semin Thromb Hemost 2003;29:37-42.
24.Astrup T,Sjolin KE.Thromboplastic and fibrinolytic activity of human synovial membrane and fibrous capsular tissue.Proc Soc Exp Biol Med 1958;97:852.
25.Hooiveld M,Roosendaal G,et al.Blood-induced joint damage:longterm effects in vitro and in vivo.J Rheumatol 2003;30:339-44.
26.Thynn Thynn and Christine A.Transfusion-transmitted infection in hemophilia in developing countries.Semin Thromb Hemost 2005;31:527-37.
27.Evatt B.Observations from Global Survey 2001:an emerging database for progress.Haemophilia 2002;8:153-I56.
28.Busch,M.P.(2001) Closing the windows on viral transmission by blood transfusion.In:Blood Safety in the New Millennium:AABB 2000 Seminar Book(ed.Stramer,S.L.),33-54.AABB Press,Bethesda,Maryland.
29.Kleinman,S.H.& Busch,M.P.(2000) The risks of transfusion transmitted infection: direct estimation and mathematical modelling. In: New Aspects of Blood Transfusion (ed. Contreras, M.), 13,631-649. Baillere Tindall, London.
30. Soldan, K., Barbara, J.A., Ramsay, M.E.&Hall, A.J. Estimation of the risk of HBV, HCV and HIV infectious donations entering the blood supply in England, 1993-2001. Vox Sanguinis 2003;84:274-286.
31. O'Brien, S.F., Yi, Q.L., Foon, W. et al. Current incidence and estimated residual risk of transfusion transmitted infections in donations made for Canadian Blood Service. Transfusion 2007;47:316-325.
32. Busch, M.P., Glynn, S.A., Stramer, S.L. et al. A new strategy for estimating risks of transfusion transmitted viral infections based on rates of detection of recently infected donors. Transfusion 2005;45:254-264.
33. Davenport, R.D. and Mintz, P.D. Transfusion medicine. In: Henry's Clinical Diagnosis (eds McPherson, R.A. & Pincus, M.R.), 669-684. Saunders, Oxford, UK. 2007.
34. Mansour-Ghanaei F, Fallah MS, Shafaghi A, et al. Prevalence of hepatitis B and C seromarkers and abnormal liver function tests among hemophiliacs in Guilan (northern province of Iran). Med Sci Monit 2002;8:797-800.
35. Timan IS, Aulia D, Atmakusma D, et al. Some hematological problems in Indonesia. Int J Hematol 2002;76(suppl 1):286-290.
36. Seme K, Poljak M, Begovac J, et al. Low prevalence of hepatitis C virus infection among human immunodeficiency virus type 1-infected individuals from Slovenia and Croatia. Acta Virol 2002;46:91-94.
37. Wharfe G, Smikle M, Dowe G, et al. Seroprevalence of hepatitis C virus in haemophiliacs in Jamacia. Hum Antibodies 2002;11:61-64.
38. Singhvi A, Pulimood RB, John TJ, et al. The prevalence of markers for hepatitis B and human immunodeficiency viruses, malarial parasites, and microfilaria in blood donors in a large hospital in south India. J Trop Med Hyg 1990;93:178.
39. Onwuzurike N, Warrier I, Lusher JM. Types of bleeding seen during the first 30 months of life I children with severe hemophilia A and B. Haemophilia 1996;2: 137-40.
40. Van Dijk K, van der Bom JG, Fischer K, et al. Variability in clinical phenotype of severe haemophilia; the role of the first joint bleed. Haemophilia 2005; 11:438-43.
41. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VHI-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994;236:391-9.
42. Rainsford SG, Hall A. A three-year study of adolescent boys suffering from haemophilia and allied disorders. B J Haematol 1973;24:539-51.
43. Molho P, Rolland N, Lebrun T, et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. Haemophilia 2000;6:23-32.
44. Plug I, Van der Bom JG, PetersM, et al. Thirty years of hemophilia treatment in the Netherlands, 1972-2001. Blood 2004;104:3494-500.
45. NicholsWC,AmanoK, Cacheris PM, et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996;88:1183-7.
46. 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.
47. 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.
48. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006;133:591-605.
49. Sharathkumar A, Lillicrap D, Blanchette VS et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003;1:1228-36.
50. McMillan CW, Shapiro SS, et al. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII.C inhibitors. Blood 1988;71(2):344-8.
51. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006;12 (Suppl. 6): 8-14.
52. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418-35.
53. Lorenzo JI, Lopez A, Altisent C, et al. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001;113:600-3.
54. van der Bom JG, Mauser-Bunschoten EP, et al. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003;89:475-9.
55. S . C. GOUW et.al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost 2007;5:1383-1390.
56. McMillan CW, Shapiro SS, et al. The natural history of factor VIII.C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988;71:344-8.
57. Rosendaal FR, Nieuwenhuis HK, et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993 ;81:2180-6.
58. Ignacio Lorenzo J, Garcia R, Molina R.Factor VIII and factor DC inhibitors in haemophiliacs. Lancet 1992;339:1550-1.
59. Addiego J, Kasper C, et al. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993;342:462-4.
60. de Biasi R, Rocino A, Papa ML,et.al. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost 1994;71:544-7.
61. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994;83:2428-35.
62. Carmo RA, Oliveira GC, et al. Hepatitis C virus infection among Brazilian hemophiliacs: a virological, clinical and epidemiological study. Braz J Med Biol Res 2002;35:589-98.
63. Wedemeyer H, He XS, Nascimbeni M, et al. Impaired effector function of hepatitis C virus-specific CD8+T cells in chronic hepatitis C virus infection. J Immunol 2002;169:347-353.
64.Tsai SL,Liaw YF,Chen MH,et al.Detection of type 2-like T-helper cells in hepatitis C virus infection:implications for hepatitis C virus chronicity.Hepatology 1997;25:449-458.
65.Kasper CK et al.Letter:A more uniform measurement of factor Ⅷ inhibitors.Thromb Diath Haemorrh 1975;34:869-72.
66.Verbruggen B,Novakova I,et al.The Nijmegen modification of the Bethesda assay for factor Ⅷ:C inhibitors:improved specificity and reliability.Thromb Haemost 1995;73:247-51.
67.Blomb(a|¨)ck M,Dybkaer R,et al.Properties and units in the clinical laboratory sciences.V.Properties and units in thrombosis and haemostasis:ISTH-IUPAC-IFCC recommendations 1995.Clin Chim Acta 1996;245:S23-8.
68.Giles AR,Verbruggen B,et al.A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor Ⅷ:C inhibitors in the haemophilia A population of Canada.Thromb Haemost 1998;79:872-5.
1.Leon W.Hoyer.Hemophilia A.N Engl J Med 1994;330:38-47.
2.Levine PH.Clinical manifestations and therapy of hemophilias A and B.In:Colman RW,Hirsh J,Marder VJ,Salzman EW,eds.Hemostasis and thrombosis:basic principles and clinical practice.2nd ed.Philadelphia:J.B.Lippincott,1987:97-111.
3.Prevention and control of haemophilia:memorandum from a joint WHO/WFH meeting(World Federation of Haemophilia).Bull World Health Organ 1991;69:17-26.
4.Rosendaal FR,Smit C,Briet E.Hemophilia treatment in historical perspective:a review of medical and social developments.Ann Hematol 1991;62:5-15.
5.Tuddenham EGD,Cooper DN.The molecular genetics of haemostasis and its inherited disorders.Oxford monographs in medical genetics no.25.Oxford,England:Oxford University Press,1994.
6.Foster PA,Zimmerman TS.Factor Ⅷ structure and function.Blood Rev 1989;3:180-191.
7.Christine A.Lee et al.Textbook of Hemophilia.Blackwell publishing,2005.
8.R.MEHTA,R.PARAMESWARAN and A.D.SHAPIRO.An overview of the history,clinical practice concerns,comparative studies and strategies to optimize therapy of bypassing agents Haemophilia 2006;12(Suppl.6):54-61.
9.McMillan CW,Shapiro SS,Whitehurst D,Hoyer LW,Rao AV,Lazerson J.The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIIP.C inhibitors. Blood 1988;71:344-8.
10. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006;12 (Suppl. 6):8—14.
11. Lorenzo JI, Lopez A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600-3.
12. van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003;89:475-9.
13. Goudemand J, Rothschild C, Demeiguel V et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 2006; 107:46-51.
14. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007 Jun 1;109:4693-7.
15. Santagostino E, Mancuso ME, Rocino A et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study.Br J Haematol 2005;130:422-7.
16. E. A. CHALMERS, S. A. BROWN et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007;13:149-155.
17. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006,12 (Suppl. 6), 8-14
18. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003 ;9:418-35.
19. Vlot AJ, Koppelman SJ, Bouma BN, Sixma JJ. Factor VIII and von Willebrand factor. Thromb Haemost 1998;79:456-65.
20. Lin Y, Yang X, Chevrier MC et al. Relationships between factor VIII:Ag and factor VIII in recombinant and plasma derived factor VIII concentrates. Haemophilia 2004;10:459-69.
21.Scandella D.New characteristics of anti-factor Ⅷ inhibitor antibody epitopes and unusual immune responses to Factor Ⅷ.Semin Thromb Hemost 2002;28:291-6.
22.Dasgupta S,Repesse Y,Bayry J et al.VWF protects FⅧ from endocytosis by dendritic cells and subsequent presentation to immune effectors.Blood 2007;109:610--2.
23.Behrmann M,Pasi J,Saint-Remy JM,Kotitschke R,Kloft M.Von Willebrand factor modulates factor Ⅷ immunogenicity:comparative study of different factor Ⅷ concentrates in a haemophilia A mouse model.Thromb Haemost 2002;88:221-9.
24.Hodge G,Flower R,Han P.Effect of factor Ⅷ concentrate on leucocyte cytokine production:characterization of TGF-beta as an immunomodulatory component in plasma derived factor Ⅷ concentrate.Br J Haematol 1999;106:784-91.
25.Hodge G,Saxon B,Revesz T.Effect of factor Ⅷ concentrate on leucocyte cytokine receptor expression in vitro:relevance to inhibitor formation and tolerance induction.Haemophilia 2006;12:133-9.
26.Hoots WK,Lusher J.High-titer inhibitor development in hemophilia A-lack of product specificity.J Thromb Haemost 2004;2:358-9.
27.Kreuz W,Ettingshausen CE,Zyschka A et al.Inhibitor development in previously untreated patients with hemophilia A:a prospective long-term follow-up comparing plasma-derived and recombinant products.Semin Thromb Hemost 2002;28:285-90.
28.Knobe KE,Sjorin E,Tengborn LI,Petrini P,Ljung RC.Inhibitors in the Swedish population with severe haemophilia A and B:a 20-year survey.Acta Paediatr 2002;91:910-4.
29.Darby SC,Keeling DM,Spooner RJ et al.The incidence of factor Ⅷ and factor Ⅸ inhibitors in the hemophilia population of the UK and their effect on subsequent mortality,1977-99.J Thromb Haemost 2004;2:1047-54.
30.DiMichele DM.In praise of long-term prospective data collection:questions and perspectives.J Thromb Haemost 2004;2:1044-6.
31.K.PEERLINCK and C.HERMANS Epidemiology of inhibitor formation with recombinant factor Ⅷ replacement therapy.Haemophilia 2006;12:579-590.
32.McMillan CW,Webster WP,Roberts HR et al.Continuous intravenous infusion of factor Ⅷ in classic haemophilia.Br J Haematol 1970;18:659-67.
33.von Auer Ch,Oldenburg J,von Depka M et al.Inhibitor development in patients with hemophilia A after continuous infusion of FⅧ concentrates.Ann N Y Acad Sci 2005;1051:498-505.
34.Sharathkumar A,Lillicrap D,Blanchette VS et al.Intensive exposure to factor Ⅷ is a risk factor for inhibitor development in mild hemophilia A.J Thromb Haemost 2003;1:1228-36.
35.S.C.GOUW et.al.Treatment characteristics and the risk of inhibitor development:a multicenter cohort study among previously untreated patients with severe hemophilia A J Thromb Haemost 2007;5:1383-1390.
36.Nilsson IM,Berntorp E,Lofqvist T,Pettersson H.Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.J Intern Med 1992;232:25-32.
37.M.MORADO,A.VILLAR,V.et al.Prophylactic treatment effects on inhibitor risk:experience in one centre.Haemophilia 2005;11:79-83.
2.Levine PH.Clinical manifestations and therapy of hemophilias A and B.In:Colman RW,Hirsh J,Marder VJ,Salzman EW,eds.Hemostasis and thrombosis:basic principles and clinical practice.2nd ed.Philadelphia:J.B.Lippincott,1987:97-111.
3.Prevention and control of haemophilia:memorandum from a joint WHO/WFH meeting(World Federation of Haemophilia).Bull World Health Organ 1991;69:17-26.
4.Rosendaal FR,Smit C,Briet E.Hemophilia treatment in historical perspective:a review of medical and social developments.Ann Hematol 1991;62:5-15.
5.Tuddenham EGD,Cooper DN.The molecular genetics of haemostasis and its inherited disorders.Oxford monographs in medical genetics no.25.Oxford,England:Oxford University Press,1994.
6.Foster PA,Zimmerman TS.Factor Ⅷ structure and function.Blood Rev 1989;3:180-191.
7.S.V.ANTUNES Haemophilia in the developing world:the Brazilian experience Haemophilia 2002;8:199-204.
8.Christine A.Lee et al.Textbook of Hemophilia.Blackwell publishing 2005.
9.Mahony B,Black C.Expanding hemophilia care in developing countries.Semin Thromb Hemost 2005;31:561-8.
10.杨仁池等,血友病,上海科学技术出版社 2007.
11.van den Berg HM,De Groot PH,Fischer K.Phenotypic heterogeneity in severe hemophilia.J Thromb Haemost 2007;5 Suppl 1:151-6.
12.Jayandharan GR,Srivastava A.The phenotypic heterogeneity of severe hemophilia.Semin Thromb Hemost 2008;34:128-41.
13.张之南 沈悌,血液病诊断及疗效标准,2007.
14.张之南等,协和血液病学,2004.
15.Larsson SA,Nilsson IM,Blomback M.Current status of Swedish hemophiliacs.I.A demographic survey.Acta Med Scand 1982;212:195.
16.Koumbarelis E,Rosendaal FR,Gialeraki A et al.Epidemiology of haemophilia in Greece:an overvier.Thromb Haemost 1994;72:808.
17.Ikkala E,Helske T,Myllya G et al.Changes in the life expectancy of patients with severe haemophilia A in Finland in 1930-79.Br J Haematol 1982;52:7.
18.Rasi V,Ikkala E,MYllyla G et al.Low prevalence of antibodies against human immunodeficiency virus in Finnish haemophiliacs.Vox Sang 1991;60:159.
19.Walker I,Pai M,Akabatu B et al.The Canadian Hemophilia Registry as the basis for a national system for monitoring the use of factor concentrates.Transfusion 1995;35:548.
20.J.TUSELL.Prophylaxis in developed and in emerging countries.Haemophilia 2002;8:183-188.
21.J.S.STONEBRAKER,R.E.AMAND and A.J.NAGLE.A country-by-country comparison of FⅧ concentrate consumption and economic capacity for the global haemophilia community.Haemophilia 2003;9:245-250.
22.K.GHOSH.Management of haemophilia and its complications in developing countries.Clin Lab Haem 2004;26:243-251.
23.Roosendaal G,Lafeber FP.Blood-induced joint damage in hemophilia.Semin Thromb Hemost 2003;29:37-42.
24.Astrup T,Sjolin KE.Thromboplastic and fibrinolytic activity of human synovial membrane and fibrous capsular tissue.Proc Soc Exp Biol Med 1958;97:852.
25.Hooiveld M,Roosendaal G,et al.Blood-induced joint damage:longterm effects in vitro and in vivo.J Rheumatol 2003;30:339-44.
26.Thynn Thynn and Christine A.Transfusion-transmitted infection in hemophilia in developing countries.Semin Thromb Hemost 2005;31:527-37.
27.Evatt B.Observations from Global Survey 2001:an emerging database for progress.Haemophilia 2002;8:153-I56.
28.Busch,M.P.(2001) Closing the windows on viral transmission by blood transfusion.In:Blood Safety in the New Millennium:AABB 2000 Seminar Book(ed.Stramer,S.L.),33-54.AABB Press,Bethesda,Maryland.
29.Kleinman,S.H.& Busch,M.P.(2000) The risks of transfusion transmitted infection: direct estimation and mathematical modelling. In: New Aspects of Blood Transfusion (ed. Contreras, M.), 13,631-649. Baillere Tindall, London.
30. Soldan, K., Barbara, J.A., Ramsay, M.E.&Hall, A.J. Estimation of the risk of HBV, HCV and HIV infectious donations entering the blood supply in England, 1993-2001. Vox Sanguinis 2003;84:274-286.
31. O'Brien, S.F., Yi, Q.L., Foon, W. et al. Current incidence and estimated residual risk of transfusion transmitted infections in donations made for Canadian Blood Service. Transfusion 2007;47:316-325.
32. Busch, M.P., Glynn, S.A., Stramer, S.L. et al. A new strategy for estimating risks of transfusion transmitted viral infections based on rates of detection of recently infected donors. Transfusion 2005;45:254-264.
33. Davenport, R.D. and Mintz, P.D. Transfusion medicine. In: Henry's Clinical Diagnosis (eds McPherson, R.A. & Pincus, M.R.), 669-684. Saunders, Oxford, UK. 2007.
34. Mansour-Ghanaei F, Fallah MS, Shafaghi A, et al. Prevalence of hepatitis B and C seromarkers and abnormal liver function tests among hemophiliacs in Guilan (northern province of Iran). Med Sci Monit 2002;8:797-800.
35. Timan IS, Aulia D, Atmakusma D, et al. Some hematological problems in Indonesia. Int J Hematol 2002;76(suppl 1):286-290.
36. Seme K, Poljak M, Begovac J, et al. Low prevalence of hepatitis C virus infection among human immunodeficiency virus type 1-infected individuals from Slovenia and Croatia. Acta Virol 2002;46:91-94.
37. Wharfe G, Smikle M, Dowe G, et al. Seroprevalence of hepatitis C virus in haemophiliacs in Jamacia. Hum Antibodies 2002;11:61-64.
38. Singhvi A, Pulimood RB, John TJ, et al. The prevalence of markers for hepatitis B and human immunodeficiency viruses, malarial parasites, and microfilaria in blood donors in a large hospital in south India. J Trop Med Hyg 1990;93:178.
39. Onwuzurike N, Warrier I, Lusher JM. Types of bleeding seen during the first 30 months of life I children with severe hemophilia A and B. Haemophilia 1996;2: 137-40.
40. Van Dijk K, van der Bom JG, Fischer K, et al. Variability in clinical phenotype of severe haemophilia; the role of the first joint bleed. Haemophilia 2005; 11:438-43.
41. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VHI-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994;236:391-9.
42. Rainsford SG, Hall A. A three-year study of adolescent boys suffering from haemophilia and allied disorders. B J Haematol 1973;24:539-51.
43. Molho P, Rolland N, Lebrun T, et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. Haemophilia 2000;6:23-32.
44. Plug I, Van der Bom JG, PetersM, et al. Thirty years of hemophilia treatment in the Netherlands, 1972-2001. Blood 2004;104:3494-500.
45. NicholsWC,AmanoK, Cacheris PM, et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996;88:1183-7.
46. 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.
47. 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.
48. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006;133:591-605.
49. Sharathkumar A, Lillicrap D, Blanchette VS et al. Intensive exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. J Thromb Haemost 2003;1:1228-36.
50. McMillan CW, Shapiro SS, et al. The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII.C inhibitors. Blood 1988;71(2):344-8.
51. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006;12 (Suppl. 6): 8-14.
52. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418-35.
53. Lorenzo JI, Lopez A, Altisent C, et al. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001;113:600-3.
54. van der Bom JG, Mauser-Bunschoten EP, et al. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003;89:475-9.
55. S . C. GOUW et.al. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A. J Thromb Haemost 2007;5:1383-1390.
56. McMillan CW, Shapiro SS, et al. The natural history of factor VIII.C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988;71:344-8.
57. Rosendaal FR, Nieuwenhuis HK, et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993 ;81:2180-6.
58. Ignacio Lorenzo J, Garcia R, Molina R.Factor VIII and factor DC inhibitors in haemophiliacs. Lancet 1992;339:1550-1.
59. Addiego J, Kasper C, et al. Frequency of inhibitor development in haemophiliacs treated with low-purity factor VIII. Lancet 1993;342:462-4.
60. de Biasi R, Rocino A, Papa ML,et.al. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost 1994;71:544-7.
61. Bray GL, Gomperts ED, Courter S, et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 1994;83:2428-35.
62. Carmo RA, Oliveira GC, et al. Hepatitis C virus infection among Brazilian hemophiliacs: a virological, clinical and epidemiological study. Braz J Med Biol Res 2002;35:589-98.
63. Wedemeyer H, He XS, Nascimbeni M, et al. Impaired effector function of hepatitis C virus-specific CD8+T cells in chronic hepatitis C virus infection. J Immunol 2002;169:347-353.
64.Tsai SL,Liaw YF,Chen MH,et al.Detection of type 2-like T-helper cells in hepatitis C virus infection:implications for hepatitis C virus chronicity.Hepatology 1997;25:449-458.
65.Kasper CK et al.Letter:A more uniform measurement of factor Ⅷ inhibitors.Thromb Diath Haemorrh 1975;34:869-72.
66.Verbruggen B,Novakova I,et al.The Nijmegen modification of the Bethesda assay for factor Ⅷ:C inhibitors:improved specificity and reliability.Thromb Haemost 1995;73:247-51.
67.Blomb(a|¨)ck M,Dybkaer R,et al.Properties and units in the clinical laboratory sciences.V.Properties and units in thrombosis and haemostasis:ISTH-IUPAC-IFCC recommendations 1995.Clin Chim Acta 1996;245:S23-8.
68.Giles AR,Verbruggen B,et al.A detailed comparison of the performance of the standard versus the Nijmegen modification of the Bethesda assay in detecting factor Ⅷ:C inhibitors in the haemophilia A population of Canada.Thromb Haemost 1998;79:872-5.
1.Leon W.Hoyer.Hemophilia A.N Engl J Med 1994;330:38-47.
2.Levine PH.Clinical manifestations and therapy of hemophilias A and B.In:Colman RW,Hirsh J,Marder VJ,Salzman EW,eds.Hemostasis and thrombosis:basic principles and clinical practice.2nd ed.Philadelphia:J.B.Lippincott,1987:97-111.
3.Prevention and control of haemophilia:memorandum from a joint WHO/WFH meeting(World Federation of Haemophilia).Bull World Health Organ 1991;69:17-26.
4.Rosendaal FR,Smit C,Briet E.Hemophilia treatment in historical perspective:a review of medical and social developments.Ann Hematol 1991;62:5-15.
5.Tuddenham EGD,Cooper DN.The molecular genetics of haemostasis and its inherited disorders.Oxford monographs in medical genetics no.25.Oxford,England:Oxford University Press,1994.
6.Foster PA,Zimmerman TS.Factor Ⅷ structure and function.Blood Rev 1989;3:180-191.
7.Christine A.Lee et al.Textbook of Hemophilia.Blackwell publishing,2005.
8.R.MEHTA,R.PARAMESWARAN and A.D.SHAPIRO.An overview of the history,clinical practice concerns,comparative studies and strategies to optimize therapy of bypassing agents Haemophilia 2006;12(Suppl.6):54-61.
9.McMillan CW,Shapiro SS,Whitehurst D,Hoyer LW,Rao AV,Lazerson J.The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIIP.C inhibitors. Blood 1988;71:344-8.
10. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006;12 (Suppl. 6):8—14.
11. Lorenzo JI, Lopez A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113: 600-3.
12. van der Bom JG, Mauser-Bunschoten EP, Fischer K, van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemost 2003;89:475-9.
13. Goudemand J, Rothschild C, Demeiguel V et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 2006; 107:46-51.
14. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007 Jun 1;109:4693-7.
15. Santagostino E, Mancuso ME, Rocino A et al. Environmental risk factors for inhibitor development in children with haemophilia A: a case-control study.Br J Haematol 2005;130:422-7.
16. E. A. CHALMERS, S. A. BROWN et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007;13:149-155.
17. J. ASTERMARK Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors. Haemophilia 2006,12 (Suppl. 6), 8-14
18. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003 ;9:418-35.
19. Vlot AJ, Koppelman SJ, Bouma BN, Sixma JJ. Factor VIII and von Willebrand factor. Thromb Haemost 1998;79:456-65.
20. Lin Y, Yang X, Chevrier MC et al. Relationships between factor VIII:Ag and factor VIII in recombinant and plasma derived factor VIII concentrates. Haemophilia 2004;10:459-69.
21.Scandella D.New characteristics of anti-factor Ⅷ inhibitor antibody epitopes and unusual immune responses to Factor Ⅷ.Semin Thromb Hemost 2002;28:291-6.
22.Dasgupta S,Repesse Y,Bayry J et al.VWF protects FⅧ from endocytosis by dendritic cells and subsequent presentation to immune effectors.Blood 2007;109:610--2.
23.Behrmann M,Pasi J,Saint-Remy JM,Kotitschke R,Kloft M.Von Willebrand factor modulates factor Ⅷ immunogenicity:comparative study of different factor Ⅷ concentrates in a haemophilia A mouse model.Thromb Haemost 2002;88:221-9.
24.Hodge G,Flower R,Han P.Effect of factor Ⅷ concentrate on leucocyte cytokine production:characterization of TGF-beta as an immunomodulatory component in plasma derived factor Ⅷ concentrate.Br J Haematol 1999;106:784-91.
25.Hodge G,Saxon B,Revesz T.Effect of factor Ⅷ concentrate on leucocyte cytokine receptor expression in vitro:relevance to inhibitor formation and tolerance induction.Haemophilia 2006;12:133-9.
26.Hoots WK,Lusher J.High-titer inhibitor development in hemophilia A-lack of product specificity.J Thromb Haemost 2004;2:358-9.
27.Kreuz W,Ettingshausen CE,Zyschka A et al.Inhibitor development in previously untreated patients with hemophilia A:a prospective long-term follow-up comparing plasma-derived and recombinant products.Semin Thromb Hemost 2002;28:285-90.
28.Knobe KE,Sjorin E,Tengborn LI,Petrini P,Ljung RC.Inhibitors in the Swedish population with severe haemophilia A and B:a 20-year survey.Acta Paediatr 2002;91:910-4.
29.Darby SC,Keeling DM,Spooner RJ et al.The incidence of factor Ⅷ and factor Ⅸ inhibitors in the hemophilia population of the UK and their effect on subsequent mortality,1977-99.J Thromb Haemost 2004;2:1047-54.
30.DiMichele DM.In praise of long-term prospective data collection:questions and perspectives.J Thromb Haemost 2004;2:1044-6.
31.K.PEERLINCK and C.HERMANS Epidemiology of inhibitor formation with recombinant factor Ⅷ replacement therapy.Haemophilia 2006;12:579-590.
32.McMillan CW,Webster WP,Roberts HR et al.Continuous intravenous infusion of factor Ⅷ in classic haemophilia.Br J Haematol 1970;18:659-67.
33.von Auer Ch,Oldenburg J,von Depka M et al.Inhibitor development in patients with hemophilia A after continuous infusion of FⅧ concentrates.Ann N Y Acad Sci 2005;1051:498-505.
34.Sharathkumar A,Lillicrap D,Blanchette VS et al.Intensive exposure to factor Ⅷ is a risk factor for inhibitor development in mild hemophilia A.J Thromb Haemost 2003;1:1228-36.
35.S.C.GOUW et.al.Treatment characteristics and the risk of inhibitor development:a multicenter cohort study among previously untreated patients with severe hemophilia A J Thromb Haemost 2007;5:1383-1390.
36.Nilsson IM,Berntorp E,Lofqvist T,Pettersson H.Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.J Intern Med 1992;232:25-32.
37.M.MORADO,A.VILLAR,V.et al.Prophylactic treatment effects on inhibitor risk:experience in one centre.Haemophilia 2005;11:79-83.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |