遗传性出血性疾病的临床和发病机理研究
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摘要
近年来随着人类基因组序列图测定的完成,几乎所有的凝血因子、血小板膜糖蛋白以及其它有关成分的基因都已被克隆,有助于深入探索其结构与功能的关系。很多遗传性出血性疾病的基因异常已被发现,基因诊断是今后遗传性出血性疾病研究发展的一个主要方向。
遗传性出血性疾病常导致严重的出血,需要特殊的诊断方法与特别的治疗措施。我们利用在血栓与止血领域的优势,深入开展遗传性出血性疾病的基础与临床研究,阐明其发病的分子机制,解决这类特殊患者的痛苦,并提高我院血栓与止血的研究水平。
目的:分别对1例遗传性无纤维蛋白原血症(hereditary afibrinogenemia, HAF)和遗传性凝血因子XIII缺乏症(hereditary factor XIII deficiency , HFXIIID)进行基因分析和家系调查,阐明HAF和HFXIIID发病的分子机制;研究一种具有异常超微结构的遗传性巨血小板减少症(hereditary macrothrombocytopenia, HMTC)的形态与功能。
方法:1.凝血酶法与免疫比浊法测定纤维蛋白原(Fg),提取HAF家系先证者及其家系成员外周血基因组DNA,PCR法扩增其Fg的FGA、FGB和FGG基因所有外显子和侧翼序列,DNA序列分析确定Fg的基因异常。将先证者突变序列、家系成员和50名正常人相应序列的PCR产物用限制性内切酶RsaⅠ消化,以进一步确定基因突变并排除基因多态性。2.分别用尿素溶解法和试剂盒法检测HFXIIID患者及其家系成员血浆FXIII的活性,并用火箭电泳法和酶联免疫吸附实验测定其FXIII抗原含量。PCR法扩增F13A基因的所有外显子和侧翼序列,DNA测序分析基因异常,用直接测序法和限制性内切酶(SfaNⅠ、NspⅠ)分析80名正常人相应序列的PCR产物以排除基因多态性。应用生物信息学软件对所发现的突变进行分子模建,探讨其致病的分子机制。3.采集HMTC患者外周静脉血,分离富血小板血浆,用流式细胞术结合多种抗血小板膜糖蛋白(GP)单克隆抗体,测定血小板膜GP Ib、GP IIb、GP IIIa、P选择素和CD63的表达;以常规超薄切片术、免疫电镜技术检测患者血小板及其异常超微结构的性质;用荧光分光光度法测定血小板5-羟色胺含量。
结果:1. HAF先证者及其父亲的血浆Fg用Clauss法检测不到,免疫比浊法测定时,Fg含量均<0.02g/L,两者FGA基因外显子4第3108位核苷酸发生C→T纯合性改变,使Fg的Aa链第150位密码子(CAG,编码Gln)突变为终止密码TAG,即Q150X。
Both hereditary FXIII deficiency and hereditary afibrinogenaemia are very rare and severe autosomal bleeding disorder with an average frequency of one case in 1~2 million in the general population. To date, owing to the rarity of these two kinds of deficiencies, both clinical and basic problems related to them such as the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes have not been fully characterized and continue to confront hematologists.
Hereditary macrothrombocytopenia is a heterogeneous group of rare bleeding disorders characterized by prolonged bleeding time, thrombocytopenia and giant platelets. The pathogenic mechanism of some macrothrombocytopenias is still unresolved. In addition, some novel disorders were constantly discovered in the last few years. Recently, we found a patient with inherited macrothrombocytopenia, the morphology of whose platelets was very special containing many large electron opaque organelles.
Part I: Hereditary afibrinogenemia associated with a novel nonsense mutation in the FGA gene.
The molecular basis of hereditary afibrinogenemia is still poorly characterized. Up to date, only 33 abnormalities of genes encoding fibrinogen A alpha-chains (FGA), fibrinogen B beta-chains (FGB), and fibrinogen gamma-chains (FGG) have been identified. Here we reported the identification of the genetic defect underlying afibrinogenamia in a Chinese family. The proposita was a 17-year-old Chinese girl, born of a consanguineous marriage, and consanguinity is a recurrent feature in her family, besides her parents, her paternal grandparents also are first cousins The proposita displayed haemorrhagic manifestations, her blood clotting indices were prolonged and her coagulation factors were in normal ranges, whereas functional and immunological tests indicate absence of fibrinogen (<0.2g/l). The other family members were
遗传性出血性疾病常导致严重的出血,需要特殊的诊断方法与特别的治疗措施。我们利用在血栓与止血领域的优势,深入开展遗传性出血性疾病的基础与临床研究,阐明其发病的分子机制,解决这类特殊患者的痛苦,并提高我院血栓与止血的研究水平。
目的:分别对1例遗传性无纤维蛋白原血症(hereditary afibrinogenemia, HAF)和遗传性凝血因子XIII缺乏症(hereditary factor XIII deficiency , HFXIIID)进行基因分析和家系调查,阐明HAF和HFXIIID发病的分子机制;研究一种具有异常超微结构的遗传性巨血小板减少症(hereditary macrothrombocytopenia, HMTC)的形态与功能。
方法:1.凝血酶法与免疫比浊法测定纤维蛋白原(Fg),提取HAF家系先证者及其家系成员外周血基因组DNA,PCR法扩增其Fg的FGA、FGB和FGG基因所有外显子和侧翼序列,DNA序列分析确定Fg的基因异常。将先证者突变序列、家系成员和50名正常人相应序列的PCR产物用限制性内切酶RsaⅠ消化,以进一步确定基因突变并排除基因多态性。2.分别用尿素溶解法和试剂盒法检测HFXIIID患者及其家系成员血浆FXIII的活性,并用火箭电泳法和酶联免疫吸附实验测定其FXIII抗原含量。PCR法扩增F13A基因的所有外显子和侧翼序列,DNA测序分析基因异常,用直接测序法和限制性内切酶(SfaNⅠ、NspⅠ)分析80名正常人相应序列的PCR产物以排除基因多态性。应用生物信息学软件对所发现的突变进行分子模建,探讨其致病的分子机制。3.采集HMTC患者外周静脉血,分离富血小板血浆,用流式细胞术结合多种抗血小板膜糖蛋白(GP)单克隆抗体,测定血小板膜GP Ib、GP IIb、GP IIIa、P选择素和CD63的表达;以常规超薄切片术、免疫电镜技术检测患者血小板及其异常超微结构的性质;用荧光分光光度法测定血小板5-羟色胺含量。
结果:1. HAF先证者及其父亲的血浆Fg用Clauss法检测不到,免疫比浊法测定时,Fg含量均<0.02g/L,两者FGA基因外显子4第3108位核苷酸发生C→T纯合性改变,使Fg的Aa链第150位密码子(CAG,编码Gln)突变为终止密码TAG,即Q150X。
Both hereditary FXIII deficiency and hereditary afibrinogenaemia are very rare and severe autosomal bleeding disorder with an average frequency of one case in 1~2 million in the general population. To date, owing to the rarity of these two kinds of deficiencies, both clinical and basic problems related to them such as the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes have not been fully characterized and continue to confront hematologists.
Hereditary macrothrombocytopenia is a heterogeneous group of rare bleeding disorders characterized by prolonged bleeding time, thrombocytopenia and giant platelets. The pathogenic mechanism of some macrothrombocytopenias is still unresolved. In addition, some novel disorders were constantly discovered in the last few years. Recently, we found a patient with inherited macrothrombocytopenia, the morphology of whose platelets was very special containing many large electron opaque organelles.
Part I: Hereditary afibrinogenemia associated with a novel nonsense mutation in the FGA gene.
The molecular basis of hereditary afibrinogenemia is still poorly characterized. Up to date, only 33 abnormalities of genes encoding fibrinogen A alpha-chains (FGA), fibrinogen B beta-chains (FGB), and fibrinogen gamma-chains (FGG) have been identified. Here we reported the identification of the genetic defect underlying afibrinogenamia in a Chinese family. The proposita was a 17-year-old Chinese girl, born of a consanguineous marriage, and consanguinity is a recurrent feature in her family, besides her parents, her paternal grandparents also are first cousins The proposita displayed haemorrhagic manifestations, her blood clotting indices were prolonged and her coagulation factors were in normal ranges, whereas functional and immunological tests indicate absence of fibrinogen (<0.2g/l). The other family members were
引文
1. 王 兆 钺 . 血 小 板 与 凝 血 因 子 的 相 互 作 用 及 其 意 义 . 中 华 血 液 学 杂志,2004,25(3):187-189.
2. Ahmad SS , London FS , Walsh PN. The assembly of the factor Ⅹ-activating complex on activated human platelets. J Thromb Haemost ,2003,1(1) :48-59.
3. Aird WC. Hemostasis and irreducible complexity. J Thromb Haemost, 2003 ,1(2):227-230.
4. Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.Haemophilia, 2004, 10(5):593-628.
5. Pulanic D, Rudan I. The past decade: fibrinogen. Coll Antropol, 2005,29(1):341-9.
6. Lal AB, Maruthavanan R, Scott NB. Aortic valve repair in a patient with congenital afibrinogenemia. Anesth Analg, 2005,101(6):1628-30.
7. Nahrendorf M, Hu K, Frantz S, et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction.Circulation, 2006,113(9):1196-1202.
8. Bhattacharya M, Biswas A, Ahmed RP, et al. Clinico-hematologic profile of factor XIII-deficient patients.Clin Appl Thromb Hemost, 2005, 11(4):475-480.
9. Inbal A, Lubetsky A, Krapp T, et al. Impaired wound healing in factor XIII deficient mice.Thromb Haemost, 2005, 94(2):432-437.
10. Albanese A, Tuttolomondo A, Anile C, et al. Spontaneous chronic subdural hematomas in young adults with a deficiency in coagulation factor XIII. Report of three cases. J Neurosurg, 2005, 102(6):1130-1132.
11. Ichinose A, Asahina T, Kobayashi T. Congenital blood coagulation factor XIII deficiency and perinatal management.Curr Drug Targets, 2005, 6(5):541-549.
12. 赵小娟综述,王兆钺审校.巨大血小板综合征的分子机制与临床研究进展. 国外医学生理病理科学与临床分册,2004,24(2):150-152.
13. 杨海燕综述,王兆钺审校.遗传性巨大血小板病的研究进展.国外医学输血及血液学分册,2005,28(5): 459-462.
14. Seri M, Pecci A, Di Bari F, et al. MYH9—related disease:May-Hegglin anomaly,Sebastian syndrome,Fechtner syndrome,and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine, 2003,82(3):203-215.
15. Heath KE, Campos-Barros A, TorenA. Nonmuscle myosin heavy chain IIA mutation define a spectrum of autosomal dominant macrothrombocytopenias:May-Hegglin anomaly and Fechtner,Sebastian,Epstein,and Alport-like syndromes. Am J Hum Genet,2001,69(5):1033-1045.
16. Hu A, Wang F, Sellers JR. Mutation in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. J Biol Chem,2002,277(48):46512-46517.
17. Deutsch S, Rideau A, Bochaton-Piallat M, et al.Asp1424Asn MYH9 mutationresults in unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. Blood ,2003,102(2):529-534.
18. 张广森,易彦,徐敏,等.一个May-Hegglin异常家系非肌性肌球蛋白重链9基因突变位点的鉴定.中华医学杂志,2002,82(13):918-920.
19. Pestina TI, Jackson CW, Stenberg PE. Abnormal subcellular distribution of myosin and talin in Wistar Furth rat platelet. Blood,1995,85(9):2346-2446.
20. Drouin A, Favier R, Masse JM, et al. Newly recognized cellular abnormalities in the gray platelet syndrome. Blood,2001 ,98(5):1382-1391.
21. Okita JR, Frojmovic MM, Kristopeit S, et al. Montreal platelet syndrome:a defect in calcium-activated neutral Proteinase(calpain). Blood, 1989,74(2):715-721.
22. Kunishima S, Imai T, Hamaguchi M, et al. Novel heterozygous missense mutation in the second leucine rich repeat of GPIbalpha affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura.Eur J Haematol, 2006, 76(4):348-355.
23. Pecci A, Canobbio I, Balduini A, et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet, 2005, 14(21):3169-3178.
24. Nurden AT. Qualitative disorders of platelets and megakaryocytes.J Thromb Haemost, 2005, 3(8):1773-1782.
1. Vu D, Di Sanza C, Caille D, et al. Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia, 2005,14(21):3271-3280.
2. Lak M, Keihani M, Elahi F, et al. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol, 1999,107:204–206.
3. Dear A, Daly J, Brennan SO,et al. An intronic mutation within FGB (IVS1+2076 a-->g) is associated with afibrinogenemia and recurrent transient ischemic attacks. J Thromb Haemost, 2006,4(2):471-472.
4. Monaldini L, Asselta R, Malcovati M, et al. The DNA-pooling technique allowed for the identification of three novel mutations responsible for afibrinogenemia. J Thromb Haemost 2005,3(11):2591-2593.
5. Maghzal GJ, Brennan SO, Homer VM, et al. The molecular mechanisms of congenital hypofibrinogenaemia. Cell Mol Life Sci, 2004,61:1427–1438.
6. Spena S, Duga S, Asselta R, et al. Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involvingfibrinogenA alpha-chain gene. Eur J Hum Genet, 2004, 12:891–898.
7. Neerman-Arbez M, Germanos-Haddad M, Tzanidakis K, et al. Expression and analysis of a split premature termination codon in FGG responsible for congenital afibrinogenemia: escape from RNA surveillance mechanisms in transfected cells. Blood, 2004, 104:3618-3623
8. Watanabe K, Shibuya A, Ishii E, et al. Identification of simultaneous mutation of fibrinogen [alpha] chain and protein C genes in a Japanese kindred. Br J Haematol, 2003,120:101–108.
9. Vlietman JJ, Verhage J, Vos HL, et al. Inherited afibrinogenaemia in a newborn infant due to a novel mutation in the fibrinogen A alpha gene. Br J Haematol, 2002, 119:282–283.
10. Neerman-Arbez M, Honsberger A, Antonarakis SE, et al. Deletion of the fibrinogen alpha-chain gene (FGA) causes inherited afibrinogenaemia. J Clin Invest, 1999, 103:215–218.
11. Neerman-Arbez M, de Moerloose P, Bridel C, et al. Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenaemia. Blood, 2000, 96:149–152.
12. Neerman-Arbez M. The molecular basis of inherited afibrinogenaemia. Thromb Haemost, 2001, 89:154–163.
13. Neerman-Arbez M, de Moerloose P, Honsberger A, et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenaemia: novel truncatingmutations in the FGA and FGG genes. Hum Genet, 2001, 108:237–240.
14. Neerman-Arbez M, Vu D, Abu-Libdeh B, et al. Prenatal diagnosis for congenital afibrinogenaemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood, 2003, 101:3492–3494.
15. Remijn JA, Van Wijk R, Nieuwenhuis HK, et al. Molecular basis of congenital afibrinogenaemia in a Dutch family. Blood Coagul Fibrinolysis, 2003,14:299–302.
16. Attanasio C, de Moerloose P, Antonarakis SE, et al. Activation of multiple cryptic donor splice sites by the common congenital afibrinogenaemia mutation, FGA IVS4+1 G→ T. Blood,2001, 97:1879–1881.
17. Attanasio C, David A, Neerman-Arbez M. Outcome of donor splice site mutations accounting for inherited afibrinogenaemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood, 2003,101:1851–1856.
18. Asselta R, Duga S, Simonic T, et al. Afibrinogenaemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation.Blood, 2000, 96:2496–2500.
19. Asselta R, Spena S, Duga S, et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenaemia. Haematologica, 2002,87:855–859.
20. Asselta R, Duga S, Spena S, et al. Inherited afibrinogenaemia: mutations leading to premature termination codons in fibrinogen A alpha-chain gene are not associated with the decay of the mutant mRNAs. Blood, 2001, 98:3685–3692.
21. Duga S, Asselta R, Santagostino E, et al. Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenaemia by impairing fibrinogen secretion. Blood,2000, 95:1336–1341.
22. Iida H, Ishii E, Nakahara M, et al. A case of congenital afibrinogenaemia: fibrinogen Hakata, a novel nonsense mutation of the fibrinogen gamma-chain gene. Thromb Haemost, 2000, 84:49–53.
23. Margaglione M, Santacroce R, Colaizzo D, et al. A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenaemia due to abnormal RNA splicing. Blood, 2000, 96:2501–2505.
24. Spena S, Duga S, Asselta R, et al. Congenital afibrinogenaemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood, 2002, 100:4478–4484.
25. Spena S, Asselta R, Duga S, et al. Congenital afibrinogenaemia: intracellular retention of fibrinogen due to a novel W437G mutation on the fibrinogen Bbeta-chain gene. Biochim Biophys Acta, 2003,1639:87–94.
26. Meyer M. Molecular biology of haemostasis: fibrinogen, factor XIII. Hamostaseologie,2004, 24:108–115.
27. 徐修才,周荣富,吴竞生,等.β链基因突变导致遗传性无纤维蛋白原血症一例报告.中华血液学杂志,2005,26:137-139
28. 方怡,王学锋,王鸿利,等.一个先天性无纤维蛋白原血症家系的基因分析.中华医学杂志,2003,83:2054-2057.
29. 张子彦,王兆钺,傅建新,等.先天性纤溶酶原激活物抑制剂-1缺乏症的诊断研究.中华血液学杂志,2004,25:129-131.
30. Blomback B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res, 1996,83:1–75.
31. Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation and association with lipid synthesis and secretion. Ann NY Acad Sci, 2001, 936:480–495.
32. Brennan SO, Maghzal G, Shneider BL,et al.Novel fibrinogen gamma375 Arg→Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology, 2002,36:652–658.
33. Fellowes AP, Brennan SO, Holme R, et al. Homozygous truncation of the fibrinogen A alpha chain within the coiled coil causes congenital afibrinogenaemia. Blood,2000, 96:773–775.
1 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res, 1999,94: 271-305.
2 Dufner GS, Marbet GA. Factor XIII in man: a review. Hamostaseologie, 2002,22:11-19.
3 Anwar R, Milozewski KJA. Factor XIII deficiency, Br J Haematol, 1999, 107: 468-484
4 Lak M, Peyvandi F, Ali Sharifian A, et al. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency. J Thromb Haemost, 2003, 1: 1852-1853.5 Al-Sharif FZ, Aljurf MD, Al-Momen AM, et al. Clinical and laboratory features of congenital factor XIII deficiency. Saudi Medical Journal, 2002, 23:552-554.
6 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost, 2001, 86:57-65.
7 Burrows RF, Ray JG. Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstetrical & Gynecological Survey, 2000, 55:103-108.
8 段宝华,王鸿利,储海燕,等.遗传性凝血因子XIII缺陷症两种新的基因突变的确定.中华血液学杂志,2002,23:117-130.
9 Yee VC, Pedersen LC, Le Trang I, et al.. Three dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci USA, 1994,91: 7296-7300.
10 Board P, Coggan M, Miloszewski K: Identification of a point mutation in factor XIII sub A subunit deficiency. Blood, 1992, 80:937-941.
11 Jayandharan GR, Viswabandya A, Baidya S, et al. Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach.Thromb Haemost, 2006, 95(3):551-556.
12 Halverstadt A, Walsh S, Roth SM, et al. Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States. Int J Hematol, 2006, 83(2):144-146.
13 Onland W, Boing AN, Meijer AB, et al. Congenital deficiency of factor XIII caused by two missense mutations in a Dutch family.Haemophilia, 2005,11(5):539-547.
14 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood, 2004,104:1243-1252.
15 Peyvandi F, Duga S, Akhavan S, et al. Rare coagulation deficiencies. Haemophilia, 2002, 8:308-321.
16 Peyvandi F, Tagliabue L, Menegatti M, et al. Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency. Hum Mutat, 2004, 23:98.
17 Vysokovsky A, Saxena R, Landau M, et al. Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families. JThromb Haemost, 2004, 2:1790-1097.
18 Birben E, Oner C, Oner R, et al. Identification of an inframe deletion and a missense mutation in the factor XIIIA gene in two Turkish patients. Eur J Haematol, 2003, 71:39-43.
19 Inbal A, Yee VC, Kornbrot N, et al. Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families. Thromb Haemost, 1997, 77:1062-1067.
20 Aslam S, Poon MC, Yee VC, et al. Factor XIII sub A Calgary : a candidate missense mutation (Leu667Pro) in the beta barrel 2 domain of the factor XIII sub A subunit. Br J Haematol, 1995,91:452-457.
21 Mikkola H, Syrjala M, Rasi V, et al. Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels. Blood, 1994, 84: 517–525.
22 Birben E, Oner C, Oner R, et al. Identification of an inframe deletion and a missense mutation in the factor XIIIA gene in two Turkish patients. Eur J Haematol, 2003, 71: 39-43.
1 White JG. Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder I. Megakaryocytes. Platelets, 2003,14:53-60.
2 Balduini CL, Savoia A. Inherited thrombocytopenias: molecular mechanisms. Semin Thromb Hemost, 2004,30:513-23.
3 Wang Z, Zhao X, Duan W, Fu J, Lu M, Wang G, et al. A novel mutation in the transmembrane region of glyco-protein IX associated with Bernard-Soulier syndrome. Thromb Haemost, 2004,92:606-13.
4 Nurden AT. Inherited abnormalities of platelets. Thromb Haemost,1999,82 :468-80.
5 Sachs UJ, Kroll H, Matzdorff AC, Berghofer H, Lopez JA, Santoso S. Bernard-Soulier syndrome due to the homozygous Asn-45Ser mutation in GPIX: an unexpected, frequent finding in Germany. Br J Haematol, 2003,123:127-31.
6 Nurden P, Jandrot-Perrus M, Combrie R, Winckler J, Arocas V, Lecut C, et al. Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome. Blood, 2004, 104:107-14.
7 Falik-Zaccai TC, Anikster Y, Rivera CE, Horne MK 3rd, Schliamser L, Phornphutkul C, et al. A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics. Mol Genet Metab, 2001, 74:303-13.
8 Drouin A, Favier R, Masse JM, Debili N, Schmitt A, Elbim C, et al. Newly recognized cellular abnormalities in the gray platelet syndrome. Blood, 2001, 98:1382-91.
9 Rees DC, Iolascon A, Carella M, O'marcaigh AS, Kendra JR, Jowitt SN, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol, 2005, 130:297-309.
10 Dong F, Li S, Pujol-Moix N, Luban NL, Shin SW, Seo JH, et al. Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol, 2005, 130:620-7.
11 Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet, 2001, 46:722-9.
12 Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M, et al. First description of somatic mosaicism in MYH9 disorders. Br J Haematol, 2005, 128:360-5.
13 庞毅,梁河涛,余世禄,等. 川崎病患儿血小板膜糖蛋白变化的动态观察.中华血液学杂志,2002,23:134-137.
14 颜永碧,王英,陆月良.游离细胞内抗原的免疫电镜胶金标记方法.第二军医大学学报,2003,24:10.
15 Smid HM. Microwave applications on small insect brain tissue irradiated in a water-perfused cooling-jacket for temperature control. J Neurosci Methods, 1994, 55:155-61.
16 黎明,邓承祺主编. 现代血栓与止血的实验室检测及其应用. 第 1 版.北京:人民卫生出版社,2004. 244-245.
17 Jernej B, Banovic M, Cicin-Sain L, Hranilovi D, Balija M, Oreskovic D, et al. Physiological characteristics of platelet/circulatory serotonin: study on a large human population. Psychiatry Res, 2000,94:153-62.
18 Jernej B, Cicin-Sain L, Iskric S. A simple and reliable method for monitoringplatelet serotonin level in rats. Life Sci, 1988,43:1663-70.
19 Jernej B, Vladic A, Cicin-Sain L, Hranilovic D, Banovic M, Balija M, et al. Platelet serotonin measures in migraine. Headache, 2002, 42:588-95.
20 Pujol-Moix N, Hernandez A, Escolar G, Espanol I, Martinez-Brotons F, Mateo J. Platelet ultrastructural morphometry for diagnosis of partial delta-storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases. Haematologica, 2000, 85:619-26.
21 Biddle DA, Neto TG, Nguyen AN, Platelet storage pool deficiency of alpha and delta granules. Arch Patho Lab Med, 2001,125:1125-6.
22 Krishnamurti L, Neglia J P, Nagarajan R, Berry S, Hirsch B, Matsunaga A, et al. Paris-Trousseau platelets: a manifestation of Jacobsen Syndrome. Am Soc Pediatr Hematol, 2001,66: 295–299.
23 Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood, 2005,106:40-2.
24 Lazarchick J, McRae B. Chediak-Higashi syndrome. Blood, 2005, 105:4162.
25 Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. Defective lysosomal exocytosis and plasma membrane repair in Chediak-Higashi/beige cells. Proc Natl Acad Sci USA, 2004,101:16795-800.
26 Wang Z, Shi J, Han Y, Wang Y, Ruan C. Spontaneous platelet aggregation with congenital giant platelet containing large granules and thick membrane. Clin Appl Thromb Hemost, 2001,7:305-10.
27 White J G. Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder IV. Ultrastructural cytochemistry and analytical electron microscopy. Platelets,2003, 14:313-24.
1 van’t Hooft FM, von Bahr SJ, Silveira A, et al. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol,1999,19(12):3063-3070.
2 Folsom AR, Aleksic N, Ahn C,et al. Beta-fibrinogen gene G/A-455 polymorphisms and coronary heart disease incidence: the Atherosclerosis risk in Communities(ARIC) study. Ann epidemiol, 2001,11(3):166-170.
3 刘蓉,李家增,穆红,等.纤维蛋白原基因多态性与缺血性心脑血管病的关系.中华血液学杂志,2002,23(9):453-456.
4 Lim BC, Ariens RA, Carter AM, et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet,2003, 361(9367):1424-1431.
5 Cunningham MT, Brandt JT, Laposata M, et al. Laboratory diagnosis of dysfibrinogenemia. Archives of Pathology&Laboratory Medicine, 2002,126(4):499-505.
6 Plendl H, Caliebe A, Grote W, et al. Molecular variants of fibrinogen. Haemostaseologie, 2002,22(2):36-41.
7 Stucki B, Zenhausern R, Biedermann B, et al. Fibrinogens Bern IV, Bern V and Milano XI: three dysfunctional variants with amino acid substitutions in the thrombin cleavage site of the A alpha-chain. Blood Coagulation & Fibrinolysis, 1999,10(2):93–99.
8 Watanabe K, Shibuya A, Ishii E, et al. Identification of simultaneous mutation of fibrinogen [alpha] chain and protein C genes in a Japanese kindred. Platelets , Haemostasis And Thrombosis, 2003,120(1):101-108.
9 Vlietman JJ, Verhage J, Vos HL, et al. Congenital afibrinogenemia in a newborn infant due to a novel mutation in the fibrinogen aalpha gene. Br J Haematol, 2002,119(1):282-283.
10 Neerman-Arbez M, Honsberger A, Antonarakis SE,et al. Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital afibrinogenemia. J Clin invest,1999,103:215-218.
11 Neerman-Arbez M. The molecular basis of inherited afibrinogenemia. Thromb Haemost, 2001,89(1):154-163.
12 Spena S, Duga S, Asselta R ,et al. Congenital afibrinogenemia: first identification of splicing in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood, 2002,100(13):4478-4484.
13 Remijn JA, Van Wijk R, Nieuwenhuis HK, et al. Molecular of congenital afibrinogenemia in a Dutch family. Blood Coagul Fibrinolysis, 2003,14(3):299-302.
14 Attanasio C, David A, Neerman-Arbez M. Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood, 2003,101(5):1851-1856.
15 Asselta R, Spena S, Duga S, et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain genecausing afibrinogenemia. Haematologica, 2002,87(8):855-859.
16 Vu D, Bolton-Maggs PH, Parr JR, et al. Congenital afibrinogenemia: identification and expressing of a missense mutation in FGB impairing fibrinogen secretion. Blood, 2003,102(13):4413-4415.
17 Spena S, Asselta R, Duga S, et al. Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene. Biochim Biophys Acta. 2003,1639(2):87-94.
2. Ahmad SS , London FS , Walsh PN. The assembly of the factor Ⅹ-activating complex on activated human platelets. J Thromb Haemost ,2003,1(1) :48-59.
3. Aird WC. Hemostasis and irreducible complexity. J Thromb Haemost, 2003 ,1(2):227-230.
4. Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.Haemophilia, 2004, 10(5):593-628.
5. Pulanic D, Rudan I. The past decade: fibrinogen. Coll Antropol, 2005,29(1):341-9.
6. Lal AB, Maruthavanan R, Scott NB. Aortic valve repair in a patient with congenital afibrinogenemia. Anesth Analg, 2005,101(6):1628-30.
7. Nahrendorf M, Hu K, Frantz S, et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction.Circulation, 2006,113(9):1196-1202.
8. Bhattacharya M, Biswas A, Ahmed RP, et al. Clinico-hematologic profile of factor XIII-deficient patients.Clin Appl Thromb Hemost, 2005, 11(4):475-480.
9. Inbal A, Lubetsky A, Krapp T, et al. Impaired wound healing in factor XIII deficient mice.Thromb Haemost, 2005, 94(2):432-437.
10. Albanese A, Tuttolomondo A, Anile C, et al. Spontaneous chronic subdural hematomas in young adults with a deficiency in coagulation factor XIII. Report of three cases. J Neurosurg, 2005, 102(6):1130-1132.
11. Ichinose A, Asahina T, Kobayashi T. Congenital blood coagulation factor XIII deficiency and perinatal management.Curr Drug Targets, 2005, 6(5):541-549.
12. 赵小娟综述,王兆钺审校.巨大血小板综合征的分子机制与临床研究进展. 国外医学生理病理科学与临床分册,2004,24(2):150-152.
13. 杨海燕综述,王兆钺审校.遗传性巨大血小板病的研究进展.国外医学输血及血液学分册,2005,28(5): 459-462.
14. Seri M, Pecci A, Di Bari F, et al. MYH9—related disease:May-Hegglin anomaly,Sebastian syndrome,Fechtner syndrome,and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine, 2003,82(3):203-215.
15. Heath KE, Campos-Barros A, TorenA. Nonmuscle myosin heavy chain IIA mutation define a spectrum of autosomal dominant macrothrombocytopenias:May-Hegglin anomaly and Fechtner,Sebastian,Epstein,and Alport-like syndromes. Am J Hum Genet,2001,69(5):1033-1045.
16. Hu A, Wang F, Sellers JR. Mutation in human nonmuscle myosin IIA found in patients with May-Hegglin anomaly and Fechtner syndrome result in impaired enzymatic function. J Biol Chem,2002,277(48):46512-46517.
17. Deutsch S, Rideau A, Bochaton-Piallat M, et al.Asp1424Asn MYH9 mutationresults in unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome. Blood ,2003,102(2):529-534.
18. 张广森,易彦,徐敏,等.一个May-Hegglin异常家系非肌性肌球蛋白重链9基因突变位点的鉴定.中华医学杂志,2002,82(13):918-920.
19. Pestina TI, Jackson CW, Stenberg PE. Abnormal subcellular distribution of myosin and talin in Wistar Furth rat platelet. Blood,1995,85(9):2346-2446.
20. Drouin A, Favier R, Masse JM, et al. Newly recognized cellular abnormalities in the gray platelet syndrome. Blood,2001 ,98(5):1382-1391.
21. Okita JR, Frojmovic MM, Kristopeit S, et al. Montreal platelet syndrome:a defect in calcium-activated neutral Proteinase(calpain). Blood, 1989,74(2):715-721.
22. Kunishima S, Imai T, Hamaguchi M, et al. Novel heterozygous missense mutation in the second leucine rich repeat of GPIbalpha affects GPIb/IX/V expression and results in macrothrombocytopenia in a patient initially misdiagnosed with idiopathic thrombocytopenic purpura.Eur J Haematol, 2006, 76(4):348-355.
23. Pecci A, Canobbio I, Balduini A, et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet, 2005, 14(21):3169-3178.
24. Nurden AT. Qualitative disorders of platelets and megakaryocytes.J Thromb Haemost, 2005, 3(8):1773-1782.
1. Vu D, Di Sanza C, Caille D, et al. Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia, 2005,14(21):3271-3280.
2. Lak M, Keihani M, Elahi F, et al. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol, 1999,107:204–206.
3. Dear A, Daly J, Brennan SO,et al. An intronic mutation within FGB (IVS1+2076 a-->g) is associated with afibrinogenemia and recurrent transient ischemic attacks. J Thromb Haemost, 2006,4(2):471-472.
4. Monaldini L, Asselta R, Malcovati M, et al. The DNA-pooling technique allowed for the identification of three novel mutations responsible for afibrinogenemia. J Thromb Haemost 2005,3(11):2591-2593.
5. Maghzal GJ, Brennan SO, Homer VM, et al. The molecular mechanisms of congenital hypofibrinogenaemia. Cell Mol Life Sci, 2004,61:1427–1438.
6. Spena S, Duga S, Asselta R, et al. Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involvingfibrinogenA alpha-chain gene. Eur J Hum Genet, 2004, 12:891–898.
7. Neerman-Arbez M, Germanos-Haddad M, Tzanidakis K, et al. Expression and analysis of a split premature termination codon in FGG responsible for congenital afibrinogenemia: escape from RNA surveillance mechanisms in transfected cells. Blood, 2004, 104:3618-3623
8. Watanabe K, Shibuya A, Ishii E, et al. Identification of simultaneous mutation of fibrinogen [alpha] chain and protein C genes in a Japanese kindred. Br J Haematol, 2003,120:101–108.
9. Vlietman JJ, Verhage J, Vos HL, et al. Inherited afibrinogenaemia in a newborn infant due to a novel mutation in the fibrinogen A alpha gene. Br J Haematol, 2002, 119:282–283.
10. Neerman-Arbez M, Honsberger A, Antonarakis SE, et al. Deletion of the fibrinogen alpha-chain gene (FGA) causes inherited afibrinogenaemia. J Clin Invest, 1999, 103:215–218.
11. Neerman-Arbez M, de Moerloose P, Bridel C, et al. Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenaemia. Blood, 2000, 96:149–152.
12. Neerman-Arbez M. The molecular basis of inherited afibrinogenaemia. Thromb Haemost, 2001, 89:154–163.
13. Neerman-Arbez M, de Moerloose P, Honsberger A, et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenaemia: novel truncatingmutations in the FGA and FGG genes. Hum Genet, 2001, 108:237–240.
14. Neerman-Arbez M, Vu D, Abu-Libdeh B, et al. Prenatal diagnosis for congenital afibrinogenaemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood, 2003, 101:3492–3494.
15. Remijn JA, Van Wijk R, Nieuwenhuis HK, et al. Molecular basis of congenital afibrinogenaemia in a Dutch family. Blood Coagul Fibrinolysis, 2003,14:299–302.
16. Attanasio C, de Moerloose P, Antonarakis SE, et al. Activation of multiple cryptic donor splice sites by the common congenital afibrinogenaemia mutation, FGA IVS4+1 G→ T. Blood,2001, 97:1879–1881.
17. Attanasio C, David A, Neerman-Arbez M. Outcome of donor splice site mutations accounting for inherited afibrinogenaemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood, 2003,101:1851–1856.
18. Asselta R, Duga S, Simonic T, et al. Afibrinogenaemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation.Blood, 2000, 96:2496–2500.
19. Asselta R, Spena S, Duga S, et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenaemia. Haematologica, 2002,87:855–859.
20. Asselta R, Duga S, Spena S, et al. Inherited afibrinogenaemia: mutations leading to premature termination codons in fibrinogen A alpha-chain gene are not associated with the decay of the mutant mRNAs. Blood, 2001, 98:3685–3692.
21. Duga S, Asselta R, Santagostino E, et al. Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenaemia by impairing fibrinogen secretion. Blood,2000, 95:1336–1341.
22. Iida H, Ishii E, Nakahara M, et al. A case of congenital afibrinogenaemia: fibrinogen Hakata, a novel nonsense mutation of the fibrinogen gamma-chain gene. Thromb Haemost, 2000, 84:49–53.
23. Margaglione M, Santacroce R, Colaizzo D, et al. A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenaemia due to abnormal RNA splicing. Blood, 2000, 96:2501–2505.
24. Spena S, Duga S, Asselta R, et al. Congenital afibrinogenaemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood, 2002, 100:4478–4484.
25. Spena S, Asselta R, Duga S, et al. Congenital afibrinogenaemia: intracellular retention of fibrinogen due to a novel W437G mutation on the fibrinogen Bbeta-chain gene. Biochim Biophys Acta, 2003,1639:87–94.
26. Meyer M. Molecular biology of haemostasis: fibrinogen, factor XIII. Hamostaseologie,2004, 24:108–115.
27. 徐修才,周荣富,吴竞生,等.β链基因突变导致遗传性无纤维蛋白原血症一例报告.中华血液学杂志,2005,26:137-139
28. 方怡,王学锋,王鸿利,等.一个先天性无纤维蛋白原血症家系的基因分析.中华医学杂志,2003,83:2054-2057.
29. 张子彦,王兆钺,傅建新,等.先天性纤溶酶原激活物抑制剂-1缺乏症的诊断研究.中华血液学杂志,2004,25:129-131.
30. Blomback B. Fibrinogen and fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res, 1996,83:1–75.
31. Redman CM, Xia H. Fibrinogen biosynthesis. Assembly, intracellular degradation and association with lipid synthesis and secretion. Ann NY Acad Sci, 2001, 936:480–495.
32. Brennan SO, Maghzal G, Shneider BL,et al.Novel fibrinogen gamma375 Arg→Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology, 2002,36:652–658.
33. Fellowes AP, Brennan SO, Holme R, et al. Homozygous truncation of the fibrinogen A alpha chain within the coiled coil causes congenital afibrinogenaemia. Blood,2000, 96:773–775.
1 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res, 1999,94: 271-305.
2 Dufner GS, Marbet GA. Factor XIII in man: a review. Hamostaseologie, 2002,22:11-19.
3 Anwar R, Milozewski KJA. Factor XIII deficiency, Br J Haematol, 1999, 107: 468-484
4 Lak M, Peyvandi F, Ali Sharifian A, et al. Pattern of symptoms in 93 Iranian patients with severe factor XIII deficiency. J Thromb Haemost, 2003, 1: 1852-1853.5 Al-Sharif FZ, Aljurf MD, Al-Momen AM, et al. Clinical and laboratory features of congenital factor XIII deficiency. Saudi Medical Journal, 2002, 23:552-554.
6 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost, 2001, 86:57-65.
7 Burrows RF, Ray JG. Burrows EA. Bleeding risk and reproductive capacity among patients with factor XIII deficiency: a case presentation and review of the literature. Obstetrical & Gynecological Survey, 2000, 55:103-108.
8 段宝华,王鸿利,储海燕,等.遗传性凝血因子XIII缺陷症两种新的基因突变的确定.中华血液学杂志,2002,23:117-130.
9 Yee VC, Pedersen LC, Le Trang I, et al.. Three dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci USA, 1994,91: 7296-7300.
10 Board P, Coggan M, Miloszewski K: Identification of a point mutation in factor XIII sub A subunit deficiency. Blood, 1992, 80:937-941.
11 Jayandharan GR, Viswabandya A, Baidya S, et al. Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach.Thromb Haemost, 2006, 95(3):551-556.
12 Halverstadt A, Walsh S, Roth SM, et al. Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States. Int J Hematol, 2006, 83(2):144-146.
13 Onland W, Boing AN, Meijer AB, et al. Congenital deficiency of factor XIII caused by two missense mutations in a Dutch family.Haemophilia, 2005,11(5):539-547.
14 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood, 2004,104:1243-1252.
15 Peyvandi F, Duga S, Akhavan S, et al. Rare coagulation deficiencies. Haemophilia, 2002, 8:308-321.
16 Peyvandi F, Tagliabue L, Menegatti M, et al. Phenotype-genotype characterization of 10 families with severe a subunit factor XIII deficiency. Hum Mutat, 2004, 23:98.
17 Vysokovsky A, Saxena R, Landau M, et al. Seven novel mutations in the factor XIII A-subunit gene causing hereditary factor XIII deficiency in 10 unrelated families. JThromb Haemost, 2004, 2:1790-1097.
18 Birben E, Oner C, Oner R, et al. Identification of an inframe deletion and a missense mutation in the factor XIIIA gene in two Turkish patients. Eur J Haematol, 2003, 71:39-43.
19 Inbal A, Yee VC, Kornbrot N, et al. Factor XIII deficiency due to a Leu660Pro mutation in the factor XIII subunit-a gene in three unrelated Palestinian Arab families. Thromb Haemost, 1997, 77:1062-1067.
20 Aslam S, Poon MC, Yee VC, et al. Factor XIII sub A Calgary : a candidate missense mutation (Leu667Pro) in the beta barrel 2 domain of the factor XIII sub A subunit. Br J Haematol, 1995,91:452-457.
21 Mikkola H, Syrjala M, Rasi V, et al. Deficiency in the A-subunit of coagulation factor XIII: two novel point mutations demonstrate different effects on transcript levels. Blood, 1994, 84: 517–525.
22 Birben E, Oner C, Oner R, et al. Identification of an inframe deletion and a missense mutation in the factor XIIIA gene in two Turkish patients. Eur J Haematol, 2003, 71: 39-43.
1 White JG. Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder I. Megakaryocytes. Platelets, 2003,14:53-60.
2 Balduini CL, Savoia A. Inherited thrombocytopenias: molecular mechanisms. Semin Thromb Hemost, 2004,30:513-23.
3 Wang Z, Zhao X, Duan W, Fu J, Lu M, Wang G, et al. A novel mutation in the transmembrane region of glyco-protein IX associated with Bernard-Soulier syndrome. Thromb Haemost, 2004,92:606-13.
4 Nurden AT. Inherited abnormalities of platelets. Thromb Haemost,1999,82 :468-80.
5 Sachs UJ, Kroll H, Matzdorff AC, Berghofer H, Lopez JA, Santoso S. Bernard-Soulier syndrome due to the homozygous Asn-45Ser mutation in GPIX: an unexpected, frequent finding in Germany. Br J Haematol, 2003,123:127-31.
6 Nurden P, Jandrot-Perrus M, Combrie R, Winckler J, Arocas V, Lecut C, et al. Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome. Blood, 2004, 104:107-14.
7 Falik-Zaccai TC, Anikster Y, Rivera CE, Horne MK 3rd, Schliamser L, Phornphutkul C, et al. A new genetic isolate of gray platelet syndrome (GPS): clinical, cellular, and hematologic characteristics. Mol Genet Metab, 2001, 74:303-13.
8 Drouin A, Favier R, Masse JM, Debili N, Schmitt A, Elbim C, et al. Newly recognized cellular abnormalities in the gray platelet syndrome. Blood, 2001, 98:1382-91.
9 Rees DC, Iolascon A, Carella M, O'marcaigh AS, Kendra JR, Jowitt SN, et al. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol, 2005, 130:297-309.
10 Dong F, Li S, Pujol-Moix N, Luban NL, Shin SW, Seo JH, et al. Genotype-phenotype correlation in MYH9-related thrombocytopenia. Br J Haematol, 2005, 130:620-7.
11 Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, et al. Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet, 2001, 46:722-9.
12 Kunishima S, Matsushita T, Yoshihara T, Nakase Y, Yokoi K, Hamaguchi M, et al. First description of somatic mosaicism in MYH9 disorders. Br J Haematol, 2005, 128:360-5.
13 庞毅,梁河涛,余世禄,等. 川崎病患儿血小板膜糖蛋白变化的动态观察.中华血液学杂志,2002,23:134-137.
14 颜永碧,王英,陆月良.游离细胞内抗原的免疫电镜胶金标记方法.第二军医大学学报,2003,24:10.
15 Smid HM. Microwave applications on small insect brain tissue irradiated in a water-perfused cooling-jacket for temperature control. J Neurosci Methods, 1994, 55:155-61.
16 黎明,邓承祺主编. 现代血栓与止血的实验室检测及其应用. 第 1 版.北京:人民卫生出版社,2004. 244-245.
17 Jernej B, Banovic M, Cicin-Sain L, Hranilovi D, Balija M, Oreskovic D, et al. Physiological characteristics of platelet/circulatory serotonin: study on a large human population. Psychiatry Res, 2000,94:153-62.
18 Jernej B, Cicin-Sain L, Iskric S. A simple and reliable method for monitoringplatelet serotonin level in rats. Life Sci, 1988,43:1663-70.
19 Jernej B, Vladic A, Cicin-Sain L, Hranilovic D, Banovic M, Balija M, et al. Platelet serotonin measures in migraine. Headache, 2002, 42:588-95.
20 Pujol-Moix N, Hernandez A, Escolar G, Espanol I, Martinez-Brotons F, Mateo J. Platelet ultrastructural morphometry for diagnosis of partial delta-storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases. Haematologica, 2000, 85:619-26.
21 Biddle DA, Neto TG, Nguyen AN, Platelet storage pool deficiency of alpha and delta granules. Arch Patho Lab Med, 2001,125:1125-6.
22 Krishnamurti L, Neglia J P, Nagarajan R, Berry S, Hirsch B, Matsunaga A, et al. Paris-Trousseau platelets: a manifestation of Jacobsen Syndrome. Am Soc Pediatr Hematol, 2001,66: 295–299.
23 Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, et al. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood, 2005,106:40-2.
24 Lazarchick J, McRae B. Chediak-Higashi syndrome. Blood, 2005, 105:4162.
25 Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. Defective lysosomal exocytosis and plasma membrane repair in Chediak-Higashi/beige cells. Proc Natl Acad Sci USA, 2004,101:16795-800.
26 Wang Z, Shi J, Han Y, Wang Y, Ruan C. Spontaneous platelet aggregation with congenital giant platelet containing large granules and thick membrane. Clin Appl Thromb Hemost, 2001,7:305-10.
27 White J G. Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder IV. Ultrastructural cytochemistry and analytical electron microscopy. Platelets,2003, 14:313-24.
1 van’t Hooft FM, von Bahr SJ, Silveira A, et al. Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol,1999,19(12):3063-3070.
2 Folsom AR, Aleksic N, Ahn C,et al. Beta-fibrinogen gene G/A-455 polymorphisms and coronary heart disease incidence: the Atherosclerosis risk in Communities(ARIC) study. Ann epidemiol, 2001,11(3):166-170.
3 刘蓉,李家增,穆红,等.纤维蛋白原基因多态性与缺血性心脑血管病的关系.中华血液学杂志,2002,23(9):453-456.
4 Lim BC, Ariens RA, Carter AM, et al. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet,2003, 361(9367):1424-1431.
5 Cunningham MT, Brandt JT, Laposata M, et al. Laboratory diagnosis of dysfibrinogenemia. Archives of Pathology&Laboratory Medicine, 2002,126(4):499-505.
6 Plendl H, Caliebe A, Grote W, et al. Molecular variants of fibrinogen. Haemostaseologie, 2002,22(2):36-41.
7 Stucki B, Zenhausern R, Biedermann B, et al. Fibrinogens Bern IV, Bern V and Milano XI: three dysfunctional variants with amino acid substitutions in the thrombin cleavage site of the A alpha-chain. Blood Coagulation & Fibrinolysis, 1999,10(2):93–99.
8 Watanabe K, Shibuya A, Ishii E, et al. Identification of simultaneous mutation of fibrinogen [alpha] chain and protein C genes in a Japanese kindred. Platelets , Haemostasis And Thrombosis, 2003,120(1):101-108.
9 Vlietman JJ, Verhage J, Vos HL, et al. Congenital afibrinogenemia in a newborn infant due to a novel mutation in the fibrinogen aalpha gene. Br J Haematol, 2002,119(1):282-283.
10 Neerman-Arbez M, Honsberger A, Antonarakis SE,et al. Deletion of the fibrinogen alpha-chain gene (FGA) causes congenital afibrinogenemia. J Clin invest,1999,103:215-218.
11 Neerman-Arbez M. The molecular basis of inherited afibrinogenemia. Thromb Haemost, 2001,89(1):154-163.
12 Spena S, Duga S, Asselta R ,et al. Congenital afibrinogenemia: first identification of splicing in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood, 2002,100(13):4478-4484.
13 Remijn JA, Van Wijk R, Nieuwenhuis HK, et al. Molecular of congenital afibrinogenemia in a Dutch family. Blood Coagul Fibrinolysis, 2003,14(3):299-302.
14 Attanasio C, David A, Neerman-Arbez M. Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA). Blood, 2003,101(5):1851-1856.
15 Asselta R, Spena S, Duga S, et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain genecausing afibrinogenemia. Haematologica, 2002,87(8):855-859.
16 Vu D, Bolton-Maggs PH, Parr JR, et al. Congenital afibrinogenemia: identification and expressing of a missense mutation in FGB impairing fibrinogen secretion. Blood, 2003,102(13):4413-4415.
17 Spena S, Asselta R, Duga S, et al. Congenital afibrinogenemia: intracellular retention of fibrinogen due to a novel W437G mutation in the fibrinogen Bbeta-chain gene. Biochim Biophys Acta. 2003,1639(2):87-94.