Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00006.x
Dorothea Scandella
The domain specificity of anti‐factor VIII (FVIII) inhibitor antibodies was determined in assays using FVIII domains generated by thrombin cleavage or expressed as recombinant polypeptides to neutralise the inhibitor. The results revealed the existence of three major types of inhibitors, and various combinations of these antibodies were found in haemophilic and autoantibody patients. Anti‐A2 domain inhibitors prevent normal function of the FVIII/factor IXa (FIXa)/phospholipid complex in an unknown manner. Binding of FVIII to phospholipid and to von Willebrand factor is blocked by anti‐C2 domain antibodies, and the binding of FVIII to FIXa is prevented by anti‐A3 domain antibodies. A rare type of inhibitor prevents release of activated FVIII from von Willebrand factor (vWf), and another probably interferes with FVIII binding to factor X (FX) because it shares the epitope of a monoclonal antibody with this property.
在使用凝血酶裂解产生的或表达为重组多肽的 FVIII 结构域来中和抑制剂的试验中，确定了抗因子 VIII（FVIII）抑制剂抗体的结构域特异性。结果显示存在三种主要类型的抑制剂，在血友病患者和自身抗体患者中发现了这些抗体的各种组合。抗A2结构域抑制剂以一种未知的方式阻止FVIII/因子IXa（FIXa）/磷脂复合物的正常功能。抗C2结构域抗体会阻止FVIII与磷脂和von Willebrand因子结合，抗A3结构域抗体会阻止FVIII与FIXa结合。一种罕见的抑制剂可阻止活化的 FVIII 从 von Willebrand 因子（vWf）中释放，另一种抑制剂可能会干扰 FVIII 与 X 因子（FX）的结合，因为它与具有这种特性的单克隆抗体的表位相同。
{"title":"Epitope Specificity and Inactivation Mechanisms of Factor VIII Inhibitor Antibodies","authors":"Dorothea Scandella","doi":"10.1111/j.1423-0410.1999.tb00006.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00006.x","url":null,"abstract":"The domain specificity of anti‐factor VIII (FVIII) inhibitor antibodies was determined in assays using FVIII domains generated by thrombin cleavage or expressed as recombinant polypeptides to neutralise the inhibitor. The results revealed the existence of three major types of inhibitors, and various combinations of these antibodies were found in haemophilic and autoantibody patients. Anti‐A2 domain inhibitors prevent normal function of the FVIII/factor IXa (FIXa)/phospholipid complex in an unknown manner. Binding of FVIII to phospholipid and to von Willebrand factor is blocked by anti‐C2 domain antibodies, and the binding of FVIII to FIXa is prevented by anti‐A3 domain antibodies. A rare type of inhibitor prevents release of activated FVIII from von Willebrand factor (vWf), and another probably interferes with FVIII binding to factor X (FX) because it shares the epitope of a monoclonal antibody with this property.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00002.x
Wolfhart Kreuz, Carmen Escuriola‐Ettingshausen, Inmaculada Martinez‐Saguer, Monika Kaiml, Bernhard Kornhuber
{"title":"Epidemiology of Inhibitor Development in Haemophilia A Patients Treated with Virus‐Inactivated Plasma‐Derived Clotting Factor Concentrates","authors":"Wolfhart Kreuz, Carmen Escuriola‐Ettingshausen, Inmaculada Martinez‐Saguer, Monika Kaiml, Bernhard Kornhuber","doi":"10.1111/j.1423-0410.1999.tb00002.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00002.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00014.x
Carol K. Kasper
{"title":"Human Factor VIII for Bleeding in Patients with Inhibitors","authors":"Carol K. Kasper","doi":"10.1111/j.1423-0410.1999.tb00014.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00014.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00020.x
Peter L. Turecek, Katalin Varadi, Herbert Gritsch, Wilfried Auer, Ludwig Pichler, Gerald Eder, Hans Peter Schwarz
A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high‐titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)‐deficient dog and controlled bleeding in rabbits with antibody‐induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.
一种由活化的 X 因子（FX）（酶）和凝血酶原（底物）组成的复合物被配制出来，这两种复合物都是从人血浆中高度纯化并经病毒灭活的，并在生物化学和动物实验中进行了表征，被命名为部分凝血酶原酶（PPT）。在体外，PPT 能缩短高滴度人类因子 VIII（FVIII）抑制剂血浆的凝血时间，其方式与活化凝血酶原复合物浓缩物 FEIBA 相似，并能触发存在因子 V（FV）的血浆样本的凝血。在黑猩猩和狒狒体内，PPT 激活凝血的能力与 FEIBA 相当。此外，PPT 还能触发缺乏 von Willebrand 因子（vWF）的狗体内的凝血过程，并控制抗体诱发的 A 型血友病兔子的出血。
{"title":"Factor Xa and Prothrombin: Mechanism of Action of FEIBA","authors":"Peter L. Turecek, Katalin Varadi, Herbert Gritsch, Wilfried Auer, Ludwig Pichler, Gerald Eder, Hans Peter Schwarz","doi":"10.1111/j.1423-0410.1999.tb00020.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00020.x","url":null,"abstract":"A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high‐titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)‐deficient dog and controlled bleeding in rabbits with antibody‐induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00009.x
H. Lenk, Study Group of German Haemophilia Centres
{"title":"The German National Immune Tolerance Registry, 1997 Update","authors":"H. Lenk, Study Group of German Haemophilia Centres","doi":"10.1111/j.1423-0410.1999.tb00009.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00009.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00024.x
Djuro Josić, Andrea Buchacher, Christoph Kannicht, Yow‐Pin Lim, Klemens Löster, Katharina Pock, Stephen Robinson, Horst Schwinn, Monika Stadler
The biochemical and immunochemical aspects of the development of inhibitors with a plasma‐derived, double‐virus inactivated factor VIII (FVIII) concentrate (marketed as Octavi SDPlus in Germany and Bisinact in Belgium) are described. A total of 12 cases of inhibitor formation (predominantly type II) were reported in Germany, 8 in Belgium but none in Portugal. Initially, the only difference between the non‐pasteurised, SD virus‐inactivated product Octavi and the pasteurised product Octavi SDPlus appeared to be pasteurisation, though subsequently, the quality of source material for the product was found to differ in different countries. Separation studies revealed the presence of a 40 kDa peptide fragment in some batches. It was subsequently shown that there was a strong correlation between inhibitor development and batches containing the 40 kDa marker, and a relationship between elevated markers of coagulation activation (FPA in particular) and the occurrence of the 40 kDa marker. Further work revealed that analytical methods commonly used for quality control were not suitable to highlight batch‐to‐batch differences. It was concluded that inhibitor potential (neoantigenicity) in Octavi SDPlus arose due to two effects; degradation of FVIII already present in source material; and heating of unstable FVIII degradation products. In this case, inhibitors were not caused by the overall production process, nor by GMP failures. The problem of inhibitor potential can be avoided if appropriate preventive measures are taken. Further work is needed to prove non‐neoantigenicity and to reinforce the scientific findings, and to characterise pilot batches.
{"title":"Degradation Products of Factor VIII Which Can Lead to Increased Immunogenicity","authors":"Djuro Josić, Andrea Buchacher, Christoph Kannicht, Yow‐Pin Lim, Klemens Löster, Katharina Pock, Stephen Robinson, Horst Schwinn, Monika Stadler","doi":"10.1111/j.1423-0410.1999.tb00024.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00024.x","url":null,"abstract":"The biochemical and immunochemical aspects of the development of inhibitors with a plasma‐derived, double‐virus inactivated factor VIII (FVIII) concentrate (marketed as Octavi SDPlus in Germany and Bisinact in Belgium) are described. A total of 12 cases of inhibitor formation (predominantly type II) were reported in Germany, 8 in Belgium but none in Portugal. Initially, the only difference between the non‐pasteurised, SD virus‐inactivated product Octavi and the pasteurised product Octavi SDPlus appeared to be pasteurisation, though subsequently, the quality of source material for the product was found to differ in different countries. Separation studies revealed the presence of a 40 kDa peptide fragment in some batches. It was subsequently shown that there was a strong correlation between inhibitor development and batches containing the 40 kDa marker, and a relationship between elevated markers of coagulation activation (FPA in particular) and the occurrence of the 40 kDa marker. Further work revealed that analytical methods commonly used for quality control were not suitable to highlight batch‐to‐batch differences. It was concluded that inhibitor potential (neoantigenicity) in Octavi SDPlus arose due to two effects; degradation of FVIII already present in source material; and heating of unstable FVIII degradation products. In this case, inhibitors were not caused by the overall production process, nor by GMP failures. The problem of inhibitor potential can be avoided if appropriate preventive measures are taken. Further work is needed to prove non‐neoantigenicity and to reinforce the scientific findings, and to characterise pilot batches.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00022.x
U. Budde, E. Drewke
{"title":"Measuring of Factor VIII Inhibitors according to the Bethesda Method in Patients with Product‐Related Inhibitors in Comparison to Non‐Product Related Inhibitors","authors":"U. Budde, E. Drewke","doi":"10.1111/j.1423-0410.1999.tb00022.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00022.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00023.x
M. Bartheis, M. Kraus, U. Bohn, B. Liese, M. von Depka, R. Eisert, A. Ganser
{"title":"Factor VIII Inhibitor‐Tests Could Be Less Sensitive Than Supposed","authors":"M. Bartheis, M. Kraus, U. Bohn, B. Liese, M. von Depka, R. Eisert, A. Ganser","doi":"10.1111/j.1423-0410.1999.tb00023.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00023.x","url":null,"abstract":"","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-13DOI: 10.1111/j.1423-0410.1999.tb00019.x
Indira Warrier
Prevalence of FIX inhibitor is ten times lower than factor VIII inhibitor. FIX inhibitor patients pose major challenges for treatment because of the simultaneous occurrence of severe allergy to FIX at the time of inhibitor development. Immune tolerance induction in haemophilia B inhibitor patients with allergy to FIX is complicated due to the development of nephrotic syndrome. Moreover, response to ITI usually is poor.
FIX 抑制剂的发病率比因子 VIII 抑制剂低十倍。FIX 抑制剂患者的治疗面临重大挑战，因为他们在研制抑制剂时同时对 FIX 严重过敏。对 FIX 过敏的血友病 B 抑制剂患者的免疫耐受诱导会因肾病综合征的发生而变得复杂。此外，对 ITI 的反应通常很差。
{"title":"Factor IX Antibody and Immune Tolerance","authors":"Indira Warrier","doi":"10.1111/j.1423-0410.1999.tb00019.x","DOIUrl":"https://doi.org/10.1111/j.1423-0410.1999.tb00019.x","url":null,"abstract":"Prevalence of FIX inhibitor is ten times lower than factor VIII inhibitor. FIX inhibitor patients pose major challenges for treatment because of the simultaneous occurrence of severe allergy to FIX at the time of inhibitor development. Immune tolerance induction in haemophilia B inhibitor patients with allergy to FIX is complicated due to the development of nephrotic syndrome. Moreover, response to ITI usually is poor.","PeriodicalId":23631,"journal":{"name":"Vox Sanguinis","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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