Warrier I, Lusher J M
Children's Hospital of Michigan, Detroit 48201, USA.
Blood Coagul Fibrinolysis. 1998 Mar;9 Suppl 1:S125-8.
The development of inhibitor antibody is a serious complication of haemophilia in young children. The incidence of factor IX (FIX) inhibitors in haemophilia B patients is five- to 10-times less common (1.5-3%) than the incidence of FVIII inhibitors in haemophilia A (15-30%). Inhibitors are commonly associated with the total absence of FIX antigen due to total deletions or other major derangements of the FIX gene. Unlike those with haemophilia A, patients with haemophilia B often experience anaphylactic reactions to FIX concentrates at the time of inhibitor development. Although the reasons for anaphylaxis at the time of inhibitor development are not yet clear, several hypotheses can be considered. One relates to the smaller molecular size of FIX compared with FVIII. With a molecular size of 55000, FIX diffuses into extravascular spaces more readily. Secondly, since the normal plasma FIX concentration is much higher compared with FVIII (5 microg/ml versus 0.1 microg/ml), haemophilia B patients are exposed to higher amounts of exogenous protein when a standard dose of 40-80 units/kg FIX is used. The routine exposure of haemophilia B patients to such large amounts of exogenous protein without any endogenous FIX antigen may contribute to the development of hypersensitivity. A third reason to consider is the absence of tolerance. Whether the lack of tolerance is due to the total absence of any FIX antigen or co-deletion of neighbouring genes that modulate the immune system is unknown. Management of bleeding in patients with inhibitors and anaphylaxis is complicated because the only readily available products for treatment are the FIX-containing prothrombin complex concentrates or activated prothrombin complex concentrates, the very same products that induce anaphylaxis. Recently, recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used effectively in several of these children, but in the USA rFVIIa is only available on a compassionate basis for the treatment of life- or limb-threatening bleeding. Eradication of the inhibitor by immune tolerance induction (ITI) has only been minimally successful in haemophilia B patients with inhibitors and anaphylaxis. Despite initial successful desensitization, the majority of these patients have had recurrent allergic reactions to FIX requiring administration of antihistamines and steroids. Recently, the development of nephrotic syndrome has been reported as a serious complication of ITI in these patients. Since inhibitor antibody is seen in association with complete gene deletions or major derangements of the FIX gene, it may be possible to select those patients with the highest risk for close monitoring during the early period of treatment by obtaining molecular diagnosis at the time of presentation.
抑制性抗体的产生是幼儿血友病的一种严重并发症。B型血友病患者中FIX抑制物的发生率比A型血友病中FVIII抑制物的发生率低5至10倍（1.5 - 3%），后者发生率为15 - 30%。抑制物通常与FIX抗原完全缺失有关，这是由于FIX基因完全缺失或其他主要紊乱所致。与A型血友病患者不同，B型血友病患者在抑制物产生时常常对FIX浓缩物发生过敏反应。虽然抑制物产生时发生过敏反应的原因尚不清楚，但有几种假说可供考虑。一种与FIX分子大小比FVIII小有关。FIX分子大小为55000，更容易扩散到血管外间隙。其次，由于正常血浆中FIX浓度比FVIII高得多（5微克/毫升对0.1微克/毫升），当使用40 - 80单位/千克FIX的标准剂量时，B型血友病患者接触到更高量的外源性蛋白质。B型血友病患者常规接触如此大量的外源性蛋白质而没有任何内源性FIX抗原，可能会导致超敏反应的发生。要考虑的第三个原因是缺乏耐受性。尚不清楚缺乏耐受性是由于完全没有任何FIX抗原，还是由于调节免疫系统的邻近基因共同缺失。有抑制物和过敏反应的患者出血的管理很复杂，因为唯一容易获得的治疗产品是含FIX的凝血酶原复合物浓缩物或活化的凝血酶原复合物浓缩物，而正是这些产品会引发过敏反应。最近，重组活化因子VII（rFVIIa；诺其，诺和诺德公司，丹麦 Bagsvaerd）已在一些此类儿童中有效使用，但在美国，rFVIIa仅在同情用药的基础上用于治疗危及生命或肢体的出血。通过免疫耐受诱导（ITI）根除抑制物在有抑制物和过敏反应的B型血友病患者中仅取得了极小的成功。尽管最初脱敏成功，但这些患者中的大多数对FIX反复出现过敏反应，需要使用抗组胺药和类固醇。最近，肾病综合征的发生已被报道为此类患者ITI的一种严重并发症。由于抑制性抗体与FIX基因的完全缺失或主要紊乱有关，在就诊时通过进行分子诊断，有可能挑选出风险最高的患者，以便在治疗早期进行密切监测。
