Hay C R, Ludlam C A, Colvin B T, Hill F G, Preston F E, Wasseem N, Bagnall R, Peake I R, Berntorp E, Mauser Bunschoten E P, Fijnvandraat K, Kasper C K, White G, Santagostino E
Department of Haematology, Manchester Royal Infirmary, United Kingdom.
Thromb Haemost. 1998 Apr;79(4):762-6.
Twenty six patients with mild or moderate haemophilia A and inhibitors are described. The inhibitor was detected at a median age of 33 years, after a median of 5.5 bleeding episodes. This usually following intensive replacement therapy. The median presenting inhibitor titre was antihuman 11.6 BU/ml, antiporcine 1.45 BU/ml. Plasma basal factor VIII level declined from a median of 0.08 IU/ml to 0.01 IU/ml following the inhibitor development. This caused spontaneous bleeding in 22 and a bleeding pattern similar to acquired haemophilia in 17. Bleeding was often severe and caused two deaths. The inhibitor disappeared spontaneously, or following immune tolerance induction, in 16 cases after a median of 9 months (range 0.5-46), with a return to the original baseline VIIIC level and bleeding pattern accompanied inhibitor loss. The inhibitor persisted in the remainder of the cases over a median period of 99 months (range 17-433 months) of follow-up. Inhibitors are an uncommon complication of mild haemophilia which frequently persist and may be associated with severe, life-threatening, haemorrhage. Forty-one percent of treated haemophilic family members had a history of factor VIII inhibitors, suggesting a familial predisposition to develop inhibitors in these kindreds. Sixteen patients from 11 families were genotyped. Seven different missense mutations affecting the light chain were detected and two in the A2 domain. Five patients from three families had a mutation causing a substitution of Trp2229 by Cys in the C2 domain which appears to predispose to inhibitor formation since 7 of the 18 affected individuals have a history of inhibitor development.
本文描述了26例患有轻度或中度甲型血友病且产生抑制剂的患者。抑制剂在中位年龄33岁时被检测到，此前中位出血发作次数为5.5次。这通常发生在强化替代治疗之后。出现抑制剂时的中位滴度为抗人11.6 BU/ml，抗猪1.45 BU/ml。随着抑制剂的产生，血浆基础因子VIII水平从中位值0.08 IU/ml降至0.01 IU/ml。这导致22例患者出现自发性出血，17例患者出现与获得性血友病相似的出血模式。出血往往很严重，导致2例死亡。16例患者的抑制剂在中位9个月（范围0.5 - 46个月）后自发消失或在免疫耐受诱导后消失，随着抑制剂的消失，VIII因子水平恢复到原来的基线水平，出血模式也随之改变。在其余病例中，抑制剂在中位99个月（范围17 - 433个月）的随访期内持续存在。抑制剂是轻度血友病的一种罕见并发症，常持续存在，并可能与严重的、危及生命的出血有关。41%接受治疗的血友病家族成员有因子VIII抑制剂病史，提示这些家族存在发生抑制剂的家族易感性。对来自11个家族的16例患者进行了基因分型。检测到7种影响轻链的不同错义突变，2种在A2结构域。来自3个家族的5例患者在C2结构域有一个导致Trp2229被Cys取代的突变，由于18名受影响个体中有7名有抑制剂形成史，该突变似乎易导致抑制剂形成。
