Autoimmune Factor VIII Inhibitor Responsive to Gammaglobulin without In Vitro Neutralisation
Autoimmune Factor VIII Inhibitor Responsive to Gammaglobulin without In Vitro Neutralisation
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自身免疫因子 VIII 抑制剂对丙种球蛋白有反应，无需体外中和
DOI：
10.1055/s-0038-1647059
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发表时间：
1988
影响因子：
6.7
通讯作者：
L. Penalva
中科院分区：
文献类型：
--
作者：
L. Carreras;G. Pérez;D. Xavier;A. Blanco;L. Penalva
苏丹等人（1）报道了使用促凝血因子VIII（FVIII：C）的获得性抑制剂，通过静脉注射合并人免疫球蛋白成功治疗口服皮质类固醇无效的非血友病患者。从那时起，文献中出现了一些病例报告，证实了这种新的治疗方法在自身抗体患者中的疗效，但在FVIII同种抗体患者中无效（2，3，4）。我们研究了一个自发性FVIII抑制剂的患者，该患者在静脉注射免疫球蛋白（IVIg）治疗后显示出令人满意的临床进展。病例报告一位61岁女性因皮肤粘膜出血和黑便而入院。她一直很好，直到5年前，当她提出了黄疸解释为肝炎的病因不明。两年后，进行腹腔镜肝活检，显示慢性肝炎演变为肝硬化。第二年，诊断为继发于脾功能亢进的全血细胞减少症。入院前6个月，她出现腹水。B型肝炎病毒标志物（HBsAg和抗HBc）调查均为阴性。1986年12月，她被转诊到我院。在检查中，患者显示四肢和臀部有大面积血肿扩散;她还出现血尿和黑便。进行了上消化道纤维检查，发现存在食管静脉曲张，无出血证据，以及消化性溃疡出血。凝血试验显示血小板减少症、凝血酶原复合物缺乏和延长的APTT在与正常血浆以1：1比例混合后未得到纠正（P：160秒; N：43秒; PA。{：79秒）。FVIII水平小于0.01 U/ml。诊断为FVIII抑制剂，滴度为356 Bethesda单位（5）。患者口服甲基强的松治疗，剂量为1 mg/kg，持续3周，无反应。她还根据需要接受血小板输注、新鲜冷冻血浆和凝血酶原复合物（Prothromblex @，Immuno，维也纳）。用最终浓度从0.25增加到20 mg/ml（最终浓度：0.25、0.5、1、2.5、5、10和20 mg/ml）的市售混合人免疫球蛋白（Endobulin，Immuno，维也纳）在37 ℃孵育60分钟后或在4 ℃孵育过夜后进行体外中和试验。在患者血浆与缓冲液或与丙种球蛋白的1：1混合物中，在测试浓度范围内进行因子VIII一阶段测定，混合物的抗体滴度显示相同的值。尽管如此，在5天内以0.4g/kg·d-1的标准剂量施用IVIg（内皮素），抑制剂的滴度显著下降至45 Bethesda单位。两周后，进行新的IVIg疗程（相同剂量的相同产品，持续2天），随后进一步降低抑制剂滴度直至抑制。在接下来的LZ月随访期间，患者保持稳定，无需额外治疗。Rossi等人（6）最近证实，从合并人血浆中制备的多特异性免疫球蛋白对FVIII：C自身抗体的抑制是通过独特型抗独特型相互作用介导的。他们已经表明，IVIg含有针对抗VIII：C自身抗体表达的独特型决定簇的抗独特型。苏丹等人（1，7）提出，对IVIg的应答取决于自身抗体上是否存在独特型异质性（公共或私人独特位）。在一些接受IVIg治疗的患者中观察到的自身抗体滴度的长期降低可能部分是由于抗独特型抑制了抗体合成（1）。关于IVIg对体外抗FVIII：C自身抗体的活性，Moffat等人（8）观察到，12种非血友病性FVIII自身抗体被完全或部分中和。另一方面，据报道，体外抗VIII：C活性的抑制可能与IVIg的体内疗效相关，并提出体外试验可预测临床应答（6）。相反，我们患者的研究结果表明，缺乏抗VIII：C活性的体外中和并不一定排除合并人IVIg的治疗效果。
Sultan et al. (1) have reported on the successful .treatment of non haemophilic patients with an acquired inhibitor to procoagulant factor VIII (FVIII : C), who failed to respond to oral corticosteroids, with the intravenous administration of pooled human immunoglobulin. A few case reports have appeared in the literature since then, confirming the efficacy of this new t[erapeutical approach in patients with autoantibodies, but not in those with alloantibodies to FVIII (2,3, 4). We have studied a patient with a spontaneous inhibitor to FVIII who showed a satisfactory clinical evolution upon treatment with intravenous immunoglobulin (IVIg). Case Report A 6l year-old woman was admitted to the hospital because of mucocutaneous bleeding and melena. She was well until 5 years ago, when she presented with ictericia interpreted as hepatitis of unknown etiology. Two years later a laparoscopic liver biopsy was performed and showed chronic hepatitis in evolution to cirrhosis. The following year the diagnosis of pancytopenia secondary to hypersplenism was made Six months before admission she presented with ascites. The investigation of viral markers for hepatitis B (HBsAg and antiHBc) was negative. In December 1986 she was referred to our hospital. On examination the patient showed large spreading hematoma on limbs and buttocks; she also had haematuria and melena. An upper gastrointestinal fiberoptic study was performed and revealed the presence of esophageal varices without evidence of bleeding, and a bleeding peptic ulcer. Coagulation tests showed thrombocytopenia, prothrombin complex deficiency and a prolonged APTT not corrected upon mixing with normal plasma in a 1:l ratio (P: 160 sec; N: 43 sec; PA.{: 79 sec). FVIII level was less than 0.01 U/ml. An inhibitor to FVIII with a titre of 356 Bethesda Units was diagnosed (5). The patient was treated with oral methylprednisone at a dose of 1 mg kg-' duy-l for 3 weeks without response. She also received platelet transfusion, fresh frozen plasma and prothrombin complex (Prothromplex@, Immuno, Vienna) as needed. In vitro neutralisation tests with commercial pooled human immunoglobulin (Endobulin@, Immuno, Vienna) at increasing final concentrations from 0.25 to 20 mg/ml (final concentration: 0.25, 0.5, l, 2.5, 5, 10 and 20 mg/ml) either at 37" C after 60 minutes or at 4" C after overnight incubation were performed. Factor VIII one stage assays on 1 : 1 mixtures of the patient's plasma, either with buffer or with gammaglobulin at the range of concentrations tested, and antibody titre of the mixtures showed the same values. Nevertheless, IVIg (Endobulin@) at the standard dose of 0.4 g kg-' duy-l was administered during 5 days, with a significant decay of the titre of the inhibitor to 45 Bethesda Units. Two weeks later a new course of IVIg (the same product at the same dose for 2 days) was performed, followed by further lowering of the inhibitor titre until its suppression. During the next LZ months of follow-up the patient has remained stable without additional therapy. Rossi et al. (6) have recently confirmed that the suppression of autoantibodies to FVIII: C by polyspecific immunoglobulins prepared from pooled human plasma is mediated through idiotypel anti-idiotype interactions. They have shown that IVIg contained anti-idiotypes directed against idiotypic determinants expressed by the anti-VIII: C autoantibodies. Sultan et al. (1, 7) have proposed that the response to IVIg depends on the presence of idiotypic heterogeneity (public or private idiotopes) on the autoantibody. The prolonged decrease in autoantibody titre observed is some patients treated with IVIg may be partly due to inhibition of antibody synthesis by anti-idiotypes (1). Regarding the activity of IVIg on anti-FVIII:C autoantibodies in vitro, Moffat et al. (8) have observed that only 3 out of. 12 non haemophilic FVIII autoantibodies were either completely or partially neutralised. On the other hand, it has been reported that the inhibition of anti-VIII:C activity in vitro may be correlated with the efficacy of IVIg in vivo, and it has been proposed that in vitro assays could be predictive of clinical response (6). In contrast, the findings in our patient suggest that the lack of in vitro neutralisation of the anti-VIII: C activity does not necessarily preclude the therapeutical efticacy of pooled human IVIg.