Dr. Sentot Santoso, PhD, Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University Giessen, Langhansstr. 7, 35385 Giessen, Germany, Tel.: +49 641 98541518, Fax: +49 641 98541529, E-mail:
Thromb Haemost. 2016 Aug 1;116(2):262-71. doi: 10.1160/TH15-12-0982. Epub 2016 Apr 21.
Treatment of bleeding in patients with Glanzmann's thrombasthenia (GT) can be hampered by iso-antibodies against the αIIbβ3 integrin, which cause rapid clearance of transfused donor platelets. Type 1 GT patients with a total absence of αIIbβ3 from the platelet surface are known to be susceptible to form such isoantibodies. In this study, we describe a type 1 GT patient with a missense mutation (Gly540Asn) located in the EGF3 domain of the β3 integrin subunit. Cotransfection analysis in CHO cells demonstrates total absence of αIIbβ3 from the surface, based on inappropriate αIIb maturation. The patient's serum was reactive with αIIbβ3 and αvβ3 integrins in a capture assay, when platelets and endothelial cells were used. Two specificities could be isolated from the patient's serum, anti-αIIbβ3 and anti-αvβ3 isoantibodies. Both specificities did not interfere with platelet aggregation. In contrast, isoantibodies against αvβ3, but not against αIIbβ3, were able to disturb endothelial cell adhesion onto vitronectin, triggered endothelial cell apoptosis and interfered with endothelial tube formation. This intriguing finding may explain more recently observed features of fetal/neonatal iso-immune thrombocytopenia in children from type 1 GT mothers with intracranial haemorrhage, which could be related to anti-endothelial activity of the maternal antibodies. In conclusion, we give evidence that two isoantibody entities exist in type 1 GT patients, which are unequivocally different, both in an immunological and functional sense. Further research on the clinical consequences of immunisation against αvβ3 is required, predominantly in GT patients of childbearing age.
血小板无力症（GT）患者的出血治疗可能会受到针对 αIIbβ3 整合素的同种抗体的阻碍，这些抗体导致输注的供体血小板迅速清除。已知血小板表面完全缺乏 αIIbβ3 的 1 型 GT 患者容易形成这种同种抗体。在这项研究中，我们描述了一名 1 型 GT 患者，其β3 整合素亚基的 EGF3 结构域存在错义突变（Gly540Asn）。CHO 细胞的共转染分析表明，由于 αIIb 成熟不当，αIIbβ3 完全不存在于表面。当使用血小板和内皮细胞时，患者的血清在捕获测定中与 αIIbβ3 和 αvβ3 整合素反应。可以从患者的血清中分离出两种特异性，即抗-αIIbβ3 和抗-αvβ3 同种抗体。这两种特异性都不干扰血小板聚集。相比之下，针对 αvβ3 的同种抗体，但不是针对 αIIbβ3 的同种抗体，能够干扰内皮细胞黏附到纤连蛋白上，引发内皮细胞凋亡，并干扰内皮细胞管形成。这一有趣的发现可以解释最近在 1 型 GT 母亲的颅内出血的儿童中观察到的胎儿/新生儿同种免疫性血小板减少症的更多特征，这可能与母体抗体的抗内皮活性有关。总之，我们提供了证据表明，1 型 GT 患者存在两种同种抗体实体，在免疫学和功能上都存在明显差异。需要进一步研究针对 αvβ3 的免疫接种的临床后果，主要是在 GT 患者的生育年龄。
