Haematology Research Unit, St. George and Sutherland Clinical School, University of New South Wales, Sydney, Australia; Department of Haematology, St. George Hospital, Kogarah, New South Wales.
Haematology Research Unit, St. George and Sutherland Clinical School, University of New South Wales, Sydney.
Haematologica. 2022 Sep 1;107(9):2195-2205. doi: 10.3324/haematol.2021.279751.
Immune thrombocytopenia (ITP) is a bleeding disorder caused by dysregulated B- and T- cell functions, which lead to platelet destruction. A well-recognized mechanism of ITP pathogenesis involves anti-platelet and anti-megakaryocyte antibodies recognizing membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa. In addition to the current view of phagocytosis of the opsonised platelets by splenic and hepatic macrophages via their Fc γ receptors, antibodyinduced platelet desialylation and apoptosis have also been reported to contribute to ITP pathogenesis. Nevertheless, the relationship between the specific thrombocytopenic mechanisms and various types of anti-platelet antibodies has not been established. In order to ascertain such association, we used sera from 61 ITP patients and assessed the capacity of anti-platelet antibodies to induce neuraminidase 1 (NEU1) surface expression, RCA-1 lectin binding and loss of mitochondrial inner membrane potential on donors' platelets. Sera from ITP patients with detectable antibodies caused significant platelet desialylation and apoptosis. Anti-GPIIb/IIIa antibodies appeared more capable of causing NEU1 surface translocation while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In ITP patients with anti-GPIIb/IIIa antibodies, both desialylation and apoptosis were dependent on FcγRIIa signaling rather than platelet activation. Finally, we confirmed in a murine model of ITP that destruction of human platelets induced by anti-GPIIb/IIIa antibodies can be prevented with the NEU1 inhibitor oseltamivir. A collaborative clinical trial is warranted to investigate the utility of oseltamivir in the treatment of ITP.
免疫性血小板减少症（ITP）是一种由 B 细胞和 T 细胞功能失调引起的出血性疾病，导致血小板破坏。ITP 发病机制的一个公认机制涉及识别血小板和巨核细胞膜糖蛋白（GP）复合物的抗血小板和抗巨核细胞抗体，主要是 GPIb/IX 和 GPIIb/IIIa。除了目前认为脾脏和肝脏巨噬细胞通过其 Fcγ受体吞噬被调理的血小板外，抗体诱导的血小板去唾液酸化和凋亡也被报道有助于 ITP 的发病机制。然而，特定的血小板减少机制与各种类型的抗血小板抗体之间的关系尚未确定。为了确定这种关联，我们使用了 61 名 ITP 患者的血清，并评估了抗血小板抗体诱导神经元酶 1（NEU1）表面表达、RCA-1 凝集素结合和供体血小板线粒体内膜电位丧失的能力。可检测到抗体的 ITP 患者的血清导致明显的血小板去唾液酸化和凋亡。抗 GPIIb/IIIa 抗体似乎更能引起 NEU1 表面易位，而抗 GPIb/IX 复合物抗体导致更高程度的血小板凋亡。在具有抗 GPIIb/IIIa 抗体的 ITP 患者中，去唾液酸化和凋亡均依赖于 FcγRIIa 信号而不是血小板激活。最后，我们在 ITP 小鼠模型中证实，抗 GPIIb/IIIa 抗体诱导的人血小板破坏可以用 NEU1 抑制剂奥司他韦预防。需要进行合作临床试验以研究奥司他韦在 ITP 治疗中的效用。
