de Laat Bas, Eckmann Carel M, van Schagen Marlies, Meijer Alexander B, Mertens Koen, van Mourik Jan A
Department of Blood Coagulation, Diagnostic Services Sanquin, The Netherlands.
Blood Coagul Fibrinolysis. 2008 Dec;19(8):757-64. doi: 10.1097/MBC.0b013e32830f1b85.
The antiphospholipid syndrome is characterized by the occurrence of vascular thrombosis combined with the presence of antiphospholipid antibodies in plasma of patients. It has been published that antibeta2-glycoprotein I (beta2-GPI) antibodies, with lupus anticoagulant activity (LAC), highly correlate with thrombosis. Resistance related to antiphospholipid antibodies against activated protein C (APC) is one of the proposed mechanisms responsible for thrombosis. We investigated a possible correlation between a beta2-GPI-dependent LAC (titration of cardiolipin into an activated partial thromboplastin time-based assay) and increased APC resistance in a population of 22 plasma samples with LAC activity. Eleven plasma samples that displayed a beta2-GPI-dependent LAC also showed increased APC resistance. In contrast, only one of the 11 plasma samples with a beta2-GPI-independent LAC displayed increased APC resistance. In addition, a monoclonal antibeta2-GPI antibody and patient-purified immunoglobulin G (both with LAC activity) were diluted in plasma with/without protein C. Both antibodies only displayed a beta2-GPI-dependent LAC in plasma in the presence of protein C. This indicates that the principle of the beta2-GPI LAC-assay was based on increased resistance against protein C. Surface plasmon resonance analysis was used to investigate binding between APC and beta2-GPI. We observed that beta2-GPI was able to bind APC directly, especially in the presence of a monoclonal antibeta2-GPI antibody. In conclusion, our observations show a direct correlation between a major clinical symptom of antiphospholipid syndrome (thrombosis), a diagnostic assay (beta2-GPI-dependent LAC) and a potential mechanism responsible for thrombosis in the antiphospholipid syndrome (increased APC resistance).
抗磷脂综合征的特征是患者血浆中出现血管血栓形成并伴有抗磷脂抗体。已有文献报道，具有狼疮抗凝活性（LAC）的抗β2糖蛋白I（β2-GPI）抗体与血栓形成高度相关。抗磷脂抗体对活化蛋白C（APC）的抵抗是血栓形成的一种可能机制。我们在22份具有LAC活性的血浆样本中，研究了β2-GPI依赖性LAC（在基于活化部分凝血活酶时间的检测中滴定心磷脂）与APC抵抗增加之间的可能相关性。11份显示β2-GPI依赖性LAC的血浆样本也显示出APC抵抗增加。相比之下，11份具有β2-GPI非依赖性LAC的血浆样本中只有1份显示出APC抵抗增加。此外，将单克隆抗β2-GPI抗体和患者纯化的免疫球蛋白G（均具有LAC活性）在有/无蛋白C的血浆中稀释。两种抗体仅在有蛋白C存在的血浆中显示出β2-GPI依赖性LAC。这表明β2-GPI LAC检测的原理是基于对蛋白C的抵抗增加。采用表面等离子体共振分析来研究APC与β2-GPI之间的结合。我们观察到β2-GPI能够直接结合APC，尤其是在存在单克隆抗β2-GPI抗体的情况下。总之，我们的观察结果表明抗磷脂综合征的主要临床症状（血栓形成）、诊断检测（β2-GPI依赖性LAC）与抗磷脂综合征中血栓形成的潜在机制（APC抵抗增加）之间存在直接相关性。
