Oosting J D, Derksen R H, Bobbink I W, Hackeng T M, Bouma B N, de Groot P G
Department of Haematology, University Hospital Utrecht, The Netherlands.
Blood. 1993 May 15;81(10):2618-25.
Despite many studies on the pathophysiology of antiphospholipid antibodies (aPL), the mechanism by which aPL causes thrombosis has not been established. We have tried to elucidate the paradox between the prolongation of the clotting time of phospholipid-dependent coagulation tests in vitro and the occurrence of thrombosis in vivo. The effect on endothelial cell-mediated prothrombinase activity of 30 IgG fractions, of which 22 prolong the aPTT of normal plasma, was investigated. Only 4 of 22 fractions (18%) inhibited prothrombinase activity when tested on this more physiologic phospholipid surface, indicating that in most patients with aPL the prolongation of clotting tests is predominantly as in vitro phenomenon. It was recently reported that in detection methods for aPL, two plasma proteins, beta 2-glycoprotein I and prothrombin, enhance the binding of aPL to phospholipids. We have studied the specificity of the 4 IgG fractions that inhibit the prothrombinase activity and found that they were directed against a combination of phospholipids and prothrombin. However, the involvement of prothrombin in binding of aPL leading to impaired thrombin generation could still result in both a bleeding and a thrombotic tendency. Therefore, we proposed a new thrombogenic mechanism for aPL in which aPL bind to complexes of phospholipids and coagulation proteins, thereby interfering in different coagulation reactions. We tested this new hypothesis by investigating the effect of IgG from the same 30 patients on the activated protein C (APC)-mediated factor Va inactivation in the absence and presence of protein S. Three IgGs that inhibited APC-mediated factor Va inactivation independent of protein S and 4 additional IgGs that inhibited in the presence of protein S were found. Furthermore, we could specifically adsorb the inhibitory IgG with cardiolipin vesicles to which APC with or without protein S was bound. In conclusion, these results suggest that subpopulations of aPL exist that are directed to complexes of phospholipids and different plasma proteins. The identity of the plasma proteins involved in the binding of aPL might determine which pathogenic mechanism causes thrombosis.
尽管针对抗磷脂抗体（aPL）的病理生理学进行了许多研究，但aPL导致血栓形成的机制尚未明确。我们试图阐明体外磷脂依赖性凝血试验凝血时间延长与体内血栓形成之间的矛盾。研究了30种IgG组分对内皮细胞介导的凝血酶原酶活性的影响，其中22种可延长正常血浆的活化部分凝血活酶时间（aPTT）。在这种更接近生理状态的磷脂表面进行检测时，22种组分中只有4种（18%）抑制了凝血酶原酶活性，这表明在大多数aPL患者中，凝血试验延长主要是一种体外现象。最近有报道称，在aPL的检测方法中，两种血浆蛋白，即β2-糖蛋白I和凝血酶原，可增强aPL与磷脂的结合。我们研究了4种抑制凝血酶原酶活性的IgG组分的特异性，发现它们针对的是磷脂和凝血酶原的组合。然而，凝血酶原参与aPL结合导致凝血酶生成受损，仍可能导致出血倾向和血栓形成倾向。因此，我们提出了一种aPL新的致血栓形成机制，即aPL与磷脂和凝血蛋白的复合物结合，从而干扰不同的凝血反应。我们通过研究来自同一30名患者的IgG在有无蛋白S存在的情况下对活化蛋白C（APC）介导的因子Va失活的影响，来验证这一新假设。发现了3种不依赖蛋白S抑制APC介导的因子Va失活的IgG和另外4种在有蛋白S存在时抑制的IgG。此外，我们可以用结合有或没有蛋白S的APC的心磷脂囊泡特异性吸附抑制性IgG。总之，这些结果表明存在针对磷脂和不同血浆蛋白复合物的aPL亚群。参与aPL结合的血浆蛋白的特性可能决定哪种致病机制导致血栓形成。
