Sakai Yoshie, Atsumi Tatsuya, Ieko Masahiro, Amengual Olga, Furukawa Shin, Furusaki Akira, Bohgaki Miyuki, Kataoka Hiroshi, Horita Tetsuya, Yasuda Shinsuke, Koike Takao
Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Arthritis Rheum. 2009 Aug;60(8):2457-67. doi: 10.1002/art.24708.
Antibodies to prothrombin (APTs) and to beta2-glycoprotein I are the major autoantibodies responsible for lupus anticoagulant (LAC) activity. APTs comprise antibodies against prothrombin alone as well as antibodies against phosphatidylserine/prothrombin complex (anti-PS/PT), the latter being highly associated with the antiphospholipid syndrome (APS). The effect of anti-PS/PT on thrombin generation has not been elucidated, and the paradoxical effect of LAC (an anticoagulant in vitro, but a procoagulant in vivo) remains an enigma. The purpose of this study was to investigate the effects of anti-PS/PT on thrombin generation and to examine the LAC paradox.
We evaluated 36 anti-PS/PT-positive APS patients and 127 healthy subjects. Markers of in vivo thrombin/fibrin generation, including prothrombin fragment F1+2, thrombin-antithrombin III complex, soluble fibrin monomer, D-dimer, and fibrin degradation products, were measured. Mouse monoclonal anti-PS/PT antibody 231D was established, and its effects on in vitro thrombin generation were investigated by chromogenic assay.
Significantly elevated levels of markers of thrombin/fibrin generation were observed in anti-PS/PT-positive patients, regardless of the presence or absence of anticardiolipin antibodies, as compared with healthy subjects. In the presence of low concentrations of human activated factor V (FVa), monoclonal antibody 231D increased thrombin generation in a dose-dependent manner. In contrast, when high concentrations of FVa were added, monoclonal antibody 231D decreased thrombin generation. Under a constant concentration of FVa, a high concentration of human FXa enhanced the effect of 231D.
The presence of anti-PS/PT greatly correlated with increased thrombin generation in APS patients. The in vitro effects of monoclonal antibody 231D on thrombin generation are "biaxial" according to the FVa/FXa balance. These data may serve as a clue to understanding the LAC paradox and the thrombogenic properties of anti-PS/PT.
抗凝血酶原抗体（APTs）和抗β2-糖蛋白I抗体是导致狼疮抗凝物（LAC）活性的主要自身抗体。APTs包括仅针对凝血酶原的抗体以及针对磷脂酰丝氨酸/凝血酶原复合物的抗体（抗PS/PT），后者与抗磷脂综合征（APS）高度相关。抗PS/PT对凝血酶生成的影响尚未阐明，而LAC的矛盾效应（体外抗凝，体内促凝）仍然是一个谜。本研究的目的是研究抗PS/PT对凝血酶生成的影响，并探讨LAC矛盾现象。
我们评估了36例抗PS/PT阳性的APS患者和127名健康受试者。检测了体内凝血酶/纤维蛋白生成的标志物，包括凝血酶原片段F1+2、凝血酶-抗凝血酶III复合物、可溶性纤维蛋白单体、D-二聚体和纤维蛋白降解产物。制备了小鼠单克隆抗PS/PT抗体231D，并通过显色法研究其对体外凝血酶生成的影响。
与健康受试者相比，无论是否存在抗心磷脂抗体，抗PS/PT阳性患者的凝血酶/纤维蛋白生成标志物水平均显著升高。在低浓度人活化因子V（FVa）存在的情况下，单克隆抗体231D以剂量依赖的方式增加凝血酶生成。相反，当加入高浓度FVa时，单克隆抗体231D减少凝血酶生成。在FVa浓度恒定的情况下，高浓度人FXa增强了231D的作用。
抗PS/PT的存在与APS患者凝血酶生成增加密切相关。根据FVa/FXa平衡，单克隆抗体231D对凝血酶生成的体外作用是“双轴的”。这些数据可能有助于理解LAC矛盾现象以及抗PS/PT的促血栓形成特性。
