Shibata S, Harpel P C, Gharavi A, Rand J, Fillit H
Department of Geriatrics, Mount Sinai Medical Center, New York, NY 10029.
Blood. 1994 May 1;83(9):2532-40.
The antiphospholipid antibody syndrome (APS) is characteristically associated with thrombosis. Heparan sulfate (HS) is a physiologic endothelial cell surface modulator of normal anticoagulation, containing a specific oligosaccharide sequence that binds antithrombin III with high affinity and also is present in heparin, a related glycosaminoglycan. We hypothesized that a subset of antiphospholipid antibodies with high affinity for heparan sulfate/heparin epitopes may inhibit the function of HS, promoting a procoagulant state. Purified IgG from all seven patients with APS studied were reactive with heparin by enzyme-linked immunosorbent assay, whereas none of five controls had antiheparin reactivity. IgG antiheparin antibodies were purified from two APS patients by affinity chromatography on heparin-Sepharose. Specificity studies showed that low-affinity electrostatic interactions clearly did not account for the observed reactivity with heparin, and that APS IgG antiheparin antibodies were specifically reactive with a disaccharide present in the heparin pentasaccharide that binds antithrombin III. Furthermore, APS IgG antiheparin antibodies inhibited heparin-accelerated formation of antithrombin III-thrombin complexes. We conclude that antiheparan sulfate/heparin antibodies may be a cause of autoimmune vascular thrombosis in the antiphospholipid antibody syndrome.
抗磷脂抗体综合征（APS）的典型特征是与血栓形成相关。硫酸乙酰肝素（HS）是正常抗凝过程中的一种生理性内皮细胞表面调节剂，它含有一种特定的寡糖序列，能与抗凝血酶III高亲和力结合，并且也存在于肝素（一种相关的糖胺聚糖）中。我们推测，对硫酸乙酰肝素/肝素表位具有高亲和力的一部分抗磷脂抗体可能会抑制HS的功能，从而促进促凝状态。通过酶联免疫吸附测定法，研究的所有7例APS患者的纯化IgG均与肝素发生反应，而5例对照者均无抗肝素反应性。通过肝素-琼脂糖亲和层析从2例APS患者中纯化出IgG抗肝素抗体。特异性研究表明，低亲和力的静电相互作用显然不能解释所观察到的与肝素的反应性，并且APS IgG抗肝素抗体与肝素五糖中存在的一种与抗凝血酶III结合的二糖具有特异性反应。此外，APS IgG抗肝素抗体抑制了肝素加速的抗凝血酶III-凝血酶复合物的形成。我们得出结论，抗硫酸乙酰肝素/肝素抗体可能是抗磷脂抗体综合征中自身免疫性血管血栓形成的一个原因。
