Hoylaerts M F, Thys C, Arnout J, Vermylen J
Center for Molecular and Vascular Biology, Katholieke Universtiteit Leuven, Leuven, Belgium.
Blood. 1998 Apr 15;91(8):2810-7.
A patient with a history of recurrent late fetal loss associated with multiple placental infarcts and cerebrovascular ischemia at the age of 36, followed a year later by a myocardial infarction, was referred for further investigation. Coronary angiography was normal. Antinuclear factor, lupus anticoagulant, anticardiolipin antibodies, and other thrombophilia parameters were negative, but there was moderate hyperthyroidism with positive thyroid peroxidase antibodies. Platelet numbers and von Willebrand factor (vWF) were normal. Her platelets showed spontaneous aggregation that disappeared with aspirin intake. However, aggregation still was induced by low levels of ristocetin (0.3 to 0.5 mg/mL). The low-dose ristocetin aggregation in patient platelet-rich plasma (PRP) was completely blocked by neutralizing antiglycoprotein Ib (GPIb) and anti-vWF antibodies. The monoclonal anti-Fc gamma RII receptor antibody IV.3 inhibited partly, which suggests that PRP aggregation by low-dose ristocetin was elicited by vWF-immunoglobulin (Ig) complexes. Upon addition to washed human platelets, with vWF (10 micrograms/mL), purified patient Igs dose-dependently enhanced ristocetin (0.15 mg/mL)-induced aggregation between 0 and 500 micrograms/mL, an effect that disappeared again above 1 mg/mL. Aggregation was dependent on the vWF concentration and was blocked by IV.3 or neutralizing anti-GPIb or anti-vWF antibodies. The spontaneous aggregation of normal platelets resuspended in patient plasma could be inhibited totally by IV.3 and partially by neutralizing anti-GPIb or anti-vWF antibodies. Perfusion with normal anticoagulated blood, enriched with 10% of control or patient plasma, over surfaces coated with vWF showed increased platelet adhesion and activation in the presence of patient antibodies. Treatment of the patient with the antithyroid drug thiamazol and temporary corticosteroids, aspirin, and ticlopidine did not correct the platelet hypersensitivity to ristocetin. These observations suggest that some autoantibodies to vWF may both enhance vWF binding to platelets and cause platelet activation through binding to the Fc gamma RII receptor, and thereby may be responsible for a new form of antibody-mediated thrombosis.
一名36岁女性患者，有反复晚期胎儿丢失病史，伴有多处胎盘梗死和脑血管缺血，一年后发生心肌梗死，遂转诊进一步检查。冠状动脉造影正常。抗核因子、狼疮抗凝物、抗心磷脂抗体及其他血栓形成倾向参数均为阴性，但存在中度甲状腺功能亢进，甲状腺过氧化物酶抗体阳性。血小板计数和血管性血友病因子（vWF）正常。其血小板显示自发聚集，服用阿司匹林后消失。然而，低水平的瑞斯托霉素（0.3至0.5mg/mL）仍可诱导聚集。患者富含血小板血浆（PRP）中的低剂量瑞斯托霉素聚集被中和抗糖蛋白Ib（GPIb）和抗vWF抗体完全阻断。单克隆抗FcγRII受体抗体IV.3部分抑制，这表明低剂量瑞斯托霉素诱导的PRP聚集是由vWF-免疫球蛋白（Ig）复合物引起的。将纯化的患者Ig（0至500μg/mL）加入洗涤后的人血小板及vWF（10μg/mL）中，剂量依赖性增强瑞斯托霉素（0.15mg/mL）诱导的聚集，在1mg/mL以上此效应再次消失。聚集依赖于vWF浓度，并被IV.3或中和抗GPIb或抗vWF抗体阻断。悬浮于患者血浆中的正常血小板的自发聚集可被IV.3完全抑制，被中和抗GPIb或抗vWF抗体部分抑制。用含10%对照或患者血浆的正常抗凝血液灌注包被有vWF的表面，在存在患者抗体的情况下，血小板黏附和活化增加。用抗甲状腺药物甲巯咪唑、临时使用的皮质类固醇、阿司匹林和噻氯匹定治疗该患者，并未纠正血小板对瑞斯托霉素的超敏反应。这些观察结果表明，一些针对vWF的自身抗体可能既增强vWF与血小板的结合，又通过与FcγRII受体结合导致血小板活化，从而可能是一种新形式的抗体介导血栓形成的原因。
