Dahlbäck B
Department of Clinical Chemistry, University of Lund, Malmö General Hospital, Sweden.
Haemostasis. 1994 Mar-Apr;24(2):139-51. doi: 10.1159/000217094.
Our laboratory recently found a novel mechanism for thrombophilia, which is characterized by an inherited resistance to activated protein C (APC). The APC-resistance test, which measures the anticoagulant response to APC in an activated partial thromboplasin time (APTT) reaction, was devised and used to screen a cohort of consecutive thrombosis patients. APC-resistance was found in approximately 40% of the cases. Other known causes for thrombosis, such as deficiencies of protein C, protein S or antithrombin, were found in another 5% of the patients. Our results, which have recently been confirmed from other laboratories, suggest APC-resistance to be highly prevalent in thrombosis patients. In a majority of cases, APC-resistance was demonstrated to be inherited and family studies revealed an autosomal dominant mode of inheritance. In the investigated families, APC-resistance was associated with thrombosis, which suggests a causal relationship between APC-resistance and thrombosis. An anticoagulant cofactor activity, which corrected APC-resistance, was found in normal plasma, whereas plasma from an individual with pronounced APC-resistance was devoid of this activity. Purification and characterization of the novel APC-cofactor suprisingly revealed that it was identical to coagulation factor V. Thus, factor V is not only an important procoagulant, but also expresses anticoagulant properties as a cofactor to APC. Our present data suggest the anticoagulant function to be a property of unactivated factor V, whereas the procoagulant activity is expressed after activation to Va. APC-resistant individuals have normal levels of procoagulant V-activity, it is now known that APC-resistance is caused by mutation in the factor V gene changing arginine 506 to a glutamine, thus affecting the APC-cleavage site.
我们实验室最近发现了一种血栓形成倾向的新机制，其特征是对活化蛋白C（APC）存在遗传性抵抗。设计了APC抵抗试验，该试验在活化部分凝血活酶时间（APTT）反应中测量对APC的抗凝反应，并用于筛查一组连续的血栓形成患者。约40%的病例中发现了APC抵抗。另外5%的患者中发现了其他已知的血栓形成原因，如蛋白C、蛋白S或抗凝血酶缺乏。我们的结果最近已得到其他实验室的证实，表明APC抵抗在血栓形成患者中非常普遍。在大多数病例中，APC抵抗被证明是遗传性的，家族研究揭示了常染色体显性遗传模式。在被调查的家族中，APC抵抗与血栓形成相关，这表明APC抵抗与血栓形成之间存在因果关系。在正常血浆中发现了一种可纠正APC抵抗的抗凝辅助因子活性，而来自具有明显APC抵抗的个体的血浆则缺乏这种活性。新型APC辅助因子的纯化和特性鉴定令人惊讶地发现它与凝血因子V相同。因此，因子V不仅是一种重要的促凝血剂，而且作为APC的辅助因子还具有抗凝特性。我们目前的数据表明抗凝功能是未活化因子V的一种特性，而促凝血活性在活化成Va后才表现出来。APC抵抗个体的促凝血V活性水平正常，现在已知APC抵抗是由因子V基因中的突变引起的，该突变将精氨酸506变为谷氨酰胺，从而影响APC切割位点。
