Jankun Jerzy, Skrzypczak-Jankun Ewa
Urology Research Center, The University of Toledo, 3000 Arlington, Toledo, Ohio, Canada.
Cardiovasc Hematol Disord Drug Targets. 2013 Aug;13(2):144-50. doi: 10.2174/1871529x11313020007.
This review summarizes our current knowledge of plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition. PAI-1 is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). PAI-1 controls/slows clot lysis triggered by tPA activated plasminogen. PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged bleeding episodes. PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the PAI-1 gene that produce a dysfunctional PAI-1 protein or slow the secretion of PAI-1 into the circulation. PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent bleeding episodes. Patients with this condition form normal blood clots that are quickly lysed by unopposed tPA-activated plasmin. Spontaneous bleeding is rare in PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild trauma. Additionally, prolonged bleeding after surgery is common and menstrual bleeding may be severe. Moderate PAI-1 deficiency is associated with a lifelong bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of PAI-1 deficiency as well as a lack of standardized tests. Patients with mild PAI-1 deficiency may be treated with antifibrinolytic agents (ε-aminocaproic acid or tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use PAI-1 with an extended half-life to treat these patients.
本综述总结了我们目前对纤溶酶原激活物抑制剂（PAI-1）缺乏症的认识，并提出了针对这种情况的一些新治疗方法。PAI-1是组织型和尿激酶型纤溶酶原激活物（tPA和uPA）的快速作用抑制剂。PAI-1控制/减缓由tPA激活的纤溶酶原引发的血凝块溶解。PAI-1缺乏症曾被认为是一种极其罕见的疾病，其特征是频繁且长期的出血发作。现在认为PAI-1缺乏症比最初报道的更为常见，已知是由PAI-1基因突变引起的，这些突变会产生功能失调的PAI-1蛋白或减缓PAI-1分泌到循环系统中。PAI-1缺乏症的特征是纤维蛋白溶解亢进，导致频繁出血发作。患有这种疾病的患者形成正常的血凝块，但会被未受抑制的tPA激活的纤溶酶迅速溶解。PAI-1缺乏症患者很少出现自发性出血，但轻微创伤可引发膝盖、肘部、鼻子和牙龈的中度出血。此外，手术后出血时间延长很常见，月经出血可能很严重。中度PAI-1缺乏症与终身出血倾向相关，但严重缺乏可能危及生命。由于缺乏PAI-1缺乏症的明确定义以及缺乏标准化检测，这种疾病的诊断仍然具有挑战性。轻度PAI-1缺乏症患者可用抗纤维蛋白溶解剂（ε-氨基己酸或氨甲环酸）治疗；然而，并非所有患者对这些治疗都有良好反应。这些患者可用野生型PAI-1治疗；然而，这种分子会迅速转化为其无活性形式。我们建议使用半衰期延长的PAI-1来治疗这些患者。
