Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu Shizuoka, Japan.
J Thromb Haemost. 2011 Jun;9(6):1200-6. doi: 10.1111/j.1538-7836.2011.04288.x.
Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological regulator of urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) activity. A number of studies have shown that elevated levels of PAI-1 are related to pathological states such as an increased risk of arterial thrombotic events and a poor prognosis for cancer patients; however, there are few reports about PAI-1 deficiency in humans because the disorder is very rare.
To understand the in vivo impact of a complete PAI-1 deficiency, Serpine1(-/-) mice were generated; a number of in vivo studies have been conducted to elucidate the function of PAI-1 using Serpine1(-/-) mice. The phenotypes demonstrated in Serpine1(-/-) mice, however, were quite different from those in humans. Therefore, it is necessary to find out and analyze SERPINE1 deficiency in humans.
The patient is a 47-year-old woman who has had multiple episodes of major bleeding. Although most of the patient's blood coagulation factors were functionally normal, her PAI-1 antigen levels were undetectable. Therefore, DNA sequencing of the SERPINE1 gene were analyzed.
The proband had a homozygous 1-bp duplication (C) at exon 3 (c.356dupC; p.Ile120AspfsX42). Both wild-type PAI-1 (42.7 kDa) and mutated (Mut) PAI-1 (14.7kDa) were expressed in COS-1 cells, although the level of Mut PAI-1 expressed in the cell lysates was much lower. Wild-type PAI-1 was observed in the culture supernatant, whereas no Mut PAI-1 was detected in the supernatant.
Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.
纤溶酶原激活物抑制剂-1（PAI-1）是尿激酶型纤溶酶原激活物（uPA）和组织型纤溶酶原激活物（tPA）活性的主要生理调节剂。许多研究表明，PAI-1 水平升高与动脉血栓事件风险增加和癌症患者预后不良等病理状态有关；然而，由于该疾病非常罕见，因此关于人类 PAI-1 缺乏症的报道很少。
为了了解完全缺乏 PAI-1 的体内影响，生成了 Serpine1（-/-）小鼠；已经进行了许多体内研究，以使用 Serpine1（-/-）小鼠阐明 PAI-1 的功能。然而，Serpine1（-/-）小鼠表现出的表型与人类非常不同。因此，有必要在人类中发现并分析 SERPINE1 缺乏症。
患者是一名 47 岁女性，曾多次发生大出血。尽管患者的大多数凝血因子功能正常，但她的 PAI-1 抗原水平无法检测到。因此，分析了 SERPINE1 基因的 DNA 测序。
先证者在第 3 外显子（c.356dupC；p.Ile120AspfsX42）中存在纯合 1 个碱基重复（C）。野生型 PAI-1（42.7 kDa）和突变型（Mut）PAI-1（14.7 kDa）均在 COS-1 细胞中表达，尽管细胞裂解物中表达的 Mut PAI-1 水平要低得多。在培养上清液中观察到野生型 PAI-1，而在上清液中未检测到 Mut PAI-1。
考虑到本研究的结果，必须非常谨慎地将小鼠研究转化为人类研究。
