title: Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Considering the results of the present study, the translation of mouse studies to humans must be performed with great care.
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu Shizuoka, Japan. tiwaki@hama-med.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Iwaki
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Miyawaki
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: J
authors.initials: J
authors.lastname: Takamatsu
authors.forename: T
authors.initials: T
authors.lastname: Matsushita
authors.forename: K
authors.initials: K
authors.lastname: Umemura
authors.forename: T
authors.initials: T
authors.lastname: Urano
authors.forename: T
authors.initials: T
authors.lastname: Kojima
authors.forename: T
authors.initials: T
authors.lastname: Terao
authors.forename: N
authors.initials: N
authors.lastname: Kanayama
mesh_terms: D000818:Animals; D016638:Critical Illness; D005260:Female; D006470:Hemorrhage / Q000209:etiology*; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics; D017422:Sequence Analysis, DNA; D058258:Serpin E2 / Q000172:deficiency* / Q000235:genetics; D014162:Transfection; D014945:Wound Healing
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D058258:Serpin E2; C511869:Serpine2 protein, mouse