title: Severity of venous insufficiency is related to the density of microvascular deposition of PAI-1, uPA and von Willebrand factor.
abstract: BACKGROUND
  Impaired microcirculation in chronic venous insufficiency leads to chronic inflammation and dystrophic changes of the skin, and finally to leg ulceration. The purpose of this study was to investigate in more detail coagulation and fibrinolytic protein response of the capillaries in skin biopsies of the lower extremity.
  
  
  METHODS
  From eighteen ambulant patients with venous leg ulcer(s) (n = 8) and controls (n = 10) with various degrees of venous insufficiency according to the CEAP classification, we obtained 4 mm punch biopsies. Immunohistochemical staining with tissue derived plasminogen activator (tPA), urokinase derived plasminogen activator (uPA), plasminogen activator inhibitor (PAI-1) and von Willebrand Factor (vWF) was performed and analyzed with bright field microscopy.
  
  
  RESULTS
  The amount of staining with vWF (p = 0.04) and uPA (p = 0.02) showed statistically significant differences, PAI-1 (p = 0.09) and tPA (p = 0.50) showed no difference between leg ulcer and control groups. A strong proliferation of capillaries with tortuous capillary loops in the papillary dermis was seen, but no statistically significant difference (M-W test, p = 0.10) was found between the groups. Comparison between CEAP classes 0-6 showed a statistically significant increased staining pattern of vWF (p = 0.06), uPA (p = 0.02) and PAI-1 (p = 0.02), but not from tPA (p = 0.30).
  
  
  CONCLUSIONS
  In skin biopsies of the lower extremity of patients with severe venous insufficiency increased deposition of vWF, PAI-1 and uPA were found in the capillaries. These findings point to a local imbalance in coagulation and fibrinolytic status, which might contribute to impaired microcirculation and finally to the development of venous leg ulceration.
authors.affiliation: Departments of Dermatology, Clinical Epidemiology and Medical Technology Assessment, Academic Hospital Maastricht, The Netherlands. dinanda.kolbach@epid.unimaas.nl
authors.forename: D N
authors.initials: DN
authors.lastname: Kolbach
authors.forename: K
authors.initials: K
authors.lastname: Hamulyák
authors.forename: M H
authors.initials: MH
authors.lastname: Prins
authors.forename: H A
authors.initials: HA
authors.lastname: Neumann
authors.forename: J P
authors.initials: JP
authors.lastname: Cleutjens
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D002196:Capillaries / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007866:Leg / Q000098:blood supply; D008297:Male; D008833:Microcirculation / Q000473:pathology; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012016:Reference Values; D012867:Skin / Q000098:blood supply*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D014647:Varicose Ulcer / Q000473:pathology; D014689:Venous Insufficiency / Q000473:pathology*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014841:von Willebrand Factor; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator