title: Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis.
abstract: Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +/- 2 ml/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +/- 8%), triglyceride (45 +/- 27%), apolipoprotein B (59 +/- 10%) and PAI-1 antigen levels from 10.2 +/- 5.2 to 6.0 +/- 3.1 ng/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +/- 1.03 ng/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre-apheresis values were low may reflect a homeostatic mechanism to maintain sufficient PAI-1 levels. Procedures that could selectively remove PAI-1 from plasma may offer a treatment option for those with very high plasma PAI-1 levels and thrombosis.
authors.affiliation: Department of Cardiology, Adelaide Meath Hospital, Dublin, Ireland. vmaher@gmail.com
authors.forename: Vincent M G
authors.initials: VM
authors.lastname: Maher
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kitano
authors.forename: Clare
authors.initials: C
authors.lastname: Neuwirth
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Davies
authors.forename: Attilio
authors.initials: A
authors.lastname: Maseri
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Thompson
authors.forename: Felicita
authors.initials: F
authors.lastname: Andreotti
mesh_terms: D000328:Adult; D001781:Blood Component Removal; D008078:Cholesterol, LDL / Q000302:isolation & purification; D003324:Coronary Artery Disease / Q000628:therapy*; D016264:Dextran Sulfate / Q000627:therapeutic use; D005260:Female; D006706:Homeostasis; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000302:isolation & purification
chemical_list: D008078:Cholesterol, LDL; D017395:Plasminogen Activator Inhibitor 1; D016264:Dextran Sulfate