title: Effect of nafamostat mesilate on bradykinin generation during low-density lipoprotein apheresis using a dextran sulfate cellulose column.
abstract: The dextran sulfate (DS) cellulose column usually used for low-density lipoprotein (LDL) apheresis, is an activator of the contact phase of intrinsic coagulation pathway. Hageman factor (factor XII), high-molecular-weight kininogen (HMWK) and prekallikrein (PK) form a complex on the surface of this activator, and bradykinin is released from HMWK by the action of kallikrein converted from PK. Heparin, a frequently used anticoagulant, has no effect on this process, whereas a protease inhibitor, nafamostat mesilate (FUT-175) is thought to inhibit the process. Five patients with severe hypercholesterolemia were treated with LDL apheresis using heparin or FUT-175, each on a different day. During treatment with heparin, factor XII, HMWK, and PK were markedly decreased by passing through the DS column. A distinct generation of bradykinin was observed by passing through the DS column, which led to an increase of blood bradykinin levels from 12.5 +/- 5.3(Mean +/- SEM) pg/ml to 127.3 +/- 67.1 pg/ml after 1000 ml plasma treatment. FUT-175 almost completely suppressed this bradykinin generation. Because bradykinin generated during LDL apheresis seems to have some vasodilative effect, FUT-175 might be preferred in cases with unstable hemodynamics, although this presumption remains to be demonstrated.
authors.affiliation: Department of Medicine, National Cardiovascular Center Hospital, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kojima
authors.forename: M
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: S
authors.initials: S
authors.lastname: Nomura
authors.forename: G
authors.initials: G
authors.lastname: Kimura
authors.forename: M
authors.initials: M
authors.lastname: Tsushima
authors.forename: M
authors.initials: M
authors.lastname: Kuramochi
authors.forename: A
authors.initials: A
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Omae
mesh_terms: D000328:Adult; D001550:Benzamidines; D001781:Blood Component Removal / Q000379:methods*; D001920:Bradykinin / Q000378:metabolism*; D016264:Dextran Sulfate; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000628:therapy*; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D001550:Benzamidines; D006146:Guanidines; D008077:Lipoproteins, LDL; D015842:Serine Proteinase Inhibitors; D006493:Heparin; D016264:Dextran Sulfate; D001920:Bradykinin; C032855:nafamostat