title: Plasma contact activation: a revised hypothesis.
abstract: A new hypothesis for activation of the contact system of plasma proteolysis (i.e., the plasma kallikrein/kinin system) is presented. Kininogens have a multiprotein receptor on endothelial cells which consists of at least cytokeratin 1, urokinase plasminogen activator receptor, and gC1qR. When contact proteins (high molecular weight kininogen followed by prekallikrein) assemble on the kininogen receptor on endothelial cells, an endothelial cell membrane cysteine protease is expressed to activate prekallikrein to kallikrein. On endothelial cells, prekallikrein activation is independent of factor XIIa activation. Activation of prekallikrein on endothelial cells results in kallikrein cleaving its receptor high molecular weight kininogen to liberate bradykinin. Bradykinin liberation stimulates release of tissue-type plasminogen activator from endothelial cells. Kallikrein formation also results in kinetically favorable pro-urokinase activation on endothelial cells with subsequent plasminogen activation. In addition to stimulating cellular fibrinolysis, kininogens contribute to the constitutive anticoagulant nature of the intravascular compartment. Kininogens block calpain's participation in forming the heterodimeric complex of platelet integrin alpha IIb beta 3. Kininogens also block thrombin from binding to the thrombin receptor(s) on platelets. Last, kininogens prevent thrombin from cleaving protease activated receptor 1 after arginine41. These combined data indicate a biologic system for activation of the plasma kallikrein/kinin system and physiologic consequences as result of this activation.
authors.affiliation: Department of Internal Medicine and Pathology, University of Michigan, Ann Arbor 48109-0640, USA. aschmaie@umich.edu
authors.forename: A H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D001920:Bradykinin / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism*; D004727:Endothelium / Q000737:chemistry; D005342:Fibrinolysis; D016234:Kallikrein-Kinin System; D007704:Kininogens / Q000378:metabolism*; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D010949:Plasma / Q000378:metabolism*; D011288:Prekallikrein / Q000378:metabolism; D018000:Receptors, Peptide; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007704:Kininogens; D018000:Receptors, Peptide; D011288:Prekallikrein; D017038:Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase; D013917:Thrombin; D001920:Bradykinin