title: Anticoagulant and fibrinolytic activities are promoted, not retarded, in vivo after thrombin generation in the presence of a monoclonal antibody that inhibits activation of protein C.
abstract: This study examines the assumption that both the anticoagulant and fibrinolytic activity that follow the generation of thrombin induced by infusion of factor Xa/PCPS are due to generation of activated protein C. Untreated controls or animals given unrelated antibody were compared with animals pretreated with a specific monoclonal antibody to protein C (HPC4). Compared with untreated controls excess HPC4 substantially reduced the level of protein C activation as observed by protein C immunoblotting and enzyme-linked immunosorbent assay for antitrypsin/activated protein C complexes. Despite this, the anticoagulant activity as reflected by the decline of factors Va and VIIIa levels (as observed by coagulation assays and by factor V immunoblotting) was significantly greater than controls. The fibrinolytic activity (as observed by assays of tissue plasminogen activator, D-Dimer, alpha 2-antiplasmin) also was significantly greater than controls. We conclude that neutralization of the protein C anticoagulant system while resulting in a significantly more intense coagulant response to Xa/PCPS does not preclude inactivation of factors Va and VIIIa and the full expression of the fibrinolytic response. We conclude further that after thrombin generation in vivo, protein C activation is not a prerequisite for the promotion of the fibrinolytic response previously observed, and that the inactivation of factors Va/VIIIa may be mediated by enzymes other than activated protein C. The reduction in alpha 2-antiplasmin levels in association with increased tissue plasminogen activator activity suggests that plasmin is a likely candidate.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City 73104.
authors.forename: F B
authors.initials: FB
authors.lastname: Taylor
authors.forename: H
authors.initials: H
authors.lastname: Hoogendoorn
authors.forename: A C
authors.initials: AC
authors.lastname: Chang
authors.forename: G
authors.initials: G
authors.lastname: Peer
authors.forename: M E
authors.initials: ME
authors.lastname: Nesheim
authors.forename: R
authors.initials: R
authors.lastname: Catlett
authors.forename: D C
authors.initials: DC
authors.lastname: Stump
authors.forename: A R
authors.initials: AR
authors.lastname: Giles
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001777:Blood Coagulation; D002320:Cardiovascular Physiological Phenomena; D002319:Cardiovascular System / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005165:Factor V / Q000378:metabolism; D015944:Factor VIIIa / Q000378:metabolism; D015943:Factor Va / Q000378:metabolism; D015951:Factor Xa / Q000008:administration & dosage / Q000494:pharmacology; D005342:Fibrinolysis; D006801:Humans; D015151:Immunoblotting; D010215:Papio; D010713:Phosphatidylcholines / Q000008:administration & dosage; D010718:Phosphatidylserines / Q000008:administration & dosage; D011486:Protein C / Q000037:antagonists & inhibitors* / Q000502:physiology; D013917:Thrombin / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011486:Protein C; D015943:Factor Va; D015944:Factor VIIIa; D005165:Factor V; D013917:Thrombin; D015951:Factor Xa