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.
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.
Taylor
F B
FB
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City 73104.
Hoogendoorn
H
H
Chang
A C
AC
Peer
G
G
Nesheim
M E
ME
Catlett
R
R
Stump
D C
DC
Giles
A R
AR
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*
D000911:Antibodies, Monoclonal; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011486:Protein C; D015943:Factor Va; D015944:Factor VIIIa; D005165:Factor V; D013917:Thrombin; D015951:Factor Xa