Recombinant human, active site-blocked factor VIIa reduces infarct size and no-reflow phenomenon in rabbits.
Oxygen free radicals induce de novo synthesis of tissue factor (TF), the initiator of the extrinsic pathway of coagulation, within the coronary vasculature during postischemic reperfusion. In the present study we wanted to assess whether TF expression might cause myocardial injury during postischemic reperfusion. Anesthetized rabbits underwent 30 min of coronary occlusion followed by 5.5 h of reperfusion. At reperfusion the animals received 1) saline (n = 8), 2) human recombinant, active site-blocked activated factor VII (FVIIai, 1 mg/kg, n = 8), or 3) human recombinant activated FVII (FVIIa, 1 mg/kg, n = 8). FVIIai binds to TF as native FVII, but with the active site blocked it inhibits TF procoagulant activity. The area at risk of infarction (AR), the infarct size (IS), and the no-reflow area (NR) were determined at the end of the experiment. FVIIai resulted in a significant reduction in IS and NR with respect to control animals (28.1 +/- 11.3 and 11.1 +/- 6.1% of AR vs. 59.8 +/- 12.8 and 24.4 +/- 2.7% of AR, respectively, P < 0.01), whereas FVIIa resulted in a significant increase in IS and NR to 80.1 +/- 13. 1 and 61.9 +/- 13.8% of AR, respectively (P < 0.01). In conclusion, TF-mediated activation of the extrinsic coagulation pathway makes an important contribution to myocardial injury during postischemic reperfusion.
Golino
P
P
Division of Cardiology, Department of Internal Medicine, Second School of Medicine, University of Naples, 80131 Naples, Italy. golino@unina.it
Ragni
M
M
Cirillo
P
P
Scognamiglio
A
A
Ravera
A
A
Buono
C
C
Guarino
A
A
Piro
O
O
Lambiase
C
C
Botticella
F
F
Ezban
M
M
Condorelli
M
M
Chiariello
M
M
D000590:Amino Acid Chloromethyl Ketones / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005340:Fibrinogen / Q000378:metabolism; D006439:Hemodynamics; D006490:Hemostatics / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D006490:Hemostatics; D011994:Recombinant Proteins; C027587:phenylalanyl-phenylalanyl-arginine chloromethyl ketone; D005340:Fibrinogen; D013925:Thromboplastin; D015942:Factor VIIa