Effect of factor Xa inhibitors on thrombin formation and complement and neutrophil activation during in vitro extracorporeal circulation.
BACKGROUND
Even when large doses of heparin are administered during cardiopulmonary bypass, thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of prothrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress thrombin formation and activity during in vitro extracorporeal circulation.


RESULTS
Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or prothrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes.


CONCLUSIONS
rTAP does not reduce thrombin formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.
Gikakis
N
N
Department of Surgery, School of Medicine, University of Pennsylvania, Philadelphia, USA.
Khan
M M
MM
Hiramatsu
Y
Y
Gorman
J H
JH
Hack
C E
CE
Sun
L
L
Rao
A K
AK
Niewiarowski
S
S
Colman
R W
RW
Edmunds
L H
LH
D000244:Adenosine Diphosphate / Q000494:pharmacology; D060829:Arthropod Proteins; D003167:Complement Activation / Q000187:drug effects*; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D017984:Enoxaparin / Q000494:pharmacology; D005112:Extracorporeal Circulation; D065427:Factor Xa Inhibitors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D018375:Neutrophil Activation / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*
D060829:Arthropod Proteins; D003174:Complement C1 Inactivator Proteins; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011994:Recombinant Proteins; C063967:tick anticoagulant peptide; D000244:Adenosine Diphosphate; D013917:Thrombin