A randomized clinical trial investigating the relationship between aprotinin and hypercoagulability in off-pump coronary surgery.
BACKGROUND
Off-pump coronary artery bypass (OPCAB) surgery is associated with a hypercoagulable state in which the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), helps propagate a thrombin burst within saphenous vein grafts. Aprotinin, used in cardiothoracic surgery mainly for its antifibrinolytic properties, also spares platelet PAR-1 activation due to thrombin. We hypothesized that this PAR-1 antagonistic property provides an antithrombotic benefit during OPCAB surgery.


METHODS
Patients were randomly assigned to receive saline (n = 38) or a modified full-dose regimen of aprotinin (n = 37) IV during OPCAB surgery. Blood sampled perioperatively from the coronary sinus, skin wounds, and systemic circulation was analyzed to test coagulation and platelet function. Major adverse cardiovascular events were monitored by obtaining troponin I at 24 h (myocardial infarction), predischarge computed tomography angiography (vein graft thrombosis), and by clinical examination for stroke.


RESULTS
Coronary sinus blood obtained immediately after OPCAB surgery showed significantly less activation in the aprotinin group, as judged by reduced formation of platelet-leukocyte conjugates (P < 0.02) and platelet-derived microparticles (P < 0.05). The aprotinin group showed inhibition of platelet aggregation induced by thrombin (P = 0.007) but not adenosine diphosphate. Thrombin generation, defined by F1.2 levels, was significantly reduced by aprotinin in the coronary sinus but not in skin wound incisions. Major adverse cardiovascular events were significantly reduced in aprotinin-treated patients (5.4% vs 29.7%, P < 0.05). Aprotinin also demonstrated antifibrinolytic properties through diminished red blood cell transfusion (P < 0.04) and reduced blood loss postoperatively (603 +/- 330 vs 810 +/- 415 mL, P < 0.004).


CONCLUSIONS
This study demonstrates that aprotinin protects patients undergoing OPCAB surgery from a hypercoagulable state by diminishing thrombin-induced platelet activation and thrombin generation within saphenous vein grafts, while maintaining systemic hemostatic and antifibrinolytic benefits. These results support further investigation of aprotinin and other PAR-1 antagonists in OPCAB surgery.
Department of Cardiothoracic Surgery, Boston University and School of Medicine and Boston Medical Centre, Boston, MA 02118, USA.
Pranjal H
PH
Desai
Dinesh
D
Kurian
Nannan
N
Thirumavalavan
Sneha P
SP
Desai
Pluen
P
Ziu
Michael
M
Grant
Charles
C
White
R Clive
RC
Landis
Robert S
RS
Poston
D007611:Aprotinin / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D047549:Coronary Artery Bypass, Off-Pump / Q000009:adverse effects*; D004311:Double-Blind Method; D017707:Erythrocyte Transfusion; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006083:Graft Occlusion, Vascular / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D010446:Peptide Fragments / Q000097:blood; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests; D019106:Postoperative Hemorrhage / Q000517:prevention & control; D011446:Prospective Studies; D011516:Prothrombin; D044463:Receptor, PAR-1 / Q000097:blood; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors
D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D044463:Receptor, PAR-1; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D007611:Aprotinin; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors