on July 19, 2004
Published online before print July 19, 2004, doi: 10.1161/01.CIR.0000138027.80056.31
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 23, 2004
From the British Heart Foundation Cardiac Surgery (J.R.S.D., P.P.P., K.M.T.) and Cardiovascular Medicine (A.M.R., D.O.H.) Units, Eric Bywaters Centre, Imperial College, London, UK; and Edmund Cohen Laboratory for Vascular Research (R.C.L.), Chronic Disease Research Centre, UWI, Bridgetown, Barbados. * To whom correspondence should be addressed. E-mail: j.day{at}imperial.ac.uk.
Background--Protease-activated receptor-1 (PAR1) is the principal thrombin receptor in the vasculature, and antagonists against this receptor are in preclinical trials. Aprotinin, already approved for clinical use to reduce transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for thrombin generation in humans to examine whether aprotinin can inhibit platelet PAR1 activation clinically. Methods and Results--PAR1 expression and function on platelets was examined in coronary artery bypass grafting (CABG) patients randomized into 2 groups: (1) those receiving saline infusion during CPB (n=17) and (2) those receiving aprotinin (2x106 kallikrein inhibitor units [KIU] in pump prime, 2x106 KIU loading dose, followed by 0.5x106 KIU/h [n=13]). Platelets in the saline group showed loss of PAR1-specific function at 2 hours after CPB, but this was preserved in the aprotinin group (P<0.001). These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (P<0.05), and (3) supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage (P<0.001) and platelet aggregation (P<0.001) in the presence of aprotinin. Conclusions--This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin. Our results extend the clinical mechanism of action of aprotinin and provide the first proof of principle that PAR1 can be inhibited clinically. This has implications beyond cardiac surgery for the development of therapeutic PAR1 blockade.
Revised on June 16, 2004
Accepted on June 17, 2004
Clinical Inhibition of the Seven-Transmembrane Thrombin Receptor (PAR1) by Intravenous Aprotinin During Cardiothoracic Surgery
J. R.S. Day MRCS*,
Key words: thrombin • platelets • cardiopulmonary bypass
Related Article:
Circulation 2004 110: 2551.
This article has been cited by other articles:
 |
|
 |
|
  P. H. Desai, D. Kurian, N. Thirumavalavan, S. P. Desai, P. Ziu, M. Grant, C. White, R. C. Landis, and R. S. Poston A Randomized Clinical Trial Investigating the Relationship Between Aprotinin and Hypercoagulabilityin Off-Pump Coronary Surgery Anesth. Analg., November 1, 2009; 109(5): 1387 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Landis Redefining the Systemic Inflammatory Response Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2009; 13(2): 87 - 94. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Nurozler, T. Kutlu, and G. Kucuk Aprotinin for Patients Exposed to Clopidogrel Before Off-Pump Coronary Bypass Asian Cardiovasc Thorac Ann, December 1, 2008; 16(6): 483 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Ofosu, L. Dewar, S. J. Craven, Y. Song, A. Cedrone, J. Freedman, and J. W. Fenton II Coordinate Activation of Human Platelet Protease-activated Receptor-1 and -4 in Response to Subnanomolar {alpha}-Thrombin J. Biol. Chem., October 3, 2008; 283(40): 26886 - 26893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Mengistu, K. D. Rohm, J. Boldt, J. Mayer, S. W. Suttner, and S. N. Piper The Influence of Aprotinin and Tranexamic Acid on Platelet Function and Postoperative Blood Loss in Cardiac Surgery Anesth. Analg., August 1, 2008; 107(2): 391 - 397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Becker Emerging constructs to maintain safety among patients with acute coronary syndromes requiring surgical coronary revascularization Eur. Heart J. Suppl., May 1, 2008; 10(suppl_D): D12 - D22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. McEvoy, S. T. Reeves, J. G. Reves, and F. G. Spinale Aprotinin in Cardiac Surgery: A Review of Conventional and Novel Mechanisms of Action Anesth. Analg., October 1, 2007; 105(4): 949 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kahn, M. E. Stone, and D. M. Moskowitz Anesthetic Consideration for Descending Thoracic Aortic Aneurysm Repair Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2007; 11(3): 205 - 223. [Abstract] [PDF]
|
|
|
|
|
|
S. C. Body and C. D. Mazer Pro: Aprotinin Has a Good Efficacy and Safety Profile Relative to Other Alternatives for Prevention of Bleeding in Cardiac Surgery Anesth. Analg., December 1, 2006; 103(6): 1354 - 1359. [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Murkin Pathophysiological Basis of CNS Injury in Cardiac Surgical Patients: Detection and Prevention Perfusion, July 1, 2006; 21(4): 203 - 208. [Abstract] [PDF]
|
|
|
|
|
|
J. R. S. Day, R. C. Landis, and K. M. Taylor Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction. Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2006; 10(2): 132 - 142. [Abstract] [PDF]
|
|
|
|
 |
|
 J. Jaggers and J. H. Lawson Coagulopathy and Inflammation in Neonatal Heart Surgery: Mechanisms and Strategies Ann. Thorac. Surg., June 1, 2006; 81(6): S2360 - S2366. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Weerasinghe, T. Athanasiou, P. Philippidis, J. Day, K. Mandal, O. Warren, J. Anderson, and K. Taylor Platelet-monocyte pro-coagulant interactions in on-pump coronary surgery Eur. J. Cardiothorac. Surg., March 1, 2006; 29(3): 312 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R.S. Day, D. O. Haskard, K. M. Taylor, and R. C. Landis Effect of Aprotinin and Recombinant Variants on Platelet Protease-Activated Receptor 1 Activation Ann. Thorac. Surg., February 1, 2006; 81(2): 619 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R.S. Day, K. M. Taylor, E. A. Lidington, J. C. Mason, D. O. Haskard, A. M. Randi, and R. C. Landis Aprotinin inhibits proinflammatory activation of endothelial cells by thrombin through the protease-activated receptor 1 J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 21 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Levy Overview of clinical efficacy and safety of pharmacologic strategies for blood conservation Am. J. Health Syst. Pharm., September 15, 2005; 62(18_Supplement_4): S15 - S19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Khan, C. Bianchi, E. Araujo, P. Voisine, S.-H. Xu, J. Feng, J. Li, and F. W. Sellke Aprotinin Preserves Cellular Junctions and Reduces Myocardial Edema After Regional Ischemia and Cardioplegic Arrest Circulation, August 30, 2005; 112(9_suppl): I-196 - I-201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. van der Linden, G. Lindvall, and U. Sartipy Aprotinin Decreases Postoperative Bleeding and Number of Transfusions in Patients on Clopidogrel Undergoing Coronary Artery Bypass Graft Surgery: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial Circulation, August 30, 2005; 112(9_suppl): I-276 - I-280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Akowuah, V. Shrivastava, B. Jamnadas, D. Hopkinson, P. Sarkar, R. Storey, P. Braidley, and G. Cooper Comparison of Two Strategies for the Management of Antiplatelet Therapy During Urgent Surgery Ann. Thorac. Surg., July 1, 2005; 80(1): 149 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Khan, C. Bianchi, P. Voisine, J. Sandmeyer, J. Feng, and F. W. Sellke Aprotinin Inhibits Protease-Dependent Platelet Aggregation and Thrombosis Ann. Thorac. Surg., May 1, 2005; 79(5): 1545 - 1550. [Abstract] [Full Text] [PDF]
|
|