Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction.
Cardiopulmonary bypass, although remaining an indispensable asset in cardiac surgery, especially in more complex and repeat operations, is associated with significant thrombin generation in the bypass circuit, leading to the activation of platelets, the coagulation system, an inflammatory response, and perioperative stroke. Recent clinical studies and meta-analyses of clinical trials in coronary artery bypass grafting surgery have confirmed that aprotinin not only reduces transfusion requirements in cardiac surgery but also confers significant protection against platelet dysfunction, activation of the systemic inflammatory response, and perioperative stroke when administered at the full (or "Hammersmith") dose. This article reviews research from several independent groups to propose a novel mechanism through which the antithrombotic, anti-inflammatory, and neuroprotective mechanism might be mediated, via protection of the high-affinity thrombin receptor protease-activated receptor 1 (PAR1).
Day
J R S
JR
British Heart Foundation Cardiac Surgery Unit, Imperial College, London, UK. j.day@imperial.ac.uk
Landis
R C
RC
Taylor
K M
KM
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002315:Cardiopulmonary Bypass / Q000009:adverse effects* / Q000401:mortality; D002986:Clinical Trials as Topic; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D044463:Receptor, PAR-1 / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D010975:Platelet Aggregation Inhibitors
D044463:Receptor, PAR-1; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors