FOREWORD

This issue of Seminars in Vascular Medicine is dedicated to antiplatelet and anticoagulant agents in cardiovascular disease and produced in a joint effort by Guest Editors Dr. Schrör, pharmacologist, and Dr. Gawaz, cardiologist.

Dr. Schrör synoptically provides a historical perspective of antithrombotic drugs in vascular medicine and reviews the pharmacologic aspects and clinical applications for cardiovascular diseases of the antiplatelet agents aspirin, ticlopedine, and clopidogrel, glycoprotein (GP) IIbIIa inhibitors, and the anticoagulants coumarin, ximlagatran, and heparins.

Dr. Wu presents new scientific insights on the effect of acetylsalicylic acid (aspirin) on cyclooxygenase-1 (COX-1) and the effects of aspirin and sodium salicylate on COX-2 activity and the regulation of COX-2 protein expression. Whether the combined use of low-dose aspirin and low-dose selective COX-2 inhibitors (celecoxib and rofecoxib) will have additional cardiovascular protective properties remains elusive.

Drs. Herbert and Savi provide exiting new information on the platelet ADP receptor P2Y₁₂ as the target of ticlopedine and clopidogrel. The authors nicely elucidate that the active metabolite of clopidogrel binds in a covalent manner to the ADP receptor, by which it irreversibly blocks the aggregation effect of ADP on platelets and thus explains its favorable antithrombotic properties for the prevention of recurrent ischemic events in patients with acute coronary syndromes (ACS) and coronary stenting.

Drs. Nurden and Nurden perfectly describe basic research in platelet physiology. They nicely elucidate the interactions of von Willebrand factor and the platelet GP Ib-IV-V complex and the importance of platelet collagen receptor GP VI for platelet adhesion to subendothelium, which is followed by the interaction of fibrinogen and platelet GPIIbIIa for platelet aggregation at a high shear rate to form firm nonocclusive or occlusive platelet-fibrin clots on the damaged vessel wall such as atherosclerotic plaques. The authors describe the efficacy of the intravenous GPIIbIIa inhibitors abciximab, eptifibatide, and tirofiban and the inefficacy of the oral GP IIbIIIa inhibitors for the prevention of recurrent thrombotic events in ACS and percutaneous coronary intervention.

Dr. Weitz nicely elucidates the current status and future perspectives of ximelagatran, an oral thrombin inhibitor, as an alternative of oral anticoagulation with coumarin because a fixed or weight-adjusted dose of ximelagatran has a wide therapeutic range without the need of laboratory monitoring.

Dr. Haas presents a state-of-the-art review on the pharmacology and clinical applications of unfractionated heparin, low molecular weight heparins, pentasaccharide, and hirudin for prophylaxis and treatment of venous thromboembolism and thrombotic complications in ACS.

Dr. Massberg and associates describe in great detail the crucial role of platelets in the pathophysiology of ACS. Platelets appear to play a key role in thrombotic vascular occlusions at the ruptured coronary atherosclerotic plaque. Good evidence is produced that embolization of platelet aggregates and direct, receptor-mediated platelet adhesion to damaged endothelial cells in the postischemic microvasculature further result in obstruction and impairment of coronary microcirculation. This may indicate a need to search for novel antiplatelet strategies preventing platelet-endothelial interaction to improve the prognosis of patients with ACS.

Dr. Gawaz and colleagues present a state-of-the-art review on basic research related to clinical applications of aspirin, clopidogrel, dipyridamole, GPIIbIIIa inhibitors, and anticoagulant in ACS. Aspirin is accepted as the standard therapy in ACS. Loading dose clopidogrel on top of aspirin during and after elective coronary stent implantation has been demonstrated to be effective to prevent recurrence of ACS. Whether patients with ACS should be treated with GPIIbIIIa inhibitors on top of clopidogrel/aspirin needs to be evaluated in prospective management studies. GPIIbIIIa inhibitors have been approved for initial treatment of high-risk ACS patients at the time of percutaneous coronary intervention or coronary stent implantation. The combination of antiplatelet therapy and oral anticoagulation in patients after myocardial infarction has been shown to be effective in the secondary prevention of ACS.

Dr. Bredie and associates state that the protective effect of low-dose aspirin for primary prevention of thrombotic events is apparently most prominent in those patients with already-manifest atherosclerotic vascular disease such as diabetes or hypertension or with the presence of vascular risk factors such as hyerlipidemia, smoking, etc. For each of these patients at risk it is essential to balance the risk reduction for atherothrombotic complications against the small increased risk of bleeding elicited by aspirin.

Dr. Ott draws attention to the possible role of tissue factor (TF) in ACS. Much attention is paid to the initiation and regulation of the TF/FVIIa-FXa-TFPI coagulation pathway, TFPI in endothelial cells and TFPI expression on endothelial cells, the origin of TF from monocytes, the presence of TF in atherosclerotic plaques, and increased circulating TF in ACS.

Dr. Mackman focuses on the role of the TF-thrombin pathway in the rabbit cardiac ischemia-reperfusion (I/R) injury model. His studies reveal that the predominant site of TF expression in cardiac I/R injury was cardiac myocytes. The author observed increased intravascular and extravascular fibrin deposition in the myocardium and colocalization of TF and fibrin within the myocardium after I/R injury. Anti-TF given 15 minutes before coronary ligation reduced the infarction size by 62% and anti-TF given 30 minutes after coronary ligation reduced the infarction size by 44%. FVIIai (ASIS) given after coronary ligation at the time of reperfusion reduced infarct size by 63% and FVIIa increased the infarct size. These observations demonstrate that the TF/FVIIa pathway significantly contributes to myocardial injury during postischemic reperfusion. A reduction of infarct size by 59% with hirudin clearly indicates that the TF/FVIIa-thrombin pathway significantly contributes to the fibrin deposition and pathology of cardiac I/R injury.

Dr. Sorensen and colleagues demonstrate that inactivated recombinant factor VIIa (rFVIIai) in animal models prevented or diminished immediate thrombus formation at the site of vessel wall injury as well as the development of long-term intima thickening. In the rabbit ischemia-reperfusion model, rFVIIai induced a marked reduction in platelet and fibrinogen accumulation in the ischemic but viable myocardium, which was associated with a significant reduction of infarct size. In healthy male volunteers, rFVIIai blocks endotoxine-induced thrombin and fibrinogen formation. Preliminary clinical experiments indicate that rFVIIai does prolong the prothrombin time (PT), has no effect on the activated partial thromboplastine time (APTT), and does not induce significant bleeding complications. Using a perfusion chamber, rFVIIai markedly reduced thrombus formation at high shear rate. These results indeed demonstrate that rFVIIai has a potent antithrombotic effect at different shear rates and in several arterial injury conditions. Therefore, rFVIIai may be a good candidate for the prevention of reocclusion in patients undergoing percutaneous transluminal coronary angioplasty, stent implantation, athroplasty, or other form of mechanical interventions.

Drs. Golino and Cimmino put forward an interesting new concept of targeting tissue factor/factor VIIa (TF/FVIIa) as an antithrombotic strategy in cardiovascular medicine. A large number of experimental animal and basic research studies has shown that inhibition of TF/FVIIa by anti-TF or FVIIai (ASIS) is a powerful inhibitor of in vivo arterial thrombosis and that this approach usually results in a less-pronounced bleeding tendency compared with classical antithrombotic interventions. In contrast, systemic administration of TFPI led to a significant prolongation of the prothrombin time (PT), suggesting that TFPI at doses effective in preventing arterial thrombosis is associated with a substantial risk of bleeding. Further clinical studies are warranted to determine the efficacy and safety of targeting TF/FVIIa by FVIIai (ASIS) or anti-TF as a new antithrombotic strategy or to be used on top of classical antithrombotic interventions in patients with cardiovascular disease at the time of the thrombotic event or during intervention procedures.

It is hoped that this comprehensive review helps researchers and clinicians in vascular medicine to maintain and improve the high-quality care and cure of their patients with ACS. I thank the authors for their excellent contributions, and especially thank Dr. Karsten Schrör and Dr. Meinrad Gawaz for assembling this very important issue in vascular medicine.