Abstract-von Willebrand factor (VWF) plays a pivotal role in platelet adhesion and aggregation at sites of high shear rates (eg, in coronary arteries that have stenotic or ruptured atherosclerotic plaque lesions). Numerous studies have investigated the relationship between VWF plasma levels and thromboembolic cardiovascular events. In contrast to the rather weak association in the general population, in patients with preexisting vascular disease, VWF is significantly predictive for adverse cardiac events, including death. Likewise, VWF typically rises during the course of acute coronary syndrome, and the extent of this VWF release is an independent predictor of adverse clinical outcome in these patients. Key Words: coronary disease Ⅲ myocardial infarction Ⅲ platelets Ⅲ thrombosis Ⅲ von Willebrand factor F or Ͼ150 years, it has been known that alterations in blood flow, vascular wall, and blood components, the so-called Virchow's triad, 1 may progressively lead to thrombus formation. Yet, a more complete understanding of the complex interactions among the vascular endothelium, platelet adhesion, activation, aggregation, and clotting factor activation involved in this process is still emerging from contemporary research.Under physiological conditions, the vascular endothelium produces many substances that contribute importantly to hemostasis, fibrinolysis, and regulation of vessel tone and permeability. One such substance is the multimeric glycoprotein von Willebrand factor (VWF), which is produced almost exclusively by endothelial cells. 2 Plasma levels of VWF are raised in different states of endothelial damage and have therefore been proposed as useful markers of endothelial dysfunction. 3 Along this line, blockade of nitric oxide enhances the stimulated release of VWF in humans. 4,5 Furthermore, VWF plays a crucial role in platelet adhesion and aggregation under high shear conditions. 6 Finally, VWF supports the third component of Virchow's triad, clotting factor activation, by acting as a carrier protein and stabilizer for factor VIII. 7 Almost all acute coronary syndromes (ACS) result from thrombus formation in preexisting coronary atherosclerosis. As a result of plaque rupture and exposure of prothrombotic subendothelial matrix, local thrombus formation occurs, which subsequently leads to coronary artery occlusion and acute myocardial infarction (AMI). The presence of VWF has been shown to play a pivotal role in platelet aggregation at sites of high shear, eg, at the sites of lesions in the coronary arteries. 8 Accordingly, VWF is a well-characterized marker of cardiovascular risk, and VWF plasma levels are increased in patients with ACS. 9 Considering the central role of VWF in thrombogenesis, therapies that specifically inhibit VWF are of particular interest as potential new antiplatelet drugs.

Background-ARC1779 is a therapeutic aptamer antagonist of the A1 domain of von Willebrand Factor (vWF), the ligand for receptor glycoprotein 1b on platelets. ARC1779 is being developed as a novel antithrombotic agent for use in patients with acute coronary syndromes. Methods and Results-This was a randomized, double-blind, placebo-controlled study in 47 healthy volunteers of doses of ARC1779 from 0.05 to 1.0 mg/kg. Pharmacodynamic effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer. In terms of pharmacokinetics, the concentration-time profile of ARC1779 appeared monophasic. The observed concentration and area under the curve were dose proportional. The mean apparent elimination half-life was Ϸ2 hours, and mean residence time was Ϸ3 hours. The mean apparent volumes of distribution (at steady state and during terminal phase) were approximately one half the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance ranged from Ϸ10% to Ϸ21% of the glomerular filtration rate, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. Inhibition of vWF A1 binding activity was achieved with an EC 90 value of 2.0 g/mL (151 nmol/L) and of platelet function with an EC 90 value of 2.6 g/mL (196 nmol/L). ARC1779 was generally well tolerated, and no bleeding was observed. Adverse events tended to be minor and not dose related. Conclusions-This is the first-in-human evaluation of a novel aptamer antagonist of vWF. ARC1779 produced dose-and concentration-dependent inhibition of vWF activity and platelet function with duration of effect suitable for the intended clinical use in acute coronary syndromes.

Context The rates of appendiceal rupture and negative appendectomy in children remain high despite efforts to reduce them. Both outcomes are used as measures of hospital quality. Little is known about the factors that influence these rates. Objective To investigate the association between hospital-and patient-level characteristics and the rates of appendiceal rupture and negative appendectomy in children. Design, Setting, and Patients Retrospective review using the Pediatric Health Information System database containing information on 24 411 appendectomies performed on children aged 5 to 17 years at 36 pediatric hospitals in the United States between 1997 and 2002.

Summary. Background: von Willebrand factor (VWF) has a role in both hemostasis and thrombosis. Platelets adhere to damaged arteries by interactions between the VWF A1-domain and glycoprotein Ib receptors under conditions of high shear. This initial platelet binding event stimulates platelet activation, recruitment, and activation of the clotting cascade, promoting thrombus formation. Objective: To characterize the inhibitory activity of a VWF inhibitory aptamer. Methods: Using in vitro selection, aptamer stabilization, and conjugation to a 20-kDa poly(ethylene glycol), we generated a nuclease-resistant aptamer, ARC1779, that binds to the VWF A1-domain with high affinity (K D 2 nM). The aptamer was assessed for inhibition of VWF-induced platelet aggregation. In vitro inhibition of platelet adhesion was assessed on collagen-coated slides and injured pig aortic segments. In vivo activity was assessed in a cynomolgus monkey carotid electrical injury thrombosis model. Results and Conclusion: ARC1779 inhibited botrocetin-induced platelet aggregation (IC 90 300 nM) and shear force-induced platelet aggregation (IC 95 400 nM). It reduced adhesion of platelets to collagen-coated matrices and formation of platelet thrombi on denuded porcine arteries. ARC1779 also inhibited the formation of occlusive thrombi in cynomolgus monkeys. We have discovered a novel anti-VWF aptamer that could have therapeutic use as an anti-VWF agent in the setting of VWFmediated thrombosis.

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