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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. Various lines of evidence indicate that VWF is not only a marker but also actually an important effector in the pathogenesis of myocardial infarction. This central role of VWF in thrombogenesis has made it a promising target for research into new antiplatelet therapies that specifically inhibit VWF. This review focuses on the role of VWF in acute coronary syndrome and further outlines the relevance of therapeutic interventions targeting VWF for acute coronary syndrome patients.

Background: ARC1779 is an aptamer which blocks the A1 domain binding of the vWF A1 domain to platelet GPIb receptors that is now in development for the treatment of AMI. vWF is increased in the elderly and in the setting of AMI, as reflected in higher vWF levels in circulation and in increased shear-dependent platelet function as measured by the platelet function analyzer (PFA-100) and cone and plate analyzer (IMPACT). Conventional therapy of AMI partially reduces platelet activation and aggregation, but does not address excessive vWF activity or platelet adhesion. Methods: We studied the ex vivo dose response curves for ARC1779 on PFA-100 and IMPACT platelet function tests, agonist-induced platelet aggregation, and vWF activity (free A1 domain sites) of patients with AMI on standard treatment including aspirin and clopidogrel (n=40), young (n=20) and elderly controls (n=20). Results: ARC1779 fully blocked collagen ADP induced platelet plug formation as measured by PFA-100 with an IC100 of ~ 1–2 mcg/mL with citrate anticoagulation, and 3–5 mcg/mL with hirudin anticoagulation. ARC1779 fully blocked shear-dependent platelet adhesion measured by the IMPACT analyzer with an IC100 of ~ 1 mcg/mL with citrate anticoagulation. In contrast to GPIIb/IIIa antagonists, ARC1779 did not inhibit platelet aggregation by ADP, collagen or arachidonic acid at concentrations (10mcg/mL) that fully inhibited vWF dependent platelet function. ARC1779 fully blocked vWF activity ex vivo with an IC90 of ~ 1 mcg/mL in young controls and 6 – 8 mcg/mL in STEMI and NSTEMI patients. Conclusions: ARC1779 potently and specifically inhibits vWF activity and vWF dependent platelet function, even in the setting of AMI where vWF activity is increased. ARC1779 represents a novel therapeutic principle (vWF antagonism) and a novel therapeutic class (aptamers). Potent and specific inhibition of VWF makes ARC1779 a promising development candidate for patients with AMI. Results

Background: The prognosis of patients with cardiac arrest is still poor, and hardly any specific therapeutic options exist to improve outcome. Platelet activation has been observed in patients undergoing cardiopulmonary resuscitation (CPR). This may contribute to impairment of microcirculatory function and overall poor outcome despite return of spontaneous circulation. Data on direct platelet function in cardiac arrest are scarce. Platelets of patients with myocardial infarction are hyperfunctional, which predicts the degree of myocardial necrosis. Thus, we hypothesized that platelets may be even more hyper-functional in patients whose myocardial infarction causes cardiac arrest. We determined platelet function under high shear rates of patients with cardiac arrest and were further interested whether this may be related to the cause of cardiac arrest. Methods: We conducted a prospective study in 77 cardiac arrest patients at the Emergency Department of a tertiary care hospital. Collagen adenosine diphosphate closure time (CADP-CT) was assessed by the FDA-approved platelet function analyzer (PFA-100). In addition, plasma levels of von Willebrand factor (vWf:RiCo) were measured by turbidometry. Independent staff members of the emergency department not otherwise involved in this trial diagnosed the origin of cardiac arrest. Results: More than half of cardiac arrests were caused by myocardial ischemia. CADP-CT values (54s; 95%CI: 48–60s in 3.8% citrate) were much shorter in these patients as compared to patients with other causes of cardiac arrest (110s; 95%CI: 84–135s, p Conclusion: Patients with myocardial ischemia triggered cardiac arrest displayed the highest degree of platelet hyper-function under high shear rates, which was not solely due to increased vWF. Those patients may benefit from a rapid, more aggressive anti-platelet therapy than currently performed or an anti-vWF targeted therapy.