Abstract
Von Willebrand factor (VWF) plays a major role in arterial thrombosis. Antiplatelet drugs induce only a moderate relative risk reduction after atherothrombosis, and their inhibitory effects are compromised under high shear rates when VWF levels are increased. Therefore, we investigated the ex vivo effects of a third-generation anti-VWF aptamer (BT200) before/after stimulated VWF release. We studied the concentration-effect curves BT200 had on VWF activity, platelet plug formation under high shear rates (PFA), and ristocetin-induced platelet aggregation (Multiplate) before and after desmopressin or endotoxin infusions in healthy volunteers. VWF levels increased > 2.5-fold after desmopressin or endotoxin infusion (p < 0.001) and both agents elevated circulating VWF activity. At baseline, 0.51 µg/ml BT200 reduced VWF activity to 20% of normal, but 2.5-fold higher BT200 levels were required after desmopressin administration (p < 0.001). Similarly, twofold higher BT200 concentrations were needed after endotoxin infusion compared to baseline (p < 0.011). BT200 levels of 0.49 µg/ml prolonged collagen-ADP closure times to > 300 s at baseline, whereas 1.35 µg/ml BT200 were needed 2 h after desmopressin infusion. Similarly, twofold higher BT200 concentrations were necessary to inhibit ristocetin induced aggregation after desmopressin infusion compared to baseline (p < 0.001). Both stimuli elevated plasma VWF levels in a manner representative of thrombotic or pro-inflammatory conditions such as arterial thrombosis. Even under these conditions, BT200 potently inhibited VWF activity and VWF-dependent platelet function, but higher BT200 concentrations were required for comparable effects relative to the unstimulated state.
Highlights
Von Willebrand factor (VWF) is driving the first step and is a key component in platelet thrombus formation when vascular injury occurs under conditions of moderate to high shear force[1,2]
We hypothesized that effects of BT200 will be comparable between healthy volunteers after desmopressin/endotoxin infusion and in patients with chronically elevated VWF levels and that BT200′s concentrations and effect will depend on VWF activity
Target concentrations for Multiplate were the ones which lowered AUC values to < 20 U, because 25 U were seen in patients with von Willebrand disease (VWD) type 2 who had VWF levels of 24%, and 13 U and 9 U were seen in patients with VWD type 3 without therapy, these had VWF levels of 12% and 0% r espectively[29]
Summary
Von Willebrand factor (VWF) is driving the first step and is a key component in platelet thrombus formation when vascular injury occurs under conditions of moderate to high shear force[1,2]. The main mediator of platelet plug formation is VWF, which is why inhibitors of GPIIb/IIIa, P2Y12 receptor or cyclooxygenase-1 are less potent in conditions where VWF levels are increased[8,9,10] Those antiplatelet drugs typically only produce a limited relative risk reduction in some patients groups such as those with acute coronary syndrome or patients undergoing percutaneous coronary intervention (PCI)[11]. The vasopressin analogue desmopressin increases circulating VWF levels by stimulating its secretion from the endothelial storage site (Weibel Palade bodies)[17] Both endotoxin and desmopressin challenges are useful models in healthy volunteers to test ex-vivo VWF inhibition as would occur in patients with increased VWF plasma levels
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