Objectives: To determine the in vitro effects of unfractionated heparin, fractionated heparin and direct thrombin inhibition on platelet–monocyte aggregation, and to establish the in vivo effects of unfractionated heparin and direct thrombin inhibition on platelet–monocyte aggregates in patients scheduled for percutaneous coronary intervention (PCI).
Design: Platelet–monocyte aggregates were assessed in whole blood from 18 healthy volunteers after the addition of unfractionated heparin (1 U/ml), enoxaparin (0.8 U/ml) or lepirudin (5.6 µg/ml), and in 28 patients scheduled for elective PCI before and after administration of 100 U/kg of unfractionated heparin or 0.75 mg/kg bivalirudin. The influence of P-selectin-mediated platelet–monocyte aggregation was assessed with specific blocking antibodies.
Results: Addition of unfractionated heparin in vitro was associated with a higher level of platelet–monocyte aggregates than in controls (20.1 (1.9)% v 16.2 (1.6)%, respectively, p < 0.001). However, platelet–monocyte aggregation was not affected by enoxaparin or lepirudin (16.9 (2.0)% and 17.0 (2.2)%, respectively, NS). Intravenous unfractionated heparin in vivo also resulted in an increase in platelet–monocyte aggregates (absolute Δ 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Δ −1.5 (2.4)%, NS). The addition of P-selectin blockade abolished any increase in platelet–monocyte aggregates associated with heparin.
Conclusions: In vitro and in vivo unfractionated heparin is associated with increased platelet–monocyte aggregation through a P-selectin-dependent mechanism. These findings provide a potential explanation for the superior cardiovascular outcomes associated with fractionated heparins and direct thrombin inhibitors.
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Published Online First 18 May 2006
Drs Harding and Din were supported by grants from the British Heart Foundation (PG/2001/068; PG/03/009). This project was also supported by internal research funding from the Centre for Cardiovascular Sciences, University of Edinburgh.
Competing interests: Professor Fox has received grant support for the Global Registry of Acute Coronary Events (GRACE) from Sanofi-Aventis. All other authors have no conflict of interest to declare.