Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin.
OBJECTIVE
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).


METHODS
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 microg/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 Delta 7.1 (2.7)%, p < 0.01), whereas intravenous bivalirudin had no effect (absolute Delta -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.
Harding
S A
SA
Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.
Din
J N
JN
Sarma
J
J
Josephs
D H
DH
Fox
K A A
KA
Newby
D E
DE
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D002449:Cell Aggregation / Q000187:drug effects; D017984:Enoxaparin / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D019007:P-Selectin / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D017984:Enoxaparin; D006629:Hirudins; D019007:P-Selectin; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006493:Heparin; D013917:Thrombin; C074619:bivalirudin; C083544:lepirudin