Thrombin is a coagulation
protease that activates platelets, endothelial cells, leukocytes and mesenchymal cells.
Thrombin signaling is mediated at least in part by
protease-activated receptors (PARs). As little is known about the in vivo regulation of PAR1, this study aimed to characterize the effects of systemic
thrombin formation during human
endotoxemia on the regulation of PAR1 and the associated responsiveness of human platelets to
thrombin receptor activating peptide (TRAP).
Endotoxin (2 ng/kg) was infused into 40 healthy men to study the regulation of PAR1 in systemic human
inflammation. The SPAN12 antibody was used to determine the in vivo regulation of PAR1. To measure whether modulation of the
PAR1 receptor may be associated with altered platelet reactivity, whole blood was stimulated with TRAP ex vivo.
Thrombin generation was determined by
prothrombin (F(1+2)) fragment. F(1+2) levels increased almost 9-fold from 0.5+/-0.1 nmol/L to 4.5+/-1.9 nmol/L at 4 h (p<0.001). PAR1 decreased by approximately 8% (p<0.001) within 2 h after
endotoxin infusion and stayed at those levels until 6 h. Concomitantly, TRAP induced
P-selectin expression maximally decreased by 18% (p<0.001) at 6 h. In conclusion, PAR1 expression is down-regulated on platelets during systemic
thrombin formation induced by
inflammation in humans which results in decreased responsiveness to subsequent stimulation of the
PAR1 receptor.