Interaction between endotoxin and histones in thrombosis (671.5)

Abstract

Histones, the protein component of nucleosomes, are released from neutrophils during inflammation and have a pro‐aggregatory effect on platelets. Recent reports suggest that histones interact with toll‐like receptor‐4; therefore, we studied the effect of endotoxin (LPS) on nucleosome formation and histone‐induced platelet aggregation. We measured plasma nucleosome levels in mice exposed to either LPS or control, and the effects of exogenous histones of photochemical‐induced thombus formation in cremaster venules. Finally, we compared the effects of LPS and histones on platelet aggregation. We observed that 4 hours after LPS, mice had a 4‐fold higher level of plasma nucleosomes compared to saline‐exposed mice (p<0.01). Furthermore, exogenous histones resulted in a decreased platelet counts (from 1.1 x 106 to 0.86 x 106/µL; p< 0.05), increased thrombin‐anti‐thrombin complexes (from 0.99 to 6.1 ng/mL; p<0.01), and accelerated rates of thrombosis (time to thrombotic occlusion was reduced from 6.5 to 4.4 min; p<0.05). Finally, whereas LPS alone did not induce platelet aggregation, it enhanced the aggregatory response after histone administration in a dose‐dependent manner (22, 28, and 38% aggregation with LPS 0, 10, and 100 ng/mL, respectively; p<0.01). Taken together, these data suggest a synergistic interaction between endotoxin and histones in producing a prothrombotic state.Grant Funding Source: Supported by a BLR&D Merit Review Award from the Department of Veterans Affairs