The infectious milieu provides a variety of signals that lead to platelet activation (). It is well known that platelet-activating factor (PAF) and thrombin are generated by host cells as they encounter pathogens [8
]. Both PAF and thrombin signal through G-protein coupled receptors inducing rapid changes in platelets including secretome release and translocation of P-selection to the surface of the platelets, where it serves as a tether for leukocytes. PAF and thrombin also activate integrin αIIb
, allowing it to bind fibrinogen and bridge platelets to one another. Homotypic platelet aggregates deposit in the vasculature, leading to thrombosis, DIC and consumption of platelets. Because of their established roles in platelet activation and coagulation, PAF and thrombin have been the targets of clinical trials designed to improve outcomes in patients diagnosed with sepsis [9
While the effects of PAF and thrombin are well characterized, new agonists that induce platelet activation are continually being identified. Among these are TLR agonists, including lipopolysaccharide (LPS). Human and murine platelets express TLR2, −4 and −9 [11
]. TLR5 has also been identified in human platelets [13
]. Unlike classical agonists, however, TLR-dependent signaling typically does not have a direct effect on traditional platelet functions, such as aggregation or secretion [14
]. However, studies in knockout mice (TLR4−/ −) demonstrate that platelet TLR4 is responsible for mediating LPS-induced thrombocytopenia [15
]. Furthermore, thrombocytopenic mice inadequately produce tumor necrosis alpha (TNF-α) in the presence of LPS unless they are simultaneously transfused with platelets [16
]. Together, these in vivo
data indicate that activation of platelet TLR4 is involved in the clearance of circulating platelets and the generation of proinflammatory cytokines in endotoxemia.
Recent studies from Washington and colleagues [17
] demonstrate that LPS markedly increases plasma levels of sTLT-1 (soluble Triggering Receptor Expressed on Myeloid Cells-like [TREM] transcript-1) in mice. sTLT-1 is also increased in patients diagnosed with sepsis compared to healthy controls. The exact functions of TLT-1 in platelets, which is stored in α-granules and translocated to the surface in response to thrombin, collagen, and LPS, are still emerging. To date, it is known that activated platelets release sTLT-1, which binds fibrinogen and augments platelet aggregation. Mice that lack TLT-1 have defects in platelet aggregation and more readily succumb to challenges with LPS. TLT-1 deficient mice also display higher plasma levels of TNF-α and D-dimers when compared to their wild-type counterparts, indicating that platelet-derived TLT-1 functions to dampen the inflammatory response to infection.