TLR4 Regulates Platelet Function and Contributes to Coagulation Abnormality and Organ Injury in Hemorrhagic Shock and Resuscitation
Background—Growing evidence indicates that the presence of TLR4 on platelets is a key regulator of platelet number and function. Platelets exposed to TLR4 agonists may serve to activate other cells such as neutrophils and endothelial cells in sepsis and other inflammatory conditions. The functional significance of platelet TLR4 in hemorrhagic shock, however, remains unexplored.
Methods and Results—Using thromboelastography and platelet aggregometry, we demonstrate that platelet function is impaired in a mouse model of hemorrhagic shock with resuscitation (HS-R). Further analysis using cellular specific TLR4 deletion in mice revealed that platelet TLR4 is essential for platelet activation and function in HS-R and that platelet TLR4 regulates the development of coagulopathy after hemorrhage and resuscitation. Transfusion of TLR4 negative platelets into mice resulted in protection from coagulopathy and restored platelet function. Additionally, platelet-specific TLR4 knock-out mice were protected from lung and liver injury and exhibited a marked reduction in systemic inflammation as measured by circulating IL-6 following HS-R.
Conclusions—We demonstrate for the first time that platelet TLR4 is an essential mediator of the inflammatory response as well as platelet activation and function in hemorrhagic shock and resuscitation.
- Received October 23, 2013.
- Revision received May 19, 2014.
- Accepted June 4, 2014.