R. A. Jacobson1,2, J. G. Schoenecker1,3 1Vanderbilt University Medical Center,Pharmacology,Nashville, TN, USA 2Rush University Medical Center,Rush Medical College,Chicago, IL, USA 3Vanderbilt University Medical Center,Orthopedics,Nashville, TN, USA
Introduction: Fibrinogen (FBG) is an acute phase reactant secreted from the liver in response to injury and consumed during hemostasis at sites of tissue damage. Recent studies show that patients deficient in FBG due to traumatic consumption or dilution secondary to fluid resuscitation are coagulopathic, with an elevated risk of further bleeding. As such, repletion of FBG is a crucial step in the endogenous and therapeutic responses to injury. However, the mechanism of induction of FBG secretion after injury is incompletely understood. This study investigated the role of the inflammatory mediator interleukin-6 (IL-6) in endogenous FBG secretion following blunt trauma. Our hypothesis is that trauma-induced circulating IL-6 is essential for upregulation of circulating FBG.
Methods: 8-week-old male wild type C57BL/6 (WT) and IL-6 deficient (IL-6-/-) mice were injured, then sacrificed at the time points indicated below (n=3 mice per time point) by CO2 inhalation with cardiac puncture for blood collection. Citrated blood was processed into plasma, and ELISA for FBG and IL-6 were performed. Injury was induced using a modified version of the method described by Pape et al (J Surg Res 2011). Open muscle trauma was induced by clamping a large needle driver around the body of the gastrocnemius for 30s.
Results: Figure 1A shows plasma levels of IL-6 before and after injury in WT mice. IL-6 peaks above 60pg/mL 4-8 hours post-injury from a baseline (t=0) below 5pg/mL. Levels return to baseline at 48 hours post-injury. Plasma IL-6 was undetectable in IL-6-/- mice.
Figure 1B shows plasma fibrinogen levels in WT and IL-6-/- mice following injury. In WT mice, FBG levels began to rise at the earliest time point – 4 hours, peak at 24 hours and then decline. In IL-6-/- mice, there is no immediate rise in FBG in response to trauma. A blunted, delayed increase in circulating FBG does occur between 24 and 48 hours post-injury.
Conclusion: The results presented in this study indicate that circulating IL-6 is essential for physiologic upregulation of FBG in response to trauma. This finding is in line with past work showing that IL-6 is regulates hepatic secretion of additional coagulation proteins. In this sense, IL-6 can be viewed as an “SOS” signal released from damaged tissue, inducing the production of essential hemostatic proteins consumed at the site of injury. This schema is illustrated in Figure 1C. Future studies are needed to determine the mechanism of IL-6 release from damaged tissue, and its induction of FBG secretion from the liver. These studies could serve as proof of principle for therapeutic trials designed to treat the pathophysiologic conditions of diminished (hypocoagulable) or excessive (hypercoagulable) circulating FBG.
