Modulation of Syndecan-1 Shedding after Hemorrhagic Shock and Resuscitation

Abstract

The early use of fresh frozen plasma as a resuscitative agent after hemorrhagic shock has been associated with improved survival, but the mechanism of protection is unknown. Hemorrhagic shock causes endothelial cell dysfunction and we hypothesized that fresh frozen plasma would restore endothelial integrity and reduce syndecan-1 shedding after hemorrhagic shock. A prospective, observational study in severely injured patients in hemorrhagic shock demonstrated significantly elevated levels of syndecan-1 (554±93 ng/ml) after injury, which decreased with resuscitation (187±36 ng/ml) but was elevated compared to normal donors (27±1 ng/ml). Three pro-inflammatory cytokines, interferon-γ, fractalkine, and interleukin-1β, negatively correlated while one anti-inflammatory cytokine, IL-10, positively correlated with shed syndecan-1. These cytokines all play an important role in maintaining endothelial integrity. An in vitro model of endothelial injury then specifically examined endothelial permeability after treatment with fresh frozen plasma orlactated Ringers. Shock or endothelial injury disrupted junctional integrity and increased permeability, which was improved with fresh frozen plasma, but not lactated Ringers. Changes in endothelial cell permeability correlated with syndecan-1 shedding. These data suggest that plasma based resuscitation preserved endothelial syndecan-1 and maintained endothelial integrity, and may help to explain the protective effects of fresh frozen plasma after hemorrhagic shock.

Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids

“…In our protocol, complete glycocalyx restoration occurred following infusion of smaller plasma volumes than previously reported (32). The data support the concept of vascular stabilization by infused plasma (23), in which glycocalyx recovery is an important component. The early use of FFP as a resuscitative agent has been associated with improved survival after hemorrhagic shock (11,28,31).…”

“…The disruption of endothelial integrity by hemorrhagic shock leading to syndecan-1 shedding, observed in this work, has been reported previously (23). Measurements of glycocalyx thickness in syndecan-1-deficient mice suggest that the lack of syndecan-1 may be compensated by the increase in expression of other proteoglycans.…”

“…Rat FFP contains all known coagulation and anticoagulant proteins in concentrations found in normal rat blood. Therefore, in addition to its effects on the endothelium, the infused plasma may exert its positive effects by replacing lost coagulation factors, (re)-establishing hemostasis, and reversing coagulopathy (23).…”

Mechanisms of trauma-induced coagulopathy

“…Haywood-Watson et al found elevated plasma syndecan-1 concentration in severely injured trauma patients in hemorrhagic shock. 39 They also found that 3 proinflammatory cytokines, IFN-␥, IL-1␤, and fractalkine, were negatively associated with plasma syndecan-1 levels, presumably by their binding and activation of endothelium. These investigators then showed that endothelial barrier function was reduced in association with shedding of syndecan-1 and that this process was inhibited by application of fresh frozen plasma in vitro.…”

The volume-expanding effects of autologous liquid stored plasma following hemorrhage

“…Our hemorrhage also differs from clinical practice in which a state of systemic inflammation with increased microvascular permeability, tissue damage and prolonged hypovolemia often exist. FFP may counteract glycocalyx sheeding and permeability increases following hemorrhage indicate that the volume expanding properties of FFP may depend on the prevailing pathophysiology [19,20].…”