Activation of the protein C pathway and endothelial glycocalyx shedding is associated with coagulopathy in an ovine model of trauma and hemorrhage

Zyl, Natasha van; Milford, Elissa M.; Diab, Sara; Dunster, Kimble; McGiffin, Peter; Rayner, Stephen; Staib, Andrew; Reade, Michael C.; Fraser, John F.

doi:10.1097/ta.0000000000001190

Cited by 22 publications

(21 citation statements)

References 46 publications

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“…This finding indicates that catecholamine release activates the inflammatory response in trauma and induction of TNF‐α may be the mechanism for EG loss as previously hypothesized 157 . In experimental animal shock models and clinical human trials, a large catecholamine surge and tissue hypoperfusion that occur in shock appear to be associated with widespread loss of the EG 129,155 . Massive EG loss in trauma is associated with increased vascular permeability, increased systemic inflammation, hypocoagulability, and reduced vascular responsivess 116,129,130 …”

Section: Disease States Leading To Glycocalyx Dysfunctionsupporting

confidence: 59%

“…In people, clinical studies have demonstrated an increase in EG biomarkers, including HS, HA, SDC1, and CS, after trauma or hemorrhagic shock 130,153 . Unfortunately, there are currently no clinical veterinary studies investigating the link between EG degradation and trauma; however, animal hemorrhagic shock models have demonstrated EG loss after serious hemorrhage 154,155 …”

Section: Disease States Leading To Glycocalyx Dysfunctionmentioning

confidence: 99%

“…Acute traumatic coagulopathy has a complex and incompletely understood pathophysiology that is beyond the scope of this review 159 . However, a correlation between increased EG biomarkers and hypocoagulability in human trauma patients has been demonstrated, which suggests that EG damage may play a role in acute traumatic coagulopathy 129,155 . One theory is that GAGs, particularly HS and CS, which are shed after a traumatic insult, act systemically as anticoagulants; this phenomenon has been termed “endogenous heparinization.” 116,160 In 2 prospective studies of human trauma patients, increased SDC1, used as a marker of EG degradation, was associated with endogenous heparinization as evidenced by a hypocoagulable thromboelastography tracing 116,118 .…”

Section: Disease States Leading To Glycocalyx Dysfunctionmentioning

confidence: 99%

“…130,153 Unfortunately, there are currently no clinical veterinary studies investigating the link between EG degradation and trauma; however, animal hemorrhagic shock models have demonstrated EG loss after serious hemorrhage. 154,155 Similar to sepsis, a suggested mechanism for EG degradation in trauma is related to the large catecholamine release and tissue hypoperfusion that occurs with shock; it is hypothesized that this leads to the direct loss of the EG. 129,156 The link between sympathetic stimulation and EG degradation in trauma was demonstrated experimentally in murine hemorrhagic shock models that used either chemical sympathectomy 157 or beta-blockade to investigate the catecholamine effect.…”

Section: Trauma and Hemorrhagementioning

confidence: 99%

“…157 In experimental animal shock models and clinical human trials, a large catecholamine surge and tissue hypoperfusion that occur in shock appear to be associated with widespread loss of the EG. 129,155 Massive EG loss in trauma is associated with increased vascular permeability, increased systemic inflammation, hypocoagulability, and reduced vascular responsivess. 116,129,130 Of particular interest is the relationship between EG dysfunction and development of coagulation abnormalities in trauma.…”

Section: Trauma and Hemorrhagementioning

confidence: 99%

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The endothelial glycocalyx: Structure and function in health and critical illness

Gaudette

Hughes

Boller

2020

J Vet Emergen Crit Care

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Objective To conduct a narrative review of the current literature in reference to the structure and function of the endothelial glycocalyx (EG) and its contribution to the pathophysiology of conditions relevant to the veterinary emergency and critical care clinician. Novel therapies for restoring or preserving the EG will also be discussed. Data Sources Online databases (PubMed, CAB abstracts, Scopus) were searched between January 1st 2017 and May 1st 2017 for English language articles without publication date restriction. Keywords included EG, endothelial surface layer, degradation, syndecan‐1, heparan sulfate, critical illness, sepsis, trauma, and therapeutics. Data Synthesis The EG is a complex and important structure located on the luminal surface of all blood vessels throughout the body. It plays an important role in normal vascular homeostasis including control of fluid exchange across the vascular barrier. Loss or degradation of the EG has an impact on inflammation, coagulation, and vascular permeability and tone. These changes are essential components in the pathophysiology of many conditions including sepsis and trauma. A substantial body of experimental animal and human clinical research over the last decade has demonstrated increased circulating concentrations of EG degradation products in these conditions. However, veterinary‐specific research into the EG and critical illness is currently lacking. The utility of EG degradation products as diagnostic and prognostic tools continues to be investigated and new therapies to preserve or improve EG structure and function are under development. Conclusions The recognition of the presence of the EG has changed our understanding of transvascular fluid flux and the pathophysiology of many conditions of critical illness. The EG is an exciting target for novel therapeutics to improve morbidity and mortality in conditions such as sepsis and trauma.

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Section: Disease States Leading To Glycocalyx Dysfunctionsupporting

confidence: 59%

Section: Disease States Leading To Glycocalyx Dysfunctionmentioning

confidence: 99%

Section: Disease States Leading To Glycocalyx Dysfunctionmentioning

confidence: 99%

Section: Trauma and Hemorrhagementioning

confidence: 99%

Section: Trauma and Hemorrhagementioning

confidence: 99%

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The endothelial glycocalyx: Structure and function in health and critical illness

Gaudette

Hughes

Boller

2020

J Vet Emergen Crit Care

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The protective effect of hydroxyethyl starch solution on the glycocalyx layer in an acute hemorrhage mouse model

et al. 2019

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Purpose Fluid therapy focused on glycocalyx (GCX) protection in hemorrhagic shock is a current focus of research. Hydroxyethyl starch (HES) solution is commonly used for fluid resuscitation; however, its effects on the GCX remain unclear. The primary aim of this study was to explore the protective effect of HES130 in maintaining GCX thickness and reducing plasma syndecan-1 expression. Methods An acute hemorrhage murine model with the dorsal skin chambers was used to measure GCX thickness and to evaluate vascular permeability. Groups of mice were treated with normal saline (NS), albumin (NS-A), HES130 (NS-V), or no exsanguination or infusion (C). We measured syndecan-1 plasma concentrations, performed blood gas analysis, and analyzed the 7-day cumulative mortality. Results GCX thickness in NS mice was significantly reduced compared to that in group C, but no other groups showed a difference compared to group C. The plasma concentration of syndecan-1 was significantly higher in NS mice than in group C. There were no significant differences in the fluorescence intensity of dextran in the interstitial space. HES70 leakage was suppressed in NS-V mice compared to those in other groups. HES70 was localized to the inner vessel wall in C, NS, and NS-A mice, but not in group NS-V. Blood gas analysis indicated that pH and lactate showed the greatest improvements in NS-V mice. The 7-day cumulative mortality rate was the highest in group NS. Conclusion Resuscitation with HES130 protected the GCX and suppressed vascular permeability of HES70 during early stages of acute massive hemorrhage.

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The current understanding of trauma-induced coagulopathy (TIC): a focused review on pathophysiology

et al. 2017

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The emergency management of acute severe bleeding in trauma patients has changed significantly in recent years. In particular, greater attention is now being devoted to a prompt assessment of coagulation alterations, which allows for immediate haemostatic resuscitation procedures when necessary. The importance of an early trauma-induced coagulopathy (TIC) diagnosis has led physicians to increase the efforts to better understand the pathophysiological alterations observed in the haemostatic system after traumatic injuries. As yet, the knowledge of TIC is not exhaustive, and further studies are needed. The aim of this review is to gather all the currently available data and information in an attempt to gain a better understanding of TIC. A comprehensive literature search was performed using MEDLINE database. The bibliographies of relevant articles were screened for additional publications. In major traumas, coagulopathic bleeding stems from a complex interplay among haemostatic and inflammatory systems, and is characterized by a multifactorial dysfunction. In the abundance of biochemical and pathophysiological changes occurring after trauma, it is possible to discern endogenously induced primary predisposing conditions and exogenously induced secondary predisposing conditions. TIC remains one of the most diagnostically and therapeutically challenging condition.

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Activation of the protein C pathway and endothelial glycocalyx shedding is associated with coagulopathy in an ovine model of trauma and hemorrhage

Cited by 22 publications

References 46 publications

The endothelial glycocalyx: Structure and function in health and critical illness

The endothelial glycocalyx: Structure and function in health and critical illness

The protective effect of hydroxyethyl starch solution on the glycocalyx layer in an acute hemorrhage mouse model

The current understanding of trauma-induced coagulopathy (TIC): a focused review on pathophysiology

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