Plasma for prevention and treatment of glycocalyx degradation in trauma and sepsis

The endothelial glycocalyx, a gel-like layer that lines the luminal surface of blood vessels, is composed of proteoglycans, glycoproteins, and glycosaminoglycans. The endothelial glycocalyx plays an essential role in vascular homeostasis, and its degradation in trauma and sepsis can lead to microvascular dysfunction and organ injury. While there are no proven therapies for preventing or treating endothelial glycocalyx degradation, some initial literature suggests that plasma may have a therapeutic role in trauma and sepsis patients. Overall, the literature suggesting the use of plasma as a therapy for endothelial glycocalyx degradation is non-clinical basic science or exploratory. Plasma is an established therapy in the resuscitation of patients with hemorrhage for restoration of coagulation factors. However, plasma also contains other bioactive components, including sphingosine-1 phosphate, antithrombin, and adiponectin, which may protect and restore the endothelial glycocalyx, thereby helping to maintain or restore vascular homeostasis. This narrative review begins by describing the endothelial glycocalyx in health and disease: we discuss the overlapping disease mechanisms in trauma and sepsis that lead to its damage and introduce plasma transfusion as a potential therapy for prevention and treatment of endothelial glycocalyx degradation. Second, we review the literature on plasma as an exploratory therapy for endothelial glycocalyx degradation in trauma and sepsis. Third, we discuss the safety of plasma transfusion by reviewing the adverse events associated with plasma and other blood product transfusions, and we examine modern transfusion precautions that have enhanced the safety of plasma transfusion. We conclude that the literature proposes that plasma may have the potential to prevent and treat endothelial glycocalyx degradation in trauma and sepsis, indicating the need for further research. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-024-05026-7.


Endothelial barrier function
Pearson correlation analysis of syndecan-1 and antithrombin III (ATIII) levels, measured on the third day of hospital stay, revealed a significant negative correlation.This indicates that higher levels of syndecan-1 are associated with lower levels of ATIII .(R= -0.62;P < 0.0001).
In an in vitro model of HVLMEC FFP and ATIII prevented TNF-ɑ induced permeability (P < 0.05), and ATIII deficient FFP had no effect.ATIII restoration reestablished its protective effects in a dose-dependent manner.
In mice syndecan-1 expression was increased following FFP resuscitation and no improvement in syndecan-1 expression was seen with ATIII deficient FFP.

White blood cell binding
In the in vitro studies, FFP and lyophilized plasma had similar protective effects on the endothelial cells.They both similarly decreased endothelial cell permeability, increased transendothelial resistance, decreased white blood cell binding and maintained the adherens junctions.
In the in vivo studies, FFP and lyophilized plasma similarly reduced injury, vascular leak and inflammation in the lungs.

Biomarkers of inflammation and endothelial function
There was no difference in short term mortality between groups (38% LR group vs 47% plasma group, p=0.62).
There was no difference in total alveolar protein between groups ( 129.7 LR group vs 123.4 mg/ml plasma group, p=0.11).
Resuscitation with plasma was associated with a decrease in the expression of inflammatory genes in the lungs.
Supplemental Table 1: Selected Preclinical Studies of Plasma in Trauma

Table 2 :
Resuscitation with FFP after shock decreased endothelial permeability by enhancing endothelial monolayer resistance.This improvement was due to the restoration of VE-cadherin and β-catenin in the endothelial cells post-FFP treatment, an effect not observed with lactated Ringer's resuscitation.Additionally, FFP inhibited WBC infiltration, reduced degradation of endothelial adherens and tight junctions, and corrected MAP and base excess induced by hemorrhagic shock.Syndecan-1 levels were significantly higher after resuscitation with lactated Ringer or Hextend compared to FFP, showing about a 160% increase from baseline, versus an 80% increase with FFP.Despite this, all resuscitation methods-lactated Ringer, Hextend, and FFP-improved blood pH, lactic acid, base excess, and respiratory rate, with FFP yielding the most significant recovery.Selected Clinical Studies of Plasma in Trauma Syndecan-1 immunostaining decreased after endothelial injury but was restored to higher levels upon resuscitation with FFP (114 RFU vs. 228 RFU, respectively).Fresh Frozen Plasma (FFP), Tumor necrosis factor alpha (TNF-ɑ), Antithrombin-III (ATIII), Human Lung Microvascular Endothelial Cells (HLMVEC), Relative Fluorescence Units Supplemental

Table 3 :
Preclinical Studies of Plasma in Sepsis The use of FFP resulted in a significant increase in survival rates, with 57% in the FFP group compared to 14% in the control group at 48 hours.Additionally, FFP was associated with reduced levels of norepinephrine (3.8 ng/mL in the FFP group vs 8.9 ng/mL in the control group), interleukin-6 (IL-6) (3.8 ng/mL in the FFP group vs 18.7 ng/mL in the control group), and syndecan-1 (21.8 ng/mL in the FFP group vs 31.0 ng/mL in the control group).DIC was significantly higher in the standard of care group compared to the intervention group (45 % vs 10 % respectively, p<0.0001)