Secondary Logo

Journal Logo

Methodological Aspects

Resuscitative Strategies to Modulate the Endotheliopathy of Trauma: From Cell to Patient

Wu, Feng; Chipman, Amanda; Pati, Shibani; Miyasawa, Byron; Corash, Laurence‡,§; Kozar, Rosemary A.

Author Information
doi: 10.1097/SHK.0000000000001378
  • Free
  • Editor's Choice



Trauma is the leading cause of death in individuals up to age 46 both in the United States and worldwide, with hemorrhage remaining the number one cause of early trauma deaths in both military and civilian settings (1, 2). Modern resuscitation strategies have significantly reduced early mortality and are based on the experience from combat casualties in recent conflicts. In 2007, Borgman et al. (3) first reported that the ratio of transfused plasma to red blood cells influenced survival. Subsequent civilian studies have confirmed their results and are the foundation for hemostatic-based resuscitation. This strategy incorporates the early use of blood component therapy approximating a 1:1:1 ratio of plasma, platelets, and red blood cells into the initial management of injured patients in hemorrhagic shock (4–8).

Severely injured patients can present coagulopathic. This distinct form of traumatic-induced coagulopathy (TIC) occurs early and is associated with increased transfusions, complications, and mortality (9). The pathophysiology of TIC is attributed to activation of coagulation, hyperfibrinolysis, and consumption coagulopathy. Some argue that the pathophysiological mechanisms are similar to the characteristics of disseminated intravascular coagulation with the fibrinolytic phenotype (10, 11). The decrease in mortality from plasma-based resuscitative strategies appears to extend beyond its ability to correct trauma-induced coagulopathy and provide hemorrhage control and is hypothesized to involve additional protective effects to the post-shock dysfunctional endothelium. Survivors of hemorrhagic shock (HS) demonstrate an “endotheliopathy of trauma (EoT)” which is a systemic response resulting in disturbances of coagulation, inflammation, and endothelial barrier integrity (12). Clinically, this is manifested as a pro-inflammatory state with vascular leak and tissue edema, which contributes to organ dysfunction and late morbidity and deaths. Therefore, restoring the endothelium and barrier integrity is integral to further reducing hemorrhage-related morbidity and mortality.



The endothelial glycocalyx is a complex network of soluble components that projects from the cell surface of the endothelium into the vessel lumen (13–16). This network is a thick (about 0.2–3.0 μm in vivo), negatively charged carbohydrate-rich layer lining the vascular endothelium (17, 18). It is formed by cell membrane-bound sulfated proteoglycans, consisting of a core protein (e.g., transmembrane syndecan, membrane-bound glypican, or matrix-associated perlecan) with glycosaminoglycan side chains (e.g., heparan sulfate, hyaluronic acid, and chondroitin sulfate), and cell membrane glycoproteins attached with sialoproteins (13–16). The syndecan family is comprised of four members (syndecan-1 through -4) and is the major source of cell surface heparan sulfate (13, 14, 19, 20). Cell surface syndecans function primarily as receptors for heparan sulfate-binding molecules or as modulators when their extracellular domain is released from the cell surface by ectodomain shedding (13, 14, 20–23). Syndecan-1 is found on endothelial cells and believed to account for endothelial integrity (18, 24–28). Under physiologic conditions, positively charged soluble components (such as plasma proteins, enzymes, growth factors, cytokines, amino acids, and cations) and water are trapped in the glycocalyx forming an extended endothelial surface layer (16, 17, 22, 23). The glycocalyx serves as an effective barrier to prevent leukocyte-endothelial cell and platelet-endothelial cell adhesion by providing steric hindrance between receptor and ligand, thereby blocking adhesion to the underlying endothelium (18, 19–21, 24, 25). Although much of the literature assumes that shed syndecan-1 is a marker of injury to the endothelial glycocalyx, it also found on epithelial cells including in the intestine and lung (29). Additionally, both platelets and red blood cells contain a glycocalyx, though much less is understood regarding their functions (30–33).

Injury to the glycocalyx and shedding of syndecan-1

Shedding of endothelial glycocalyx components has been shown to occur in response to a variety of stressors (34–37). As recently reviewed by Becker et al. (27), loss of the glycocalyx is mediated by “sheddases,” such as matrix metalloproteases, heparanases, hyaluronidases, and proteases and is responsible for endothelial inflammatory changes and vascular hyperpermeability. Shedding of the syndecan-1 ectodomain has been described in a variety of shock states that are summarized in Table 1(37–49). Ectodomains can function as danger-associated pattern molecules (DAMPs) following trauma (47–49). They are associated with enhanced shock, inflammation, and endothelial damage (31, 50–52) and independently predict mortality in injured patients (35–37). Human studies examining syndecan-1 shedding and outcomes after hemorrhagic shock are reviewed in Table 2(34–36, 53–55).

Table 1
Table 1:
Syndecan-1 shedding in human studies of shock states
Table 2
Table 2:
Syndecan-1 shedding and outcomes after hemorrhagic shock

Mechanism of syndecan-1 inhibition by hemorrhagic shock

The precise mechanism by which hemorrhagic shock affects syndecan-1 remains unclear. Although shed syndecan-1 is considered a systemic biomarker for endothelial injury much less is known about syndecan-1 expression and its effect on the endothelium. We have shown in a rodent model that pulmonary syndecan-1 mRNA is significantly reduced following hemorrhagic shock (13), suggesting that microRNAs (miRNAs) may be important. Preliminary studies from our laboratory have demonstrated that miR-19b targets pulmonary endothelial syndecan-1 and is detrimental after hemorrhagic shock, suggesting it contributes to the endotheliopathy of trauma (56, 57). Studies are in progress to determine if resuscitation can inhibit this miRNA.


Glycocalyx and syndecan-1 restitution

Crystalloids and colloids

We and others have shown that crystalloids, either saline or lactated Ringers (LR), fail to restore glycocalyx functional integrity following hemorrhagic shock (13, 58). In a rat model of fixed volume hemorrhage, Torres et al. (59) demonstrated that Hextend, similar to LR, decreased glycocalyx thickness and increased plasma syndecan-1 levels compared to levels in sham and fresh frozen plasma (FFP) treated animals. This same group then demonstrated that endothelial glycocalyx thickness was only partially restored by albumin, but was completely restored by FFP (60). However, shed syndecan-1 levels were comparably reduced by albumin and FFP. Glycocalyx thickness (negatively), and microvascular permeability (positively), were correlated with plasma syndecan-1 and heparin sulfate levels. Overall, resuscitation with crystalloid solutions (saline or LR) caused glycocalyx damage and worsened permeability. Resuscitation with fresh whole blood or plasma evoked protection, and albumin had an intermediate effect (58–61). Nelson et al. (62) using a rat model of volume-controlled hemorrhage and resuscitation with either FFP, albumin, or LR found that both FFP and albumin restored plasma volume, whereas LR did not. Systemic heparan sulfate levels were lower in the FFP and albumin groups but syndecan-1 levels did not differ.


To begin to investigate the effect of plasma-based resuscitation on the glycocalyx, our laboratory initially employed a pressure-controlled model of hemorrhagic shock followed by resuscitation with FFP or LR (13). Pulmonary syndecan-1 mRNA expression was higher in animals resuscitated with plasma in comparison with shock alone or LR and positively correlated with the intensity of cell surface syndecan-1 immunostaining and lung histopathology. To specifically examine the effect of plasma on the endothelium, we infused small bowel mesentery with a lanthanum-based solution then visualized the endothelial glycocalyx in post capillary venules by electron microscopy (13, 14, 34). We demonstrated degradation of the glycocalyx after hemorrhagic shock, which was partially restored at 3 h by plasma but not LR (13, 14, 34). Additionally, a clinically relevant effect of plasma was suggested by the observation that plasma resuscitation required significantly less volume to maintain the mean arterial pressure (MAP) (13, 14, 34).

We verified our findings in a mouse model of volume-controlled hemorrhagic shock (28). Hemorrhage was associated with systemic shedding of syndecan-1, which correlated with decreased pulmonary syndecan-1 and increased pulmonary vascular hyperpermeability and inflammation. FFP resuscitation, compared with LR resuscitation, abrogated these injurious effects by reducing endothelial cell hyperpermeability and inflammation and restoring pulmonary syndecan-1 expression. Modulation of pulmonary syndecan-1 expression may therefore mechanistically be attributed to the beneficial effects FFP. Additionally, protection by plasma via syndecan-1 was not limited to the lungs. Gut injury and inflammation were significantly increased by hemorrhage compared with shams (63). Resuscitation with LR decreased both injury and inflammation, but these effects were further lessened by FFP.

To verify the role of syndecan-1 in plasma's protection we used siRNA to silence syndecan-1 in vitro and found that while FFP enhanced pulmonary endothelial syndecan-1 expression in a time- and dose-dependent manner, the loss of syndecan-1 expression in pulmonary endothelial cells actually increased permeability and stress fiber formation after exposure to FFP (24). Loss of syndecan-1 in vivo using syndecan-1 null mice led to equivalency between LR and FFP in restoring pulmonary injury, inflammation, and permeability after shock. Similarly, syndecan-1 null mice displayed worsened gut injury and inflammation after HS compared with wild-type mice; and LR and FFP equivalently inhibited injury and inflammation in null mice, again demonstrating the link between protection by plasma and syndecan-1.

These observations were confirmed by the work of Torres et al. (58, 59). Using a 40% blood volume hemorrhage model, the authors resuscitated rats using LR. The authors confirmed that the endothelial glycocalyx was significantly damaged by hemorrhagic shock and restored only with FFP, as assessed by circulating syndecan-1 levels and glycocalyx thickness. Second, a clinically beneficial effect of plasma-based resuscitation was indicated by the fact that FFP corrected metabolic acidosis significantly better than LR and hextend, as assessed by pH, base excess, and lactate. This was associated with an improved microcirculation and a lesser degree of hemodilution by FFP compared to LR and hextend. This latter point was also observed in a recent publication of Nelson et al. (62) who demonstrated that resuscitation with FFP resulted in circulating volume expansion equaling the volume of blood loss, while circulating volume expansion by LR was less effective.

Risks and challenges with the use of plasma

The use of plasma is not without risks and challenges. Blood components are still subject to contamination from a variety of pathogens such as viruses, bacteria, and parasites, including emerging pathogens such as the Zika virus. To reduce the risk of transfusion-transmitted infectious disease (TTID), pathogen reduction technologies have been developed. There are two technologies licensed in the United States for plasma (amotosalen-UVA and solvent detergent) and one for platelet concentrates (amotosalen-UVA). A third is still under development; riboflavin (vitamin B2-UV) (64). The INTERCEPT Blood System (Cerus Corporation, Concord, Calif) uses amotosalen (a psoralen) and UVA light to target nucleic acid forming adducts to inhibit replication and inactivation of blood borne pathogens and leukocytes with minimal generation of reactive oxygen species (65). It is intended for use with whole blood derived or apheresis plasma and platelets to reduce the risk of TTID. Among riboflavin-based systems that target pathogen nucleic acids, the Mirasol Pathogen Reduction Technology (Mirasol PRT; CaridianBCT, Lakewood, Colo) uses riboflavin and UV light to introduce irreparable lesions into nucleic acids by reactive oxygen species thereby inhibiting pathogen and white blood cell replication and reducing the load of infectious pathogens (66). There is also commercially available solvent/detergent-treated pooled plasma, OctaplasLG (Octapharma AG, Lachen, Switzerland) that has recently been shown to reduce glycocalyx and endothelial injury compared with FFP in a pilot clinical trial of patients undergoing emergency surgery for thoracic aorta dissection (67).

Timing of plasma administration

Naumann et al. (68) demonstrated that the endotheliopathy of trauma occurred within 5 to 8 min of injury. This finding suggests that the early use of plasma after injury may be beneficial. Indeed, Diebel et al. (69) demonstrated in their in-vitro biomimetic model of endothelial vascular barrier dysfunction following shock that the early use of plasma restored the endothelial glyocalyx and reduced syndecan-1 shedding, while the late use was comparable to shock alone. This supports the concept that the early transfusion of plasma is important to outcomes after hemorrhage. Two prospective randomized trials have in fact examined the effect of plasma transfusion on mortality in the prehospital setting. A study by Sperry et al. (70) demonstrated significantly lower 30-day mortality in injured patients at risk for hemorrhagic shock who received prehospital plasma compared with standard of care therapy with crystalloids. However, a similar study, but with rapid ground rescue, showed no survival benefit (71).

Alternative plasma preparations

In large urban civilian trauma centers, thawed plasma with 5-day shelf life is now frequently available immediately upon patient arrival in emergency rooms. However, in military and remote or austere civilian settings, the rapid availability of plasma is limited (72). Fresh frozen plasma requires approximately 30 min to thaw and then must be stored at 4°C and used within 5 days. These logistical challenges have led to intense developments of dried plasma products, which can be lyophilized or spray dried. To date, there are no dried plasma products available that are FDA approved, though a number are in development. A French product, FLYP, is currently being used by the United States Special Operations Command (SOCOM) under an expanded use authorization. This product is lyophilized and pathogen reduced by amotosalen-UVA treatment (73). A retrospective study from France recently demonstrated that use of this product was associated with earlier and a more rapid transfusion ratio (plasma: RBC) improvement compared with FFP (74). We and others have been interested in the endothelial protective effects of dried plasma products. Both in vitro and in vivo studies have thus far confirmed similar protective effects to FFP (75–78). Pati et al. (79) evaluated the prothrombin complex factor concentrate, Kcentra (CSL Behring), in a mouse model of hemorrhagic shock-induced pulmonary vascular leak. Interestingly, Kcentra and FFP; but not albumin, inhibited vascular permeability in their model. Kcentra contains nearly 100 proteins, including albumin, prothrombin, factors VII, IX, and X, proteins C and S, and antithrombin III. As in the case of FFP, the precise proteins in Kcentra responsible for the observed effects remain uncertain.


Fibrinogen stabilization of syndecan-1

Fibrinogen is a 340-kDa homodimeric glycoprotein comprised of two alpha, two beta, and two gamma polypeptide chains linked by disulfide bridges (80, 81). The 15–42 sequence of the beta chain of fibrinogen has been shown to mediate platelet and endothelial cell spreading, fibroblast proliferation, and capillary tube formation (82–84). Interaction between this sequence and the endothelial cell receptor, vascular endothelial (VE)-cadherin, has been shown to promote capillary tube formation and angiogenesis (85). We recently investigated the contribution of fibrinogen to the endothelial protection afforded by plasma. When pulmonary endothelial cells were incubated in plasma or fibrinogen-deficient plasma, fibrinogen depleted plasma-treated cells demonstrated comparable levels of permeability to LR-treated cells (25). This finding was associated with both an increase in stress fiber formation and a decrease in pulmonary syndecan-1 immunostaining. In addition, we confirmed a comparable decrease in permeability in vitro with FFP and fibrinogen. This led us to further explore the mechanism by which fibrinogen may interact with syndecan-1 on the cell surface. Using colocalization and co-immunoprecipitation experiments, we demonstrated that fibrinogen associates with syndecan-1. We hypothesize that this occurs between the beta chain of fibrinogen that has known heparan sulfate binding sites and the heparan sulfate moieties attached to syndecan-1 (83, 85). Potential mechanisms by which fibrinogen could stabilize cell surface syndecan-1 and provide endothelial protection may include modulation of sheddases or regulation of gene expression. Binding of fibrinogen to syndecan-1 may shield the cleavage sites of syndecan-1 by its known sheddases, thus stabilizing syndecan-1 on the cell surface. The second mechanism is that fibrinogen binding may activate an intracellular signaling pathway which positively feeds back to increase syndecan-1 gene expression. Our preliminary studies suggest that the PAK1 pathway may be important (86). These results demonstrate an endothelial barrier protective effect for fibrinogen, which may support the early use of fibrinogen as a therapeutic intervention for hemorrhagic shock. Indeed, other studies also demonstrated that fibrinogen-derived peptide B-beta (15–42) preserves endothelial barrier function in shock (87, 88). Figure 1 illustrates a proposed pathway for protection of the endothelium by fibrinogen following hemorrhagic shock.

Fig. 1
Fig. 1:
Summary of proposed pathway for fibrinogen's protection of the endothelium.

Fibrinogen for hemostasis

Fibrinogen plays a key role in hemostasis by acting as an endogenous substrate for fibrin formation, promoting clot formation and platelet aggregation by binding platelet glycoprotein IIb/IIIa receptors. Hypofibrinogenemia is known to be associated with worse outcomes after trauma (89, 90); and the degree of hypofibrinogenemia is correlated with increased injury severity (91). There are an increasing number of reports describing the limitations of FFP for treating ongoing severe hypofibrinogenemia in critically injured patients (92, 93). In the RETIC trial, a prospective randomized pilot trial in Austria, patients received either fibrinogen concentrate and/or prothrombin concentrate or FFP once low fibrinogen was confirmed in bleeding patients. The trial was stopped early for futility due to possible harm in patients receiving plasma (94).

As fibrinogen is the first coagulation factor to fall below a critical value during massive bleeding, it seems plausible that it should be the first protein to be given to patients with trauma. A systematic review of 91 studies evaluating the outcome of FFP or fibrinogen concentrate administration to patients in a perioperative or massive trauma setting concluded that the use of fibrinogen concentrate was associated with improved outcomes, whereas the evidence for an FFP effect was inconclusive (93). In another retrospective analysis of trauma patients comparing FFP administration to the administration of fibrinogen concentrate, the authors found that red blood cell (RBC) transfusion was reduced in 29% of patients in the fibrinogen group (n = 80) compared with only 3% in the FFP group (n = 601) (95). A meta-analysis of six randomized controlled trials involving 248 patients undergoing elective surgery found that the administration of fibrinogen concentrate led to reduced RBC transfusion without an increase in thrombotic events or mortality (96). Thus, fibrinogen concentrate appears to be an effective and safe alternative to FFP in reducing the need for allogeneic blood transfusion in bleeding patients.

There are three randomized controlled trials in progress or recently completed investigating early fibrinogen concentrate replacement in injured patients in hemorrhagic shock. The early fibrinogen concentrate therapy for major hemorrhage in trauma (E-FIT1) trial in the United Kingdom enrolled injured patients requiring activation of a major hemorrhage protocol (97). Patients were randomized to fibrinogen concentrate or placebo. The primary outcome was the feasibility of fibrinogen concentrate administration early after patient arrival, defined as > 90% of patients receiving product within 45 min. Despite the use of a lyophilized fibrinogen concentrate with no thaw time, only 69% of patients received the study intervention (fibrinogen concentrate or placebo) within the designated period. This was primarily attributed to the study design with time required for administration of the blinded placebo in addition to the known time of reconstitution of fibrinogen concentrate. In this small study of 39 patients, there were no differences in mortality or transfusion requirements. The fibrinogen in the initial resuscitation of severe trauma (FiiRST) trial was a similar pilot feasibility study of patients randomized to fibrinogen concentrate or placebo to determine the proportion of patients receiving the intervention within 1 h (98). In this study, 96% of patients received the intervention within 1 h. Finally, the PROOF-ith (Pilot Randomized Trial of Fibrinogen in Trauma Haemorrhage, NCT02344069) study is a single-center study also randomizing patients to a pre-emptive dose of fibrinogen concentrate or placebo to determine if fibrinogen concentrate as first-line therapy can increase clot strength as evaluated by thromboelastography (99).


In the United States and United Kingdom, cryoprecipitate is used to replace fibrinogen as part of massive transfusion protocols to control bleeding after trauma. Cryoprecipitate is prepared from plasma and contains fibrinogen, von Willebrand factor, factor VIII, factor XIII and fibronectin. In the United States, at best, massive transfusion protocols include fibrinogen containing products such as cryoprecipitate only late in the protocol and/or in response to low plasma fibrinogen levels. The mean fibrinogen concentration in plasma is approximately 2 g/L and large volumes of plasma (approximately 30 mL/kg) are required to adequately supplement fibrinogen, thus additional sources of fibrinogen such as cryoprecipitate are frequently required.

The CRYOSTAT I study, recently published by Curry et al. (100), demonstrated that the early administration of cryoprecipitate as part of a major hemorrhage protocol is feasible in trauma patients. They observed that 85% of patients randomized to the cryoprecipitate arm received cryoprecipitate within 90 min and the median time to transfusion was 60 min. This is still longer than in the EFIT-1 trial using fibrinogen concentrate. Currently, the CRYOSTAT2 trial is enrolling patients in the United Kingdom. This is a prospective randomized multicenter study in injured patients in shock to receive early empiric cryoprecipitate as part of a massive hemorrhage protocol. Mortality at 30 days is the primary endpoint. Finally, in Australia there is an ongoing exploratory multicenter randomized study comparing fibrinogen concentrate to cryoprecipitate in bleeding patients, the FEISTY (Fibrinogen Early In Severe Trauma study, NCT02745041) Trial (101). Importantly, in this study, thromboelastography will guide dosing in both groups with the primary endpoint being time to fibrinogen supplementation.

We were interested in exploring whether cryoprecipitate would have endothelial protective effects similar to FFP. We therefore performed preliminary experiments to investigate the effect of cryoprecipitate on the endothelium. As there is now a pathogen-reduced cryoprecipitate, we included both conventional and pathogen-reduced cryoprecipitate. As shown in Figures 2 and 3, both conventional and pathogen-reduced cryoprecipitate had comparable endothelial protective effects.

Fig. 2
Fig. 2:
Endothelial cell permeability is reduced by cryoprecipitate.
Fig. 3
Fig. 3:
Endothelial cell resistance after treatment with cryoprecipitate.

Cryoprecipitate-reduced plasma is the residual supernatant from the process used to make cryoprecipitated antihemophilic factor (AHF) (102). The FDA has indicated in a guideline published in 2017 that cryoprecipitated AHF can be prepared from pathogen-reduced plasma frozen within 8 h of collection to provide pathogen-reduced derivative components (pathogen-reduced cryoprecipitate (PCR) and pathogen-reduced plasma cryoprecipitate reduced (PRPCR)). The effects of PRPCR on endothelial cell function are largely unknown, but the retention of some fibrinogen and data from prior studies suggests that it may be effective to maintain endothelial cell function (25). Data shown in Figure 4 suggests that it indeed maintains endothelial protective effects comparable to FFP. PRPCR retains antithrombotic protein activities (i.e., normal levels of antithrombin III, protein C, and protein S), while minimizing pro-thrombotic proteins (reduced factor VIII, fibrinogen, and von Willebrand factor) indicating that the risk of excessive prothrombotic risk should be minimal (102). This may in fact be an ideal product to treat endothelial dysfunction in nonbleeding conditions such as sepsis and burns. There are recent preclinical data supporting the use of FFP for both sepsis and burns (103, 104).

Fig. 4
Fig. 4:
Endothelial cell permeability is reduced by pathogen-reduced plasma (PRP) and pathogen-reduced plasma cryoprecipitate reduced (PRPCR).


Advances in hemostatic resuscitation have not only improved outcomes in injured patients with hemorrhagic shock but have been accompanied by a more in-depth knowledge of how hemostatic blood products mitigate the endotheliopathy of trauma and repair the dysfunctional endothelium. As mechanisms of injury are better understood, research is focusing on a more “personalized” approach to repair the endothelium using not just plasma but newer alternatives such as cryoprecipitate and fibrinogen. Additionally, as plasma becomes safer and more available with pathogen reduction and freeze-fried technologies, the use of plasma and its byproducts may be expanded to treat nonhemorrhagic-related disease states similarly associated with a dysfunctional endothelium.


1. CDC. Deaths: final data for 2009. US Department of Health and Human Services, CDC, National Center for Health Statistics. 2010.
2. Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 60:S3–11, 2006.
3. Borgman M, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB. Blood product replacement affects survival in patients receiving massive transfusions at a combat support hospital. J Trauma 63:805–813, 2007.
4. Holcomb JB, Wade CE, Michalek JE, Chisholm GB, Zarzabal L, Schreiber MA, Gonzalez EA, Pomper GJ, Perkins JG, Spinella PC, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 248:447–458, 2008.
5. Holcomb JB, del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, Alarcon LH, Bai Y, Brasel KJ, Bulger EM, et al. the PROMMTT Study Group. The prospective, observational, multicenter, massive transfusion study, PROMMTT: comparative effectiveness of a time-varying treatment and competing risks. JAMA Surg 148:127–136, 2013.
6. Holcomb JB, Zarzabal LA, Michalek JE, Kozar RA, Spinella PC, Perkins JG, Matijevic N, Dong JF, Pati S, Wade CE, et al. Trauma Outcomes Group. Increased platelet: RBC ratios are associated with improved survival after massive transfusion. J Trauma 71: (2 suppl 3): S318–S328, 2011.
7. Cotton BA, Reddy N, Hatch QM, Lefebvre E, Wade CE, Kozar RA, Gill BS, Albarado R, McNutt MK, Holcomb JB. Damage control resuscitation is associated with a reduction in resuscitation volumes and improvement in survival in 390 damage control laparotomy patients. Ann Surg 254 (4):598–605, 2011.
8. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, et al. the PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 313:471–482, 2015.
9. Chang R, Cardenas JC, Wade CE, Holcomb JB. Advances in the understanding of trauma-induced coagulopathy. Blood 128:1043–1049, 2016.
10. Hayakawa M. Pathophysiology of trauma-induced coagulopathy: disseminated coagulation with the fibrinolytic phenotype. J Intensive Care 5:14, 2017.
11. Gando S, Hayakawa M. Pathophysiology of trauma-induced coagulopathy and management of critical requiring massive transfusion. Semin Thromb Hemost 42 (2):155–165, 2016.
12. Jenkins DH, Rappold JF, Badloe JF, Berséus O, Blackbourne L, Brohi KH, Butler FK, Cap AP, Cohen MJ, Davenport R, et al. THOR position paper on remote damage control resuscitation: definitions, current practice and knowledge gaps. Shock 41: (suppl 1): 3–12, 2014.
13. Kozar RA, Peng Z, Zhang R, Holcomb JB, Pati S, Park P, Ko TC, Paredes A. Plasma restoration of endothelial glycocalyx in a rodent model of hemorrhagic shock. Anesth Analg 112:1289–1295, 2011.
14. Kozar RA, Pati S. Syndecan-1 restitution by plasma after hemorrhagic shock. J Trauma Acute Care Surg 78: (6 suppl 1): S83–S86, 2015.
15. Kolářová H, Ambrůzová B, Svihálková Šindlerová L, Klinke A, Kubala L. Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediators Inflamm 2014:694312, 2014.
16. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454:345–359, 2007.
17. Barelli S, Alberio L. The role of plasma transfusion in massive bleeding: protecting the endothelial glycocalyx? Front Med (Lausanne) 5:91, 2018.
18. Yang Y, Schmidt EP. The endothelial glycocalyx: an important regulator of the pulmonary vascular barrier. Tissue Barriers 1 (1):23494, 2013.
19. Park PW, Reizes O, Bernfield M. Cell surface heparan sulfate proteoglycans: selective regulators of ligand-receptor encounters. J Biol Chem 275:29923–29926, 2000.
20. Nam EJ, Park PW. Shedding of cell membrane-bound proteoglycans. Methods Mol Biol 836:291–305, 2012.
21. Aquino RS, Teng YH, Park PW. Glycobiology of syndecan-1 in bacterial infections. Biochem Soc Trans 46:371–377, 2018.
22. Zeng Y. Endothelial glycocalyx as a critical signalling platform integrating the extracellular haemodynamic forces and chemical signalling. J Cell Mol Med 21:1457–1462, 2017.
23. Zeng Y, Zhang XF, Fu BM, Tarbell JM. The role of endothelial surface glycocalyx in mechanosensing and transduction. Adv Exp Med Biol 1097:1–27, 2018.
24. Wu F, Peng Z, Park PW, Kozar RA. Loss of syndecan-1 abrogates the pulmonary protective phenotype induced by plasma after hemorrhagic shock. Shock 48:340–345, 2017.
25. Wu F, Kozar RA. Fibrinogen protects against barrier dysfunction through maintaining cell surface syndecan-1 in-vitro. Shock 51:740–744, 2019.
26. Becker BF, Chappell D, Jacob M. Endothelial glycocalyx and coronary vascular permeability: the fringe benefit. Basic Res Cardiol 105:687–701, 2010.
27. Becker BF, Jacob M, Leipert S, Salmon AH, Chappell D. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol 80:389–402, 2015.
28. Peng Z, Pati S, Potter D, Brown R, Holcomb JB, Grill R, Wataha K, Park PW, Xue H, Kozar RA. Fresh frozen plasma lessens pulmonary endothelial inflammation and hyperpermeability after hemorrhagic shock and is associated with loss of syndecan 1. Shock 40:195–202, 2013.
29. Zhang Y, Wang Z, Liu J, Zhang S, Fei J, Li J, Zhang T, Wang J, Park PW, Chen Y. Cell surface-anchored syndecan-1 ameliorates intestinal inflammation and neutrophil transmigration in ulcerative colitis. J Cell Mol Med 21 (1):13–25, 2017.
30. Nurden AT. Platelet membrane glycoproteins: a historical review. Semin Thromb Hemost 40:577–584, 2014.
31. Lupu C, Rizescu M, Calb M. Altered distribution of some surface glycosaminoglycans and glycoconjugates on human blood platelets in diabetes mellitus. Platelets 5:201–208, 1994.
32. Oberleithner H. Sodium selective erythrocyte glycocalyx and salt sensitivity in man. Pflugers Arch 467:1319–1325, 2015.
33. Pot C, Chen AY, Ha JN, Schmid-Schönbein GW. Proteolytic cleavage of the red blood cell glycocalyx in a genetic form of hypertension. Cell Mol Bioeng 4:678–692, 2011.
34. Haywood-Watson RJ, Holcomb JB, Gonzalez EA, Peng Z, Pati S, Park PW, Wang WW, Zaske AM, Menge T, Kozar RA. Modulation of syndecan-1 shedding after hemorrhagic shock and resuscitation. PLoS One 6:e23530, 2011.
35. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann Surg 254:194–200, 2011.
36. Ostrowski SR, Johansson PI. Endothelial glycocalyx degradation induces endogenous heparinization in patients with severe injury and early traumatic coagulopathy. J Trauma Acute Care Surg 73:60–66, 2012.
37. Ostrowski SR, Haase N, Müller RB, Møller MH, Pott FC, Perner A, Johansson PI. Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study. Crit Care 19:191, 2015.
38. Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, Bruno R, et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116:1896–1906, 2007.
39. Steppan J, Hofer S, Funke B, Brenner T, Henrich M, Martin E, Weitz J, Hofmann U, Weigand MA. Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg Res 165:136–141, 2011.
40. Sallisalmi M, Tenhunen J, Yang R, Oksala N, Pettilä V. Vascular adhesion protein-1 and syndecan-1 in septic shock. Acta Anaesthesiol Scand 56:316–322, 2012.
41. Grundmann S, Fink K, Rabadzhieva L, Bourgeois N, Schwab T, Moser M, Bode C, Busch HJ. Perturbation of the endothelial glycocalyx in post cardiac arrest syndrome. Resuscitation 83:715–720, 2012.
42. Padberg JS, Wiesinger A, di Marco GS, Reuter S, Grabner A, Kentrup D, Lukasz A, Oberleithner H, Pavenstädt H, Brand M, et al. Damage of the endothelial glycocalyx in chronic kidney disease. Atherosclerosis 234:335–343, 2014.
43. Jung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H. Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock 43:450–455, 2015.
44. Ostrowski SR, Gaïni S, Pedersen C, Johansson PI. Sympathoadrenal activation and endothelial damage in patients with varying degrees of acute infectious disease: an observational study. J Crit Care 30:90–96, 2015.
45. Puskarich MA, Cornelius DC, Tharp J, Nandi U, Jones AE. Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at high risk for intubation after large-volume intravenous fluid resuscitation. J Crit Care 36:125–129, 2016.
46. Di Battista AP, Rizoli SB, Lejnieks B, Min A, Shiu MY, Peng HT, Baker AJ, Hutchison MG, Churchill N, Inaba K, et al. Sympathoadrenal activation is associated with acute traumatic coagulopathy and endotheliopathy in isolated brain injury. Shock 46: (3 suppl 1): 96–103, 2016.
47. Bro-Jeppesen J, Johansson PI, Kjaergaard J, Wanscher M, Ostrowski SR, Bjerre M, Hassager C. Level of systemic inflammation and endothelial injury is associated with cardiovascular dysfunction and vasopressor support in post-cardiac arrest patients. Resuscitation 121:179–186, 2017.
48. Osuka A, Kusuki H, Yoneda K, Matsuura H, Matsumoto H, Ogura H, Ueyama M. Glycocalyx shedding is enhanced by age and correlates with increased fluid requirement in patients with major burns. Shock 50:60–65, 2018.
49. Frydland M, Ostrowski SR, Møller JE, Hadziselimovic E, Holmvang L, Ravn HB, Jensen LO, Pettersson AS, Kjaergaard J, Lindholm MG, et al. Plasma concentration of biomarkers reflecting endothelial cell- and glycocalyx damage are increased in patients with suspected ST-elevation myocardial infarction complicated by cardiogenic shock. Shock 50:538–544, 2018.
50. Chignalia AZ, Yetimakman F, Christiaans SC, Unal S, Bayrakci B, Wagener BM, Russell RT, Kerby JD, Pittet JF, Dull RO. The glycocalyx and trauma: a review. Shock 45:338–348, 2016.
51. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by toll-like receptor 4. J Immunol 168:5233–5239, 2002.
52. Darwiche SS, Ruan X, Hoffman MK, Zettel KR, Tracy AP, Schroeder LM, Cai C, Hoffman RA, Scott MJ, Pape HC, et al. Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury. J Trauma Acute Care Surg 74:1454–1461, 2013.
53. Johansson PI, Stensballe J, Rasmussen LS, Ostrowski SR. High circulating adrenaline levels at admission predict increased mortality after trauma. J Trauma Acute Care Surg 72:428–436, 2012.
54. Gonzalez Rodriguez E, Ostrowski SR, Cardenas JC, Baer LA, Tomasek JS, Henriksen HH, Stensballe J, Cotton BA, Holcomb JB, Johansson PI, et al. Syndecan-1: a quantitative marker for the endotheliopathy of trauma. J Am Coll Surg 225:419–427, 2017.
55. Wei S, Gonzalez Rodriguez E, Chang R, Holcomb JB, Kao LS, Wade CE. Elevated Syndecan-1 after trauma and risk of sepsis: a secondary analysis of patients from the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial. J Am Coll Surg 227 (6):S1072–S7515, 2018.
56. Kozar R, Wu F. MiR19b inhibits Syndecan-1 expression and enhances endothelial barrier dysfunction. Shock 45:S1, 2016.
57. Wu F, Kozar RA. MiRNA-19b is deleterious to syndecan-1 after hemorrhagic shock. Shock 47:S69–S70, 2017.
58. Torres LN, Chung KK, Salgado CL, Dubick MA, Torres Filho IP. Low-volume resuscitation with normal saline is associated with microvascular endothelial dysfunction after hemorrhage in rats, compared to colloids and balanced crystalloids. Crit Care 21:160, 2017.
59. Torres LN, Sondeen JL, Ji L, Dubick MA, Torres Filho I. Evaluation of resuscitation fluids on endothelial glycocalyx, venular blood flow, and coagulation function after hemorrhagic shock in rats. J Trauma Acute Care Surg 75:759–766, 2013.
60. Torres Filho IP, Torres LN, Salgado C, Dubick MA. Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids. Am J Physiol Heart Circ Physiol 310:H1468–H1478, 2016.
61. Torres Filho IP, Torres LN, Salgado C, Dubick MA. Novel adjunct drugs reverse endothelial glycocalyx damage after hemorrhagic shock in rats. Shock 248:583–589, 2017.
62. Nelson A, Statkevicius S, Schött U, Johansson PI, Bentzer P. Effects of fresh frozen plasma, Ringer's acetate and albumin on plasma volume and on circulating glycocalyx components following haemorrhagic shock in rats. Intensive Care Med Exp 4:6, 2016.
63. Ban K, Peng Z, Pati S, Witkov RB, Park PW, Kozar RA. Plasma-mediated gut protection after hemorrhagic shock is lessened in Syndecan-1-/- mice. Shock 44:452–457, 2015.
64. Kaiser-Guignard J, Canellini G, Lion N, Abonnenc M, Osselaer JC, Tissot JD. The clinical and biological impact of new pathogen inactivation technologies on platelet concentrates. Blood Rev 28:235–241, 2014.
65. Corash L, Lin L. Novel processes for inactivation of leukocytes to prevent transfusion-associated graft-versus-host disease. Bone Marrow Transplant 33:1–7, 2004.
66. Reikvam H1, Marschner S, Apelseth TO, Goodrich R, Hervig T. The Mirasol® Pathogen Reduction Technology system and quality of platelets stored in platelet additive solution. Blood Transfusion 8:186–192, 2010.
67. Stensballe J, Ulrich AG, Nilsson JC, Henriksen HH, Olsen PS, Ostrowski SR, Johansson PI. Resuscitation of endotheliopathy and bleeding in thoracic aortic dissections: the VIPER-OCTA randomized clinical pilot trial. Anesth Analg 127:920–927, 2018.
68. Naumann DN, Hazeldine J, Dinsdale RJ, Bishop JR, Midwinter MJ, Harrison P, Hutchings SD, Lord JM. Endotheliopathy of trauma is an on-scene phenomenon, and is associated with multiple organ dysfunction syndrome: a prospective observational study. Shock 49:420–428, 2018.
69. Diebel LN, Martin JV, Liberati DM. Microfluidics: a high-throughput system for the assessment of the endotheliopathy of trauma and the effect of timing of plasma administration on ameliorating shock-associated endothelial dysfunction. J Trauma Acute Care Surg 84:575–582, 2018.
70. Sperry JL, Guyette FX, Brown JB, Yazer MH, Triulzi DJ, Early-Young BJ, Adams PW, Daley BJ, Miller RS, Harbrecht BG, et al. the PAMPer Study Group. Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock. NEJM 379 (4):315–326, 2018.
71. Moore HB, Moore EE, Chapman MP, McVaney K, Bryskiewicz G, Blechar R, Chin T, Burlew CC, Pieracci F, West FB, et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet 392 (10144):283–291, 2018.
72. Pusateri AE, Given MB, Schreiber MA, Spinella PC, Pati S, Kozar RA, Khan A, Dacorta JA, Kupferer KR, Prat N, et al. Dried plasma: state of the science and recent developments. Transfusion 56: (suppl 2): S128–S139, 2016.
73. Martinaud C, Civadier C, Ausset S, Verret C, Deshayes AV, Sailliol A. In vitro hemostatic properties of French lyophilized plasma. Anesthesiology 117 (2):339–346, 2012.
74. Nguyen C, Bordes J, Cungi PJ, Esnault P, Cardinale M, Mathais Q, Cotte J, Beaume S, Sailliol A, Prunet B, et al. Use of French lyophilized plasma transfusion in severe trauma patients is associated with an early plasma transfusion and early transfusion ratio improvement. J Trauma Acute Care Surg 84:780–785, 2018.
75. Wataha K, Menge T, Deng X, Shah A, Bode A, Holcomb JB, Potter D, Kozar RA, Spinella PC, Pati S. Spray-dried plasma and fresh frozen plasma modulate permeability and inflammation in vitro in vascular endothelial cells. Transfusion 53: (suppl 1): 80S–90S, 2013.
76. Potter DR, Baimukanova G, Keating SM, Deng X, Chu JA, Gibb SL, Peng Z, Muench MO, Fomin ME, Spinella PC, et al. Fresh frozen plasma and spray-dried plasma mitigate pulmonary vascular permeability and inflammation in hemorrhagic shock. J Trauma Acute Care Surg 78: (6 suppl 1): S7–S17, 2015.
77. Pati S, Peng Z, Wataha K, Miyazawa B, Potter DR, Kozar RA. Lyophilized plasma attenuates vascular permeability, inflammation and lung injury in hemorrhagic shock. PLoS One 13:e0192363, 2018.
78. Georgoff PE, Nikolian VC, Halaweish I, Chtraklin K, Bruhn PJ, Eidy H, Rasmussen M, Li Y, Srinivasan A, Alam HB. Resuscitation with lyophilized plasma is safe and improves neurological recovery in a long-term survival model of swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma. J Neurotrauma 34:2167–2175, 2017.
79. Pati S, Potter DR, Baimukanova G, Farrel DH, Holcomb JB, Schreiber MA. Modulating the endotheliopathy of trauma: factor concentrate versus fresh frozen plasma. J Trauma Acute Care Surg 80 (4):576–584, 2016.
80. Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and fibrin in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 37:e13–e21, 2017.
81. Weisel JW, Litvinov RI. Fibrin formation, structure and properties. Subcell Biochem 82:405–456, 2017.
82. Bunce LA, Sporn LA, Francis CW. Endothelial cell spreading on fibrin requires fibrinopeptide B cleavage and amino acid residues 15-42 of the beta chain. J Clin Invest 89:842–850, 1992.
83. Odrljin TM, Shainoff JR, Lawrence SO, Simpson-Haidaris PJ. Thrombin cleavage enhances exposure of a heparin binding domain in the N-terminus of the fibrin beta chain. Blood 88:2050–2061, 1996.
84. Sporn LA, Bunce LA, Francis CW. Cell proliferation on fibrin: modulation by fibrinopeptide cleavage. Blood 86:1802–1810, 1995.
85. Yakovlev S, Gao Y, Cao C, Chen L, Strickland DK, Zhang L, Medved L. Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments. J Thromb Haemost 9:1847–1855, 2011.
86. Wu F, Kozar R. Plasma activates a novel Syndecan1-Pak1 pathway to enhance endothelial barrier integrity. Shock 45:S1, 201687.
87. Gröger M, Pasteiner W, Ignatyev G, Matt U, Knapp S, Atrasheuskaya A, Bukin E, Friedl P, Zinkl D, Hofer-Warbinek R, et al. Peptide Bbeta(15-42) preserves endothelial barrier function in shock. PLoS One 4:e5391, 2009.
88. Jennewein C, Mehring M, Tran N, Paulus P, Ockelmann PA, Habeck K, Latsch K, Scheller B, Zacharowski K, Mutlak H. The fibrinopeptide bβ15–42 reduces inflammation in mice subjected to polymicrobial sepsis. Shock 38:275–280, 2012.
89. Rourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, Stanworth S, Brohi K. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost 10:1342–1351, 2012.
90. McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: a five-year statewide cohort study. Injury 48:1074–1081, 2017.
91. Deras P, Villiet M, Manzanera J, Latry P, Schved JF, Capdevila X, Charbit J. Early coagulopathy at hospital admission predicts initial or delayed fibrinogen deficit in severe trauma patients. J Trauma Acute Care Surg 77:433–444, 2014.
92. Aubron C, Reade MC, Fraser JF, Cooper DJ. Efficacy and safety of fibrinogen concentrate in trauma patients—a systematic review. J Crit Care 29:e11–e17, 2014.
93. Kozek-Langenecker S, Sørensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care 15:R239, 2011.
94. Innerhofer P, Fries D, Mittermayr M, Innerhofer N, von Langen D, Hell T, Gruber G, et al. Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomized trial. Lancet Haematol 4:e258–e271, 2017.
95. Schöchl H, Nienaber U, Maegele M, Hochleitner G, Primavesi F, Steitz B, Arndt C, Hanke A, Voelckel W, Solomon C. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care 15:R83, 2011.
96. Wikkelsø A, Lunde J, Johansen M, Stensballe J, Wetterslev J, Møller AM, Afshari A. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 29:CD008864, 2013.
97. Curry N, Foley C, Wong H, Mora A, Curnow E, Zarankaite A, Hodge R, Hopkins V, Deary A, Ray J, et al. Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial. Crit Care 22:164, 2018.
98. Nascimento B, Callum J, Tien H, Peng H, Rizoli S, Karanicolas P, Alam A, Xiong W, Selby R, Garzon AM, et al. Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. Br J Anaesth 117:775–782, 2016.
99. Steinmetz J, Sørensen AM, Henriksen HH, Lange T, Larsen CF, Johansson PI, Stensballe J. Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial. Trials 17:327, 2016.
100. Curry N, Rourke C, Davenport R, Beer S, Pankhurst L, Deary A, Thomas H, Llewelyn C, Green L, Doughty H, et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth 115:76–83, 2015.
101. Winearls J, Wullschleger M, Wake E, Hurn C, Furyk J, Ryan G, Trout M, Walsham J, Holley A, Cohen J, et al. Fibrinogen Early In Severe Trauma studY (FEISTY): study protocol for a randomised controlled trial. Trials 18:241, 2017.
102. Yarranton H, Lawrie AS, Mackie IJ, Pinkoski L, Corash L, Machin SJ. Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light. Transfusion 45:1453–1458, 2005.
103. Chang R, Holcomb JB, Johansson PI, Pati S, Schreiber MA, Wade CE. Plasma resuscitation improved survival in a cecal ligation and puncture rat model of sepsis. Shock 49 (1):53–56, 2018.
104. Vigiola Cruz M, Carney BC, Luker JN, Monger KW, Vazquez JS, Moffatt LT, Johnson LS, Shupp JW. Plasma ameliorates endothelial dysfunction in burn injury. J Surg Res 233:459–466, 2019.

Cryoprecipitate; fibrinogen; fresh frozen plasma; glycocalyx; hemorrhagic shock; syndecan-1

Copyright © 2019 by the Shock Society