Among the etiologies of shock, septic and cardiogenic shock are the most common with an incidence of 171 per 100,000 population and 51.7 per 100,000 population, respectively (Dupuis et al., 2020; Schrage et al., 2021). While the incidence of septic and cardiogenic shock increases annually, the in-hospital mortality rate is slowly decreasing but remains high at 34% and 37%, respectively (Paoli et al., 2018; Osman et al., 2021).

Shock may be diversely defined, all definitions of which approximate the imbalance between tissue oxygen supply and demand (Millham, 2010; Johansson et al., 2017a; Standl et al., 2018). Shock has traditionally been defined by four categories based on fluid compartment volume loss (hypovolemic), volume redistribution (distributive), cardiac pump activity (cardiogenic), and circulatory obstruction (obstructive). These four etiologies of shock are summarized in Figure 1. Briefly, distributive shock pertains to the redistribution of fluid out of the intravascular space and/or away from vital organs without blood or fluid loss. Distributive shock, particularly septic shock, accounts for 59%–66% of all shock presentations (Vincent and De Backer, 2013; Standl et al., 2018). There are three subtypes of distributive shock which include septic, neurogenic, and anaphylactic/anaphylactoid (Standl et al., 2018). Primary endothelial dysfunction (as a root cause of shock) may be a key element of distributive shock and as such, primary endotheliopathy in this type of shock may be further amplified by SHINE. Hypovolemic shock results from a loss of blood or plasma and comprises an estimated 16%–27% of patients in shock (Vincent and De Backer, 2013; Standl et al., 2018). Hypovolemic shock includes four subtypes including hemorrhagic shock, traumatic hemorrhagic shock, plasma loss (non-hemorrhagic) hypovolemic shock, and traumatic hypovolemic shock (Standl et al., 2018). Whole blood loss occurs in hemorrhagic states such as trauma, gastrointestinal bleeds, and obstetrical hemorrhage. Plasma loss occurs with dehydrating conditions such as burns, pancreatitis, and diarrhea. Cardiogenic shock arises from primary pump failure of the heart and accounts for an estimated 13%–16% of shock states (Vincent and De Backer, 2013; Standl et al., 2018). Heart conditions that commonly account for cardiogenic shock include acute myocardial infraction, heart failure, arrythmia, and defective valves. Obstructive shock arises from a blockage of the circulation and accounts for 1%–2% of shock presentations (Vincent and De Backer, 2013; Standl et al., 2018). The defining treatment for obstructive shock is to find the source of obstruction (e.g., cardiac tamponade, tension pneumothorax, or pulmonary embolism) and relieve it.

This classification precludes a unified approach towards the spectrum of coagulopathies associated with shock. As opposed to the classic anatomic and pathophysiologic definitions, shock may also be described at the level of the endothelium (Fishman, 1982; Aird, 2004). The shared endothelial dysfunction in shock has recently been termed SHINE (Johansson et al., 2017a), whereby the endothelium is acknowledged as an independent “organ” which requires resuscitation in severe injury or disease. SHINE is a catecholamine-driven entity, regardless of the initial anatomic or pathophysiologic insult, which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve into phenotypes along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation (Johansson et al., 2017a; Wei et al., 2018; Napolitano, 2021; Kregel et al., 2022).

The definition of an organ requires a collection of tissues that form a unit distinct in form and function (Aird, 2004). Endothelial cells uniquely function as stress-sensing, phenotype-switching cells that respond to flow. The endothelium forms an extensive network with a collective weight of around 1 kg. In the brain alone, microvasculature represents 3%–4% of the brain compartment with a cumulative length of 400 miles and a surface area of exchange of 20 m² between the brain parenchyma and blood (Pardridge, 2002; Deracinois et al., 2015; Goncharov et al., 2017). The endothelium is comprised of a luminal glycocalyx layer maintained by simple squamous endothelial cells held together by complex transmembrane and cytoskeletal components which form intercellular junctions (Reiterer and Branco, 2020). The endothelium has distinct biochemical markers including E-selectin, intercellular adhesion molecule-1 (ICAM-1), the syndecan (Syn) family of four (Syn1-Syn4) heparan sulfate proteoglycans (HSPGs), and angiopoietin (Agpt)-1 and Agpt-2 (Goncharov et al., 2017). The endothelial luminal layer also contains anti-thrombogenic factors such as antithrombin III (AT), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), and endogenous heparan sulfates (HS) (Reitsma et al., 2007). Far from an inert layer of cells lining all blood and lymphatic vessels, the endothelium plays a vital role in moderating Starling Forces, mounting or attenuating an immune response, modulating vascular resistance, angiogenesis, and regulating coagulofibrinolysis. This is all facilitated by the rapid physical (shear; pressure; contractions/dilations to maintain vascular tone), chemical (manufacture and release of coagulofibrinolytic agents, also in response to physical and electrical stimuli; control of vascular surface/adhesive chemistry and morphology) and electrical (cell activation via central/peripheral nervous system; intercellular communication and response via chemical/ionic configurations) feedback mechanisms central to the endothelium’s role in maintaining hemostasis.

The endothelium is functionally and physically distinct and should thus be regarded as an independent organ system (Aird, 2004). Figure 2 depicts the physiology of the endothelium salient to this review. Table 1 further details biomarkers unique to the endothelial glycocalyx and endothelial-derived coagulofibrinolytic mediators.

How this large, complex multifarious system communicates nearly immediately across its vast length and surface area is an impressive capability, the understanding of which is still growing, and which finds importance in the speed with which a patient with SHINE can either deteriorate or respond to early resuscitation. The collective endothelial surface of up to 7,500 m² transmits messages from one part of the body to another via many pathways (Dobson et al., 2015). The first and most obvious pathway is the transmission of a drop in pressure from one vascular bed to another which is nearly immediate in a closed pressure system. Additionally, it has been demonstrated that direct electrical stimulation of the microvasculature causes local vasoconstriction; however, the endothelium and subendothelial smooth muscle cells propagate the depolarization along the vessel axis to cause long distance vasodilation primarily mediated by voltage-gated calcium channels and increased nitric oxide generation induced by the calcium influx (Figueroa et al., 2007).

The nearly immediate long distance signaling by the endothelium has also been observed for fibrinolysis. Hau Kwaan first noted in the 1950s that stimulation of one venous segment elicited fibrinolytic activities from another vein located far from the site of stimulation (Kwaan, 2014). This implied that there was a possible transmission of hemostatic and inflammatory markers to the intravascular space which can alter endothelial physiology at sites distant from focal injury. However, it later became apparent that perivascular sympathetic pathway activity was another pathway responsible for near-immediate signal transmission (O'Rourke et al., 2005; Kwaan, 2014). Therefore, the transmission of information regarding inflammation and thrombosis in SHINE is a function of not only the standard macrovascular and microvascular pressure gradients, and concomitant shear and blood chemistry, but also of the microvascular Starling forces and sympathetic electrical activity which in concert achieve a delicate immuno-thrombotic balance designed to simultaneously preserve microvascular flow and tissue perfusion during the development of SHINE.

Even though the concept of SHINE has only recently been proposed, earlier literature eloquently defined the endothelium’s importance. In 1982, Alfred Fishman wrote: “In recent years, as the tempo of fresh insights into the complexity of the endothelium has increased, realization has dawned that instead of serving simply as an inert barrier between blood and tissues, the endothelium is a distributed organ of considerable biological potential that not only extends throughout the body in the convenient form of an anti-thrombogenic vascular lining but also performs other distinctive biologic functions at different vascular sites and individual organs” (Fishman, 1982). For example, the endothelium of the pulmonary capillaries has evolved to enhance gas and water exchange while the endothelium of the aorta has evolved to withstand the high pressures exerted by the pumping force of the heart. This “organ” of large surface area has important physiologic functions such as maintaining blood viscosity, providing nutrients, modulating vasomotor function, and participating in immunological surveillance by maintaining innate and acquired immunity while orchestrating a communication between tissue perfusion and tissue flow (Fishman, 1982; Aird, 2006; Johansson et al., 2017a).

Differing shock etiologies cause different early responses by the endothelium. These responses often share hemostatic phenotypes but also demonstrate unique aspects which implicate the need for personalized resuscitation of the endothelium. For example, the hypotensive septic shock patient often manifests acute hypofibrinolysis, or so-called “fibrinolytic shutdown”, and thus does not benefit from administration of the anti-fibrinolytic tranexamic acid (TXA). On the contrary, a patient in severe traumatic hemorrhagic shock with a hyperfibrinolytic phenotype may benefit from TXA (Moore et al., 2020). The hypotensive hypercoagulopathic patient in septic shock and the hypotensive hypocoagulopathic patient in hemorrhage-induced shock represent two opposite extremes along the coagulofibrinolytic spectrum of shock-associated coagulopathies.

SHINE can alter hemostasis on a minute-to-minute basis by endothelial reactions (e.g., shedding of the glycocalyx layer, or “phenotype switching” among pro- or anti-thrombotic and pro- or anti-fibrinolytic), causing worsening microvascular injury and organ malperfusion. Serial bedside VHAs offer more timely goal-directed blood component therapy (BCT) and hemostatic adjunct therapy (HAT) when these coagulopathies may switch phenotypes rapidly. Therefore, assessment of endothelial function and injury pertaining to hemostasis cannot solely rely upon the plasma-based CCTs prothrombin time (PT), activated partial thromboplastin time (aPTT), as well as platelet count, fibrinogen, and D-dimer. Rather, point-of-care global hemostasis assessment with whole blood VHAs, bedside assessment of organ perfusion, and other laboratory markers for hypoperfusion such as serial arterial base deficit and lactate, enable timely physiologic and targeted hemostatic resuscitation of patients in shock (Vorweg et al., 2013; Schöchl et al., 2014; Johansson et al., 2017a; Martínez et al., 2018; Walsh et al., 2020b; Bunch et al., 2022a).

Much as SHINE is a recently proposed framework for classifying patients with shock-associated coagulopathies, a simultaneous expansion has occurred for the use of VHAs to better define the phenotype of these coagulopathies and offer goal-directed therapy (Vorweg et al., 2013; Johansson et al., 2017a; Bugaev et al., 2020; Walsh et al., 2020b). VHAs required decades of guiding resuscitation in liver transplantation, cardiac surgery, and trauma before randomized controlled trials (RCTs) demonstrated the advantage of VHAs over CCTs alone for patients with hemorrhagic shock in these settings (Curry et al., 2018; Bugaev et al., 2020; Walsh et al., 2020b). To date, there remains no robust RCTs demonstrating superiority of VHAs to guide hemostasis management of patients in shock while on extracorporeal membrane oxygenation (ECMO) or with Left Ventricular Assist Devices (LVADs). However, VHAs are overwhelmingly used in these clinical settings (Colman et al., 2019; Bunch et al., 2021; Volod et al., 2022; Volod and Wegner, 2022). The clinician should not be dissuaded from using VHAs because of the absence of large RCTs demonstrating VHA utility to treat the hemostatic derangements caused by SHINE for etiologies other than liver transplantation, cardiac surgery, and trauma. In many other settings, VHAs have demonstrated utility by numerous observational and prospective studies (Adamzik et al., 2011; Brenner et al., 2012; Collins et al., 2014; Tran et al., 2015; Hans and Besser, 2016). The “one-size-fits-all” approach of large RCTs may hinder detection of the “signal from the noise” for the benefits of VHA-guided resuscitation for shock, especially in the care of complex patients because of infrequently met inclusion criteria. On the other hand, PBM allows for personalized treatment based on the patient’s individual phenotype. TEG/ROTEM enable both real-time identification of dynamic hemostatic phenotypes (phenotype switching) and provision of real-time guidance for the treatment of coagulopathies (individualized goal-directed resuscitation). (Maslove et al., 2017; Görlinger et al., 2019; McKinley et al., 2019; Stettler et al., 2019; Walsh et al., 2020b). Hence, VHAs may aid diagnosis and guide treatment for patients with all forms of SHINE. The adherence to the “one-size-fits-all” mandate by which large RCTs must establish clear statistical evidence prior to using a diagnostic test is challenged by the long history and evolution of VHAs as PBM tools in liver transplantation, cardiac surgery, trauma, and most recently, postpartum hemorrhage (PPH), ECMO, and LVAD resuscitation (Collins and Varmus, 2015; Beckmann and Lew, 2016; Letson and Dobson, 2017; Tignanelli and Napolitano, 2018; Stettler et al., 2019; Walsh et al., 2019; Bell et al., 2022).

The remaining review describes the principles of VHAs and applying these principles to the monitoring and treatment of patients in shock afflicted by SHINE. Hemostatic phenotypes associated with SHINE are first delineated by applying the accepted pathophysiologic drivers of endotheliopathy for trauma-induced coagulopathy (TIC) and sepsis-induced coagulopathy (SIC). These prevalent causes of coagulopathy in critical illness set the foundation by which to contextualize the coagulofibrinolytic spectrum of SHINE. In turn, one may rationalize the application of VHAs for the diagnosis and treatment of all shock-associated coagulopathies. Here, we additionally emphasize VHAs for SHINE in post-cardiac arrest syndrome (PCAS), medical causes of hemorrhage, PPH, burns, and venom-induced consumption coagulopathy (VICC) (Vincent and De Backer, 2013; Standl et al., 2018). For many causes of SHINE, whether medical or surgical, the use of VHAs is in its relative infancy. The use of VHAs for these settings may be compared to the early days of liver transplantation which required years of study before large RCTs demonstrated overwhelming benefit (Kang et al., 1985; Starzl, 2002; Walsh et al., 2020b). This physiologic primer likewise serves as the cornerstone for future expansion of trials to determine the benefit of VHAs for management of patients with shock-associated coagulopathies regardless of the etiology. Briefly, we next discuss VHA parameters, interpretation, and goal-directed blood components and hemostatic adjuncts prior to discussing specific etiologies of SHINE shown in Figure 5.

The mechanics of the cup-and-pin legacy devices (TEG 5000 and ROTEM delta), as well as the Sonic Estimation of Elasticity via Resonance (SEER) technology with SonoClot, and the new generation cartridge-based devices (i.e., ClotPro, Quantra, ROTEM Sigma, and TEG 6s) output tracings that plot the amplitude of clot strength in millimeters on the y-axis versus time in minutes on the x-axis. These tracings evaluate whole blood hemostatic competence by describing clot initiation, amplification, propagation, and termination by fibrinolysis (Curry et al., 2018; Volod et al., 2022). The maximum amplitude (MA) on TEG and maximum clot firmness (MCF) on ROTEM represent the surrogate endpoint of thrombogenesis. MA/MCF correspond to the maximal platelet-fibrin clot contraction strength; declining amplitude following the MA/MCF denotes fibrinolysis. TEG and ROTEM use differing reagents and parameter terminology. However, recognizing the similar pattern between the output tracing of the two tests allows for a broad comparison between the two devices. The differing terminology of the TEG/ROTEM, as well as other VHAs, has been viewed as a barrier to widespread clinical adoption. Figure 6 exemplifies the typical normocoagulable TEG/ROTEM tracing with the respective parameters defined. (Kang et al., 1985; Shore-Lesserson et al., 1999; Luddington, 2005; Spalding et al., 2007; Trzebicki et al., 2010; Sankarankutty et al., 2012; Whiting and DiNardo, 2014; Hunt et al., 2015; Gurbel et al., 2016; Veigas et al., 2016; Curry et al., 2018; Snegovskikh et al., 2018; Field et al., 2019; Gillissen et al., 2019; Schenk et al., 2019; Hartmann et al., 2020; Volod et al., 2022).

A useful analogy to simplify TEG/ROTEM interpretation embodies the tracing as the shape of a shovel (Figure 7). With hemostatic competence or physiologic hemostasis, the shovel has an ideal handle length (R/CT), blade slope (K/CFT and α-angle), blade width (MA/MCF), and blade tip (LY30/CLI30/ML), shown as the middle shovel in Figure 6. The extremes are represented by different shovel shapes where, for the sake of analogy, the ease of tilling and moving soil corresponds to the ease of moving blood. The hypocoagulable shovel tracing has a long handle with a narrow and pointed blade (top shovel in Figure 6), with which tilling and soil transport becomes less cumbersome but markedly inefficient. The hypercoagulable shovel tracing has a short handle and a wide blade with an absent tapering of the tip (bottom shovel in Figure 6), making it difficult for the earth to be broken up and transported. In the above examples, tilling and soil transport are either difficult (hypercoagulable) or easy but inefficient (hypocoagulable). In summary, in Figure 6, the top shovel represents hypocoagulable disequilibrium, the middle shovel represents physiologic hemostasis, and the bottom shovel represents hypercoagulable disequilibrium. Goal-directed BCT and HAT may be administered based on either the shovel analogy pattern or the numerical values of the TEG/ROTEM parameters (Table 2).

Uncontrolled hemorrhage accounts for about 25% of deaths after injury, and an estimated one-quarter of these deaths likely have a TIC element (Moore et al., 2021b). TIC is not a single entity, but rather comprises a spectrum of coagulopathic phenotypes that is largely biphasic. ‘Early TIC’ generally characterizes the first 6 h following injury wherein difficulty to achieve hemostasis may lead to hemostasis exhaustion, uncontrolled hemorrhage despite adequate mechanical control of bleeding sites (i.e., coagulopathy), and progressive hemorrhagic shock (Kashuk et al., 1982; Moore et al., 2021a). ‘Late TIC’ generally describes hypercoagulability 24 h or more following the time of injury. Clinically, late TIC manifests micro- and macro-thrombotic complications such as venous thromboemboli, ultimately leading to organ failure (Moore et al., 2021a). Early TIC severity increases proportionally with the magnitude of injury severity, blood loss, and shock. Late TIC correlates to the degree of tissue injury (Moore et al., 2021a).

Following major trauma, the release of tPA from endothelial cells may be involved in the initial activation of fibrinolysis in response to a burst of thrombin and fibrin generation and sympathetic outflow. This fibrinolytic phase ends within several hours by the production of PAI-1 by endothelial cells and platelets. This dynamic change is termed “fibrinolytic shutdown” (Moore et al., 2019b) and may rapidly occur in 40%–50% of patients despite arrival to the hospital within an hour after injury (Moore et al., 2016b). Hemorrhage may invoke physiologic fibrinolysis shutdown to achieve hemostasis at bleeding sites. However, trauma patients with persistent fibrinolytic shutdown at 24 h post-injury have increased mortality (Moore et al., 2019b). On the opposite end of the fibrinolytic spectrum, roughly one-quarter of trauma patients have evidence of prior fibrinolytic activation, but only 7% have active ongoing fibrinolysis at the time of initial blood draw (Moore et al., 2019a). Hyperfibrinolysis as measured by TEG/ROTEM correlates to increasing injury severity, magnitude of shock, catecholamines, and SHINE (Holcomb, 2011; Moore et al., 2016a). Administering TXA empirically to TIC patients without evidence of hyperfibrinolysis may cause early fibrinolysis resistance and increased mortality, necessitating a PBM approach to TXA use guided by VHAs (Moore et al., 2017).

Figure 8 depicts the coagulofibrinolytic balance of TIC as a teeter totter wherein the TM-thrombin complex is one such fulcrum to determine anti- or pro-hemostatic phenotypes. This complex, also mediated by the endothelial protein C receptor (EPCR), activates the aPC anticoagulation pathway resulting in Factor V and Factor VIII degradation and enhanced fibrinolysis via PAI-1 inhibition. On the contrary, the TM-thrombin complex may activate the TAFI pathway resulting in hypercoagulation by inhibiting fibrinolysis (Sillen and Declerck, 2021). Whether the action of the TM-thrombin complex favors increased coagulation via TAFI or a hypocoagulable state mediated by aPC on the activated endothelium depends on the severity of trauma, the presence or absence of shock, endotheliopathy, and the manner, timing, and response to resuscitation (Dobson et al., 2015; Moore et al., 2020). The balance of the two opposing pathways may tip directions within seconds to minutes following trauma and involves either structural and/or posttranslational modifications of different sites on the TM-thrombin complex. Subsequent action by receptors and/or cofactors causes the modified TM-thrombin complex to bind and activate protein C or TAFI (Dobson et al., 2015; Johansson et al., 2017a).

With vascular injury, a thrombin burst mediates fibrin formation as well as a protection of the fibrin clot from dissolution via activation of TAFI (Lord, 2011; Foley et al., 2013). tPA or uPA cleavage of plasminogen to plasmin, the major fibrinolytic enzyme, then dissolves the fibrin meshwork into soluble fibrin/fibrinogen degradation products (FDPs) which mediate a positive feedback mechanism resulting in fibrinolysis (Silva et al., 2012). PAI-1 primarily prevents hyperfibrinolysis by inhibition of tPA as well as urokinase plasminogen activator (uPA) (Declerck and Gils, 2013; Sillen and Declerck, 2020). In addition, plasmin is inhibited by α2-antiplasmin (Singh et al., 2020). Importantly, activated TAFI (TAFIa) is a zinc-dependent metallocarboxypeptidase which downregulates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin; thereby preventing the upregulation of plasminogen binding and activation (Declerck, 2011; Vercauteren et al., 2013). Activation of TAFI following the thrombin burst regulates hemostasis with a fibrinolytic shutdown response and has been described as a crucial regulatory link between coagulation and fibrinolysis (Leurs and Hendriks, 2005; Claesen et al., 2021).

Recent studies have demonstrated mortality benefit and cost savings associated with early plasma resuscitation for patients with TIC (Moore et al., 2018; Brill et al., 2021). Early administration of plasma may serve therapeutic and sparing effects on the endothelial glycocalyx layer as demonstrated by decreased Syn-1 levels following plasma administration (Cannon, 2018; Sperry et al., 2018; Gruen et al., 2020; Pusateri et al., 2020; Hrebinko et al., 2021). This reduction of Syn-1 shedding may occur via reduced Tissue Inhibitor of MetalloProteinase (TIMP) activity or decreased activation of A Disintegrin And Metalloproteinase (ADAM). VHAs have been recommended as a method to gauge the adequacy of targeted resuscitation with plasma (Moore et al., 2021a).

Emphasis on resuscitation of the endothelium has led to the use of vasopressin for patients in severe shock associated with trauma (Simmons and Powell, 2016). When used in conjunction with clinical, laboratory, biologic, and standard coagulation tests, adjunctive VHAs reflect the hemostatic milieu of the endothelium and its contribution to hemostatic derangement in patients with SHINE. The combination of these tests provides a holistic view of whole blood hemostatic integrity, enabling goal-directed plasma and/or pressor therapy for patients in hemorrhagic shock (Moore et al., 2021a; Richards et al., 2021).

SHINE and mortality in TIC correlate to blood product administration (Dunne et al., 2004). It has been suggested that the pro-inflammatory extracellular vesicles (EVs) in stored blood products, particularly packed red cells, may cause or contribute to endotheliopathy (Straat et al., 2016). However, a recent observational study of 75 trauma patients demonstrated that red blood cell EVs increased following transfusion yet did not increase Syn1 levels (Dujardin et al., 2022).

Trauma can also be classified as primary or secondary based on pathophysiology (Brohi et al., 2003; Simmons and Powell, 2016), early or late based on timing (Tisherman et al., 2015), hypo- or hyperfibrinolytic based on hemostatic phenotype, and resuscitated or not resuscitated (Gando et al., 1992; Gando et al., 1995; Adrie et al., 2004; Gando et al., 2011; Tauber et al., 2011; Wohlauer et al., 2012; Gando et al., 2013; Moore et al., 2015b; Vogel et al., 2015; Gando and Hayakawa, 2016; Davenport et al., 2017; Leeper et al., 2017; Macko et al., 2017; Meizoso et al., 2017). Without treatment, these patients may progress to a DIC-like syndrome of hyperfibrinolysis in minutes to hours. Therefore, point-of-care testing with VHAs enables hemostatic monitoring to guide diagnosis and individualized ratios of BCT and HATs (Moore et al., 2019b; Moore et al., 2020). It should also be noted that surgical-related coagulopathies, such as damage control surgery or those incurred during liver transplantation and cardiac surgeries which have a long and rooted history of VHA-guided BCT and HAT, may be viewed similarly to TIC. Surgical-related coagulopathies and TIC share traumatic hemorrhagic shock pathophysiology and likewise necessitate goal-directed resuscitation.

Whereas hemorrhagic shock with TIC potentiates uncontrollable bleeding in its early phase, the early hemostatic phenotype of SIC involves a hypercoagulable state of hypofibrinolysis with consequent micro-thrombosis and sequential organ failure (Semeraro et al., 2012). Trauma and surgery patients who survive the early phase of hemorrhage may develop a late hemostatic phenotype that manifests as thrombosis and multiple organ failure like SIC. However, the stimulus of coagulation for each pathologic entity differs. In TIC, tissue factor (TF) release from injured tissue induces coagulation. Micro-thrombus formation, a fundamental event of SIC, is observed in late TIC and is under continued investigation (Vogel et al., 2015; Moore et al., 2020). In SIC, the two main drivers at the level of the endothelium are immuno-thrombosis and suppressed fibrinolysis. The influence of these systems and the mechanisms of their effect on the endothelium are depicted in Figure 9.

The mechanisms that initiate SIC have been previously described as both cell-based and humoral-based (Liaw et al., 2016; Iba and Levy, 2018). At the interface of mounting an immune response, the endothelium activates to a pro-thrombotic state in response to numerous inflammatory mediators. Biomarkers that crosstalk between inflammation and endothelial activation include leukotrienes, IL-1, IL-6, IL-8, TNF-α, reactive oxygen species, hydrogen peroxide, complement, histamine, serotonin, and shiga toxin, as well as hypoxia, thrombin, fibrin, and epinephrine (McCormack et al., 2017). The host response to sepsis involves the activation of coagulation by TF on EVs and activated endothelium (Østerud and Bjørklid, 2001). PS expressed on EVs and activated endothelium also activates the extrinsic coagulation cascade (Iba and Ogura, 2018). Among the most salient factors which are involved in the immuno-thrombotic response to sepsis are pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), high mobility group box 1 (HMGB 1), DNA, histones, neutrophil extracellular traps (NETs), damaged host cells, and activated immune cells, all of which initiate pro-inflammatory and pro-thrombotic reactions in SIC (Østerud and Bjørklid, 2001; Brinkmann et al., 2004; Adrie et al., 2005; Liaw et al., 2016; Iba and Ogura, 2018; Vulliamy et al., 2019).

FDPs and D-dimer levels have limited use for diagnosing and treating shock in either SIC of TIC. Because of their long half-life these markers do not correlate with PAI-I levels in patients with SIC or TIC. PAI-I levels are not readily available in clinical practice and therefore VHAs have been used to detect fibrinolysis in trauma patients. (Moore et al., 2014). Despite widespread use of VHA to detect fibrinolysis in trauma there is significant debate regarding its sensitivity (Larsen et al., 2012; Hunt et al., 2013; Ramos et al., 2013; Raza et al., 2013; Stettler et al., 2019).

AT is an important anticoagulant that prevents the formation of thrombi (Levy et al., 2016). In addition, prostacyclin, nitric oxide, and TFPI mediate anti-thrombotic effects at the level of the endothelium (Iba and Levy, 2019).

In SIC there is a significant suppression of anti-thrombotic activity which is affected by the methods of treatment as well as the speed of resuscitation. CCTs as well as FDPs and D-dimers do not adequately assay the importance of anti-thrombotic activity in SIC and TIC (Owings et al., 1996; Iba et al., 2012). It is instructive to compare early TIC and late TIC with SIC, whereby the increased release of TM activates protein C whereas late in TIC AT and protein C are depressed (Hess et al., 2008; Zilkens et al., 2008; Yanagida et al., 2013; Choi et al., 2014; Johansson et al., 2017a; Kornblith et al., 2019; Keshari et al., 2020). In sepsis AT levels decline and recent studies have demonstrated the possible utility of AT therapy in septic DIC (Vincent et al., 2019; Egi et al., 2021).

The similarities between SIC and TIC are instructive and are summarized in Table 3. Whereas the hemostatic derangement characteristic of hyperfibrinolytic phenotype associated with early severe TIC in shock is transformed in late TIC into a hypofibrinolytic phenotype characteristic of SIC (Taylor Jr et al., 2001; Gando and Wada, 2019; Vulliamy et al., 2019; Moore, 2022).

After TIC and SIC, the third most common cause of shock is cardiogenic of which PCAS is a major subtype. Ischemia-reperfusion injury drives the pathophysiology of PCAS-associated coagulopathy. The ensuing tissue necrosis, pro-thrombotic DAMPs, systemic inflammatory response, sympatho-adrenal activation, and SHINE account for the commonly observed hypercoagulability in these patients. The hypercoagulability arises from increased circulating TF, DAMPs, immuno-thrombosis, and an activated pro-thrombotic endothelium. Acutely, systemic hyperfibrinolysis occurs in PCAS because of tPA release from endothelial Weibel-Palade bodies. Hyperfibrinolysis occurs in about one-third to one-half of patients with PCAS, confirming the high incidence of fibrinolysis in patients with the “no-reflow phenomenon” of PCAS (Ames et al., 1968; Schöchl et al., 2013; Kloner et al., 2018). Of note, a recent observational study of 41 patients with cardiac arrest has supported conventional activation of plasminogen—as opposed to pro-inflammatory pathways of fibrinolysis activation—as the cause of hyperfibrinolysis in PCAS-associated coagulopathy (Zipperle et al., 2022b). This study also supported that hyperfibrinolysis in PCAS shares pathophysiologic similarities to TIC wherein hypoperfusion and increased aPC appear to be the incipient drivers. Moreover, it has been observed that cardiac arrest due to hypoxia has a higher incidence of hyperfibrinolysis compared to cardiac arrest from a primarily cardiogenic cause (Wada et al., 2017). Figure 10 depicts the coagulofibrinolytic equilibrium of PCAS-associated coagulopathies wherein ischemia-reperfusion injury determines the balance between hyperfibrinolytic and fibrinolysis shutdown phenotypes.

Compared to patients without the hyperfibrinolytic phenotype, patients with hyperfibrinolysis required longer CPR times, had elevated aPTT, D-dimer, and hypoperfusion markers including pH, base excess, and lactate. The lysis onset time (LOT) was directly proportional to survival and inversely related to CPR times and lactate. These data confirmed previous observations that the time to onset of clot lysis is an important marker for patient outcomes (Viersen et al., 2012). High lactate levels also predict development of PCAS-associated DIC with hyperfibrinolysis (Wada et al., 2016).

On the contrary, small increases in PAI-1 levels are measurable shortly after ROSC and may be owed to release by activated platelets or endothelium. PAI-1 levels have been shown to peak at 24 h after achieving ROSC, and increased levels correlate to multiple organ dysfunction and worse outcomes (Geppert et al., 2001; Wada, 2017). The initial hypercoagulopathic phase in patients with PCAS reflect similarly to severe TIC with early phase hyperfibrinolysis mediated by tPA and subsequent fibrinolytic shutdown mediated by PAI-1. The unique pathophysiologic moment begins with the “no-reflow phenomenon” which describes reduced antegrade coronary and/or cerebral microcirculatory blood flow despite proximal patency which is commonly seen following cardiac arrest and ROSC (Ames et al., 1968; Kloner et al., 2018). The rapid change from hyperfibrinolysis to hypofibrinolysis occurs with successful and early ROSC. Unlike TIC, these patients do not benefit from anti-fibrinolytic administration which substantiates the lack of similar causality for the coagulopathies associated with PCAS (Ames et al., 1968; Wada, 2017; Yu et al., 2020).

Studies of patients with PCAS who have attained ROSC have demonstrated the utility of TEG and ROTEM to predict intact neurologic survival as a reflection of reduced fibrinolysis. It has been shown that TEG values of R < 5 min or LY30 < 7.5% in early PCAS had more favorable neurologic outcomes. Higher D-dimer levels, PT, aPTT, lactate, and cfDNA were noted in the unfavorable outcome group. Therefore, in the earliest periods following ROSC, a normal hemostatic and fibrinolytic phenotype are early predictors of neurologically intact survival in successfully resuscitated out-of-hospital cardiac arrest patients (Yu et al., 2020). Early ROTEM analysis has likewise revealed a high incidence of hyperfibrinolysis for those patients who had long cardiac arrest times and poor prognosis. Specifically, hyperfibrinolysis criteria have been recorded in 83% of patients with long cardiac arrest times, and these patients also had lower fibrinogen levels with corresponding low levels of FIBTEM MCF (Barea-Mendoza et al., 2019).

The use of mild therapeutic hypothermia (MTH) has demonstrated increased survival. TEG may be a useful technique to evaluate hemostatic integrity in cardiac arrest survivors undergoing MTH. However, the effects of MTH on PCAS-associated coagulopathy requires appreciation for the effect of temperature on fibrin (ogen) concentration and function. When compared to physiologic temperature patients who have survived cardiac arrest, MTH has shown to lengthen TEG R, reduce the coagulation index (CI), and attenuate clot fibrinolysis. Rather than performing the VHAs at 37°C, it is therefore suggested that VHA analysis be performed at 32°C during MTH to increase the accuracy of hypothermic coagulation impairment (Trąbka-Zawicki et al., 2019). Moreover, prolonged MTH has shown to impair thrombin generation as measured by increased CT and prolonged time to maximum velocity of thrombin generation on INTEM (Jeppesen et al., 2017).

Common non-obstetrical causes of shock include gastrointestinal (GI) hemorrhage and, to a lesser extent, retroperitoneal hemorrhage of anticoagulated or hypocoagulopathic patients. The state of the endothelium in many ways reflects TIC where the degree of hemorrhage dictates the hemostatic derangement at the endothelium. However, as in TIC, pre-existing hemostatic phenotypes (e.g., liver failure and antiplatelet or anticoagulant medications) in part determine the evolution and response to therapy which requires VHAs to guide BCT and HAT for these patients (Bunch et al., 2022a). Patients treated with anticoagulants and antiplatelet agents often require replenishment of factors and/or platelets in TIC and medical hemorrhage causing shock (Kang et al., 1985; Shore-Lesserson et al., 1999; Enriquez and Shore-Lesserson, 2009; Ojito et al., 2012; Tanaka et al., 2012; Levin et al., 2014; Tanaka et al., 2014; Weitz and Eikelboom, 2016; Bliden et al., 2017; Douketis et al., 2017; Dubois et al., 2017; Gurbel et al., 2017; Mullins et al., 2018; Artang et al., 2019; Bruckbauer et al., 2019; Dias et al., 2019; Pailleret et al., 2019; Sarode, 2019; Oberladstätter et al., 2021; Pavoni et al., 2022). In patients with liver failure and GI hemorrhage, the rebalanced hemostasis caused by the reduced anticoagulants protein S, protein C, and AT require that VHAs be used in the diagnosis and resuscitation of these patients in shock. Serial hemostatic functional evaluation of a patient in liver failure with shock would not be possible with CCTs, but can be done successfully with VHAs (Groth et al., 1969; Chau et al., 1998; Starzl, 2002; Tripodi and Mannucci, 2011; Agarwal et al., 2012; Stravitz, 2012; Scarlatescu et al., 2018; Stravitz et al., 2021). Interestingly, the use of anti-fibrinolytics in patients with GI hemorrhage and shock has not shown to improve outcomes, further demonstrating the heterogeneity of coagulopathies associated with SHINE due to medical hemorrhage versus traumatic or surgery-related hemorrhage (Roberts et al., 2020).

VHA-guided BCT during PPH is expanding. TEG/ROTEM devices can be used to detect and treat clinically significant hypofibrinogenemia, although evidence to support the role of VHAs for guiding fresh frozen plasma and platelet transfusion is less clear (Collis and Collins, 2015; Bamber, 2016; Collis, 2016; Curry et al., 2018). If ROTEM/TEG tracings are normal, clinicians should investigate for another cause of bleeding, and BCT may be withheld. Guidelines support the use of VHAs during PPH if a local algorithm reaches agreement. However, wide consensus does advise that a FIBTEM amplitude at 5 min (A5) of <12 mm with ongoing bleeding necessitates fibrinogen replenishment (Curry et al., 2018; Collins, 2022). Note, however, that patients with PPH may also have reduced thrombin generation (Di Bartolomeo et al., 2017). Guidelines recommend against using VHAs to guide TXA infusion. Rather, TXA should be administered as soon as PPH is diagnosed irrespective of the TEG/ROTEM traces, however patients with PPH are also at high for venous thromboembolism suggesting this issue requires further investigation (Shakur et al., 2010; Roberts et al., 2012; Collins, 2022). The cost-effectiveness of VHAs during PPH needs to be addressed and has formed the foundation for much of the discussion regarding the utility of VHAs to guide BCTs and HATs in patients with severe PPH. (Collis and Collins, 2015; Bamber, 2016; Collis, 2016; Curry et al., 2018; Collins et al., 2019; Liew-Spilger et al., 2021; Collins, 2022).

Severe PPH, such as with amniotic fluid embolism (AFE), often associates with hyperfibrinolysis like severe TIC. However, the etiology and treatment differ significantly from severe TIC and requires VHA-guided resuscitation. The mechanism for AFE-induced coagulopathy is the release of amniotic fluid TF into the systemic and pulmonary circulation, provoking a classic DIC of overwhelming thrombin generation, consumption of clotting factors and platelets, and hyperfibrinolysis (Harnett et al., 2005; Bassily-Marcus et al., 2012).

Treatment of AFE entails the immediate delivery of the fetus, VHA-guided resuscitation of the mother, and emphasis for early administration of fibrinogen to levels that are two to three times higher than normal to outcompete platelet and clotting factor consumption, and fibrinolysis (Kramer et al., 2013; Dahlke et al., 2015; Guasch and Gilsanz, 2016; Pacheco et al., 2016; Henriquez et al., 2018; McDonnell and Browning, 2018; Amgalan et al., 2020; Liew-Spilger et al., 2021). Early PPH not associated with AFE may be diagnosed with modified VHAs designed to detect low levels of fibrinogen, which when properly treated, enable reduced incidence of shock and BCT use in women who suffer PPH (McNamara et al., 2015; Collins et al., 2017; Loughran et al., 2019; Othman et al., 2019; Liew-Spilger et al., 2021). In addition, an endogenous heparin-like substance has been associated with the coagulopathy of severe PPH and subsequent shock as identified by TEG (Wang et al., 2020). The placenta also contains high levels of TFPI (Kuczyński et al., 2002; Xiong et al., 2010).

As with late TIC and SIC as well as late PCAS, fibrinolytic shutdown post-resuscitation of PPH remains a risk factor for venous thromboembolism (VTE). Therefore, VHAs may help guide the intensity and duration of DVT prophylaxis in postpartum women, particularly those who suffered hemorrhagic shock (Maybury et al., 2008).

Figure 11 exemplifies VHA-guided resuscitation for a 35-year-old woman with cardiac arrest due to AFE (Hurwich et al., 2016). Hemostatic management of the obstetrical patient with this severe type of SHINE remains difficult without bedside adjunctive VHAs, whether due to AFE or other causes of PPH such as eclampsia, hemolysis with elevated liver enzymes and low platelets (HELLP Syndrome), or structural anomalies with and without uterine atony (Amorde et al., 2011; Loughran et al., 2019).

Severe hyperthermia, which causes burn-induced coagulopathy (BIC), can present with early hyperfibrinolysis and hypocoagulability. With treatment of shock, these patients most often develop a hypofibrinolytic and hypercoagulable state as manifested by VHAs (Marsden et al., 2017; Borgman et al., 2019). The development of hypofibrinolysis or fibrinolytic shutdown on admission does not affect prognosis, yet at 4 h following thermal injury hyperfibrinolysis as determined by TEG portends a worse prognosis (Pusateri et al., 2020).

Hemostatic profiles of patients with BIC and hyperthermia have been studied with VHAs and demonstrate superiority to CCTs for detecting BIC (Marsden et al., 2017). Additionally, VHAs have shown to be an indispensable tool for identifying the cause of hypocoagulation in patients with severe burn injury (Presnyakova et al., 2021). ROTEM was also found to be useful in providing real-time guidance for the administration of blood products in severe burns (Bugaev et al., 2020). The resuscitation of bleeding during major burn surgery has not been standardized, yet it has been noted that TEG/ROTEM analysis of intraoperative blood samples demonstrates reduced clot strength. Therefore, it has been recommended that resuscitation of patients with burn injuries in shock should aim for normal hemostasis using point-of-care VHA monitoring of hemostatic competence during surgery and resuscitation (Welling et al., 2019). Computational thrombin modeling as well as thrombin generation assays (TGA) have confirmed the validity of VHAs to guide resuscitation for patients with severe BIC who are in shock (Ball et al., 2020). The hypercoagulable state is commonly observed in post-burn patients with BIC. An etiology for this hypercoagulable state has been suggested as the hypermetabolism of fibrinogen with subsequent increase in rebound synthesis of fibrinogen. This rebound as a reaction to enhanced fibrinogen degradation manifests by increased TEG LY60 with increased clotting speed and strength by significantly increased TEG α-angle and MA (Martini et al., 2020). Recent studies of rapid TEG (rTEG) to predict resuscitation volumes and outcomes in patients with BIC have demonstrated that 75% of these patients are hypercoagulable on admission while 25% are hypocoagulable on admission. The use of VHAs to guide the complicated resuscitation of these patients has demonstrated that as much as a five-fold increase in risk of supranormal resuscitation occurs in patients with BIC and abnormally long activated clotting times. For patients with BIC and SHINE, the use of VHAs provides essential guidance for the proper utilization not only of crystalloid, but also of other blood components (Huzar et al., 2018).

An interesting therapeutic phenomenon has been reported whereby hyperthermic patients have been treated with plasma rather than crystalloids in attempt to protect the endothelial glycocalyx. Since plasma has shown to protect the glycocalyx layer of the endothelium for TIC patients, it has been proposed that plasma is a better resuscitation fluid for patients with burn wounds for its dual abilities in restoring intravascular volume and therapeutic effect on the endothelium (Gurney et al., 2019).

At the other extreme, hypothermia alters fibrinogen and platelet function as measured by VHAs. Plasma composition which is reflected by VHAs can determine the type of coagulopathy associated with hypothermia. Even moderate hypothermia can impair thrombin generation as determined by VHA analysis. Significant hypothermia demonstrates inhibition of thrombin generation as manifested by prolonged R/CT, a reduction in the α-angle, and a significant reduction of platelet function as determined by multiple electrode aggregometry (MEA) (Mitrophanov et al., 2014; Wallner et al., 2020).

VICC uncommonly causes hemorrhagic and/or distributive shock in the western world, but much more commonly afflicts rural areas and low-to-middle income countries. However, there is also increasing frequency in urban areas in Western countries due to an interest in exotic pets. In addition to the immediate treatment with antivenom to neutralize lethal toxins, transfusion of plasma, cryoprecipitate, and specific clotting factors has been clarified by using VHAs which have demonstrated procoagulant and anticoagulant effects of snake venom. It has therefore been proposed that VHAs should goal-direct hemostatic resuscitation in patients with VICC (Park et al., 2020). Using TEG with platelet mapping (TEG/PM), a case series of rattlesnake bites in North America revealed inhibition of ADP-induced platelet activation which was reversed by Crotalidae polyvalent immune Fab (ovine). Fibrinolysis was present and resolved in patients for whom serial thromboelastographs were available (Kang and Fisher, 2020).

This clinical finding has been confirmed by a study comparing the efficacy of TEG and CCTs in diagnosing simulated Crotalus atrox envenomation using human whole blood samples. TEG accurately evaluated coagulopathies caused by in vitro pit viper envenomations,confirming that VHAs are useful clinical adjuncts for evaluating VICC (Leffers et al., 2018). Figure 12 demonstrates the benefit of using adjunctive VHAs as well as CCTs to diagnose and treat the coagulopathies of patients in shock caused by envenomation (Leffers et al., 2018).

Hematologic malignancies associate with the full spectrum of hemostatic phenotypes. Acute promyelocytic leukemia (APL) and myeloproliferative disorders such as polycythemia vera best exemplify the extremes of this spectrum. APL most often manifests a hypocoagulable hyperfibrinolytic phenotype, whereas as patients with polycythemia vera are hypercoagulable (Walsh et al., 2019; Walsh et al., 2020a). Patients with APL may present with shock associated with hyperfibrinolysis which progresses soon following treatment with all-trans-retinoic acid to a fibrinolytic shutdown phenotype (Tallman and Kwaan, 1992; Zakarija and Kwaan, 2007; Stein et al., 2009; Kwaan and Rego, 2010; Kwaan et al., 2011; Liu et al., 2011; Kwaan and Cull, 2014; Dobson et al., 2015). This pattern of rapid transition from the hyperfibrinolytic phenotype to fibrinolytic shutdown reflects a similar pattern seen in the acute phase of severe TIC which progresses from hyper-to hypo-fibrinolysis within minutes to hours (Tallman and Kwaan, 1992; Zakarija and Kwaan, 2007; Stein et al., 2009; Kwaan and Rego, 2010; Kwaan et al., 2011; Liu et al., 2011; Kwaan and Cull, 2014; Moore et al., 2015a). In APL, the hyperfibrinolytic phenotype is driven by increased expression of tPA, annexin A2, and uPA. Inhibitors of the coagulation cascade such as TFPI are present in APL and may further contribute to this hyperfibrinolytic state (Kwaan and Rego, 2010; Kwaan and Cull, 2014). Therefore, whether caused by SIC or trauma, TEG/ROTEM allow for evaluation of the patient’s phenotype along the spectrum of hypocoagulable/hyperfibrinolytic to hypercoagulable/hypofibrinolytic.

For patients with non-malignant etiologies such as hemophilias or thrombocytopenias who are in shock, VHAs may direct resuscitation by defining the hemostatic phenotype and guiding BCT and HAT (Speybroeck et al., 2020; Bunch et al., 2022a).

Coagulopathy of traumatic brain injury (CTBI) perturbs primary hemostasis, and VHAs can be used to monitor the progression of platelet dysfunction (Castellino et al., 2014; Sixta et al., 2015; Maegele et al., 2017; Samuels et al., 2019; Maegele et al., 2020; Webb et al., 2021). Early after traumatic brain injury (TBI), VHAs have shown inhibition of platelet receptors resulting in impaired reactivity at the receptors for ADP, AA (Jacoby et al., 2001; Nekludov et al., 2007; Windelv et al., 2011; Wohlauer et al., 2012; Davis et al., 2013; Castellino et al., 2014), collagen, ristocetin, and thrombin receptor activating peptides (TRAP) (Solomon et al., 2011; Kutcher et al., 2012; Dragan et al., 2021). The severity of TBI correlates to the degree of platelet receptor inhibition. Evidence suggests that CTBI may arise from the disruption of local primary hemostasis and systemic endotheliopathy which are caused primarily by the overwhelming release of von Willebrand Factor (VWF) and TF from the injured brain tissue (Wu et al., 2018; Xu et al., 2020). The circulating supraphysiologic VWF and TF likely activate platelets without adhering to a surface distant from the site of injury, creating a pool of circulating activated but exhausted platelets that are incapable of aggregation (Moore et al., 2021a). VHAs may quantify dysfunction of various platelet receptors and thus, VHAs with specialized function analysis are significantly more effective in monitoring hemostasis and prognostication in CTBI than CCTs, as has been shown for both isolated and multiple systemic trauma (Nekludov et al., 2007; Simard et al., 2009; Lustenberger et al., 2010; Kurland et al., 2012; Laroche et al., 2012; Wohlauer et al., 2012; Davis et al., 2013; Castellino et al., 2014; Nekludov et al., 2014; Hijazi et al., 2015; Medcalf, 2015; Dekker et al., 2016; Di Battista et al., 2016; Foley and Conway, 2016; Yuan et al., 2016; Maegele et al., 2017; Fletcher-Sandersjöö et al., 2020; Bradbury et al., 2021; Cannon et al., 2021). In addition to local and systemic procoagulation, patients with CTBI more commonly present with hypofibrinolysis than hyperfibrinolysis. Coupled with procoagulation, fibrinolytic shutdown leads to the consumption of platelets, coagulation factors, and fibrinogen which ultimately results in bleeding and secondary hemorrhagic progression of TBI in the late phase of CTBI (Hoffman and Monroe, 2009; Tian et al., 2010; Herbert et al., 2017; Maegele et al., 2017; Maegele et al., 2020). However, the sensitivity of VHAs to detect occult fibrinolysis in patients with CTBI is a topic of ongoing discussion (Cotton et al., 2012; Medcalf, 2015; Moore et al., 2016b; Rowell et al., 2020). Resuscitation of patients with TBI who are in shock therefore requires an understanding of the numerous contributing factors to CTBI wherein VHAs provide a greater hemostatic profile.

Another area where definition of coagulopathies based on endothelial changes will result in much different treatments than reliance on CCTs alone is the pediatric patient whose endothelium differs significantly from the adult or PPH patient with SHINE. VHAs for decades have guided resuscitation of pediatric patients undergoing liver transplantation, cardiac surgery, cardiac transplantation, and traumatic injury. In addition, VHAs have been monitored hemostasis for patients on ECMO, VADs, continuous veno-venous hemofiltration, and continuous veno-venous plasma filtration (Haas and Faraoni, 2020). The endothelium of the pediatric population undergoes similar changes under conditions of SHINE as with the adult, although the urgency of diagnosis and treatment is much greater and therefore, consideration must be made for the use of these tests for pediatric patients in shock (Richter et al., 2022b).

Endothelial dysfunction has been implicated in pediatric critical illness and is theorized to result from glycocalyx disruption (Puchwein-Schwepcke et al., 2021). As the child develops, the endothelial glycocalyx thins due to blood vessel aging, cumulative exposure to inflammation, and other comorbidities (Richter et al., 2022b). Vascular stiffness increases with age due to physiologic elevations in blood pressure which contributes to the thinning of the glycocalyx via suppression of the glycocalyx core protein glypican 1 (Mahmoud et al., 2021). Additionally, the immune system develops to mount stronger responses to a wide range of pathogens, increasing baseline local and systemic inflammation in the setting of an acute response to infection (Richter et al., 2022b). Comorbid conditions such as cyanotic heart defects, lung vascular malformations, bronchopulmonary dysplasia, and type I diabetes mellitus increase endothelial exposure to reactive oxygen species which drives endothelial cells into premature senescence marked by thinning of the glycocalyx (Erusalimsky and Skene, 2009; Jackson-Weaver et al., 2019). In a critically ill pediatric patient, the joint effect of blood vessel development, immune system maturation, comorbidities, and insults such as trauma or sepsis may cause an acute disruption of the glycocalyx with subsequent vascular pathology and coagulopathies like the progression seen in SHINE. Hence, real-time monitoring of coagulopathies with VHAs may be useful in the care of critically ill pediatric patients (Saini et al., 2019).

It has been shown in pediatric intensive care units that TEG changes the treatment for 47% of patients and provides a better understanding of the hemostatic phenotype in 69% of patients (Carter et al., 2017).

The investigation of endothelial dysfunction in the pediatric population has recently been enhanced by the presence of multisystem inflammatory syndrome in children (MIS-C). Abnormal levels of angiopoietin-2, sE-selectin, and VWF antigen correlate with the vasoactive and inotropic score in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related MIS-C with shock (Borgel et al., 2021). For MIS-C, inflammatory markers and ROTEM parameters significantly correlate which are indicative of hypercoagulability and elevated fibrinogen activity by FIBTEM MCF and elevated D-dimer. Similar to the adult population with septic shock, pediatric patients with MIS-C who develop shock and SHINE may also benefit from the use of VHAs to guide diagnosis and resuscitation (Al-Ghafry et al., 2021).