These include changes in the systemic circulation that initially serve to maintain organ perfusion but can become maladaptive as sepsis progresses. These are summarized in Table 1 . The primary macrocirculatory adaptation in sepsis is arterial vasodilation, resulting in decreased systemic vascular resistance and hypotension. This vasodilation is driven by cytokine-mediated upregulation of inducible nitric oxide synthase and increased nitric oxide production, as well as activation of adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle, which impairs vasoconstrictor responses to endogenous catecholamines and angiotensin II.

To compensate for arterial underfilling, the sympathetic nervous system is activated, leading to increased release of catecholamines, which stimulate β-adrenergic receptors in the heart, resulting in positive chronotropy and inotropy. This sympathetic drive is triggered by baroreceptor unloading due to hypotension and is further amplified by inflammatory mediators and prostaglandins. Low circulating blood volume also activates the renin–angiotensin–aldosterone axis. Renin release leads to increased angiotensin II, which acts as a systemic vasoconstrictor and also stimulates aldosterone secretion. Angiotensin II increases venous return, thereby increasing preload, through vasoconstriction and sodium retention. In addition, arterial underfilling induces baroreceptor-mediated stimulation of the hypothalamus and posterior pituitary, resulting in vasopressin release. Vasopressin causes vasoconstriction through binding to V1 receptors on vascular smooth muscle, thereby increasing vascular tone and arterial blood pressure.

The microcirculatory compartment adapts early in the course of sepsis, by autoregulatory attempts to preserve capillary flow. These include vasodilation of local capillaries and low-frequency oscillations in vessel diameter that help redistribute blood flow to hypoxic tissues. This response is partially mediated by increased nitric oxide production, which promotes vasodilation and enhances flow to areas of relative hypoxia. In addition, there is recruitment of reserve capillaries to maximize the surface area for oxygen diffusion. These hemodynamic alterations early in the course of sepsis collectively support cardiac output at the macro circulatory level and tissue perfusion at the microcirculatory level.

During the trajectory of sepsis, proinflammatory cytokines and nitric oxide induce downregulation and desensitization of adrenergic and angiotensin II type 1 receptors, leading to diminished vascular contractile responses to norepinephrine and angiotensin II, even at high doses. Also, as septic shock persists, vasopressin levels decline to inappropriately low concentrations relative to the degree of hypotension. This phenomenon is termed relative vasopressin deficiency, which can occur in up to one-third of patients with septic shock. Vasopressin deficiency is thought to result from depletion of neuro hypophyseal stores after sustained baroreceptor stimulation. Clinically, this manifests as a requirement for escalating doses of catecholamines to maintain target mean arterial pressure, with reduced efficacy and increased risk of adverse effects such as arrhythmias and tissue ischemia. High levels of nitric oxide and inflammatory cytokines further blunt vascular responsiveness to vasopressors, exacerbating shock and tissue hypoperfusion.

Microcirculatory maladaptations include excessive microvascular vasoconstriction due to neurohumoral activation, which can impair organ perfusion and precipitate organ injury, despite systemic vasodilation. Other maladaptive alterations in microcirculatory function are characterized by a loss of microvascular autoregulation, with delayed capillary response to hypoxia and reduced erythrocyte ATP efflux, resulting in uncoupling of local oxygen sensing from flow regulation. Microvascular flow heterogeneity is the hallmark of maladaptation. Some capillaries have high flow, resulting in a transit time too short to exchange oxygen, while others are clogged by microthrombi. Capillary density is decreased, included occluded capillaries, even after resuscitation, further impairing oxygen delivery to tissues. Importantly, these microcirculatory changes can occur, despite normal or restored arterial blood pressure and cardiac output, a situation referred to as uncoupling . Ultimately, these maladaptive responses are associated with multiorgan dysfunction and increased mortality in septic shock. ^,

To restrict the endovascular spread of pathogens, endothelial activity shifts from antithrombotic to a prothrombotic state. This induces local thrombin generation and fibrin formation, effectively walling off the infection within the local microvasculature, in concert with local vasoconstrictive effects also mediated by ECs.

At baseline, ECs express adhesion molecules such as intercellular adhesion molecule 1 and vascular cell-adhesion molecule 1. During infection, ECs universally upregulate the expression of adhesion molecules, which act as traps to ensnare circulating leukocytes and facilitate leukocyte recruitment to the tissue endothelial beds to kill pathogens.

A transient and controlled increase in endothelial permeability via intercellular gap formation allows leukocyte transit from the bloodstream into the affected tissues, as well as the passage of antibodies and other immunomodulatory molecules into the interstitial spaces. The permeability in a controlled infectious response is balanced such that useful mediators can pass to the affected site without causing tissue edema.

The glycocalyx is a heparan sulfate–rich layer of glycosaminoglycans and proteoglycans that coats the inner wall of vascular endothelia, forming a dense gel-like surface layer ranging from 0.5 to greater than 10 mm thick. It is critically involved in vascular integrity and leukocyte trafficking.

The glycocalyx can be degraded by inflammatory processes. Its destruction exposes the procoagulant surface of the endothelium, increases the permeability of the endothelium to macromolecules and increases leukocyte adhesion in the microcirculation. Furthermore, loss of heparan sulfate glycosaminoglycans results in impaired nitric oxide (NO) production, which affects the ability of the endothelium to vasodilate in response to shear stress. The summation of these deleterious processes contributes to alterations in microvascular rheology, affecting capillary blood flow, and ultimately decreasing tissue perfusion.

Direct measurements of the glycocalyx thickness can only be done in experimental settings. Indirect biomarkers are levels of glycocalyx components that are shed into the plasma, such as syndecan-1 and hyaluronan. The levels of these markers are consistently correlated with disease severity in septic patients. ^,

After the acute septic insult, it can take up to 5 to 7 days for the glycocalyx to be restored structurally, and even longer to fully recover hydrodynamic regulatory function. The delay in functional glycocalyx recovery explains, at least in part, persistent microcirculatory dysfunction in septic shock despite the normalization of the macrocirculation. ^,

For some time, it was held that vascular leakage is a necessary step for leukocyte transit from the blood into the tissue, and that modulating leakage may also alter the local immune response. However, recent studies have found that leukocyte trafficking and vascular permeability are regulated through distinct pathways, suggesting that the maladaptive sepsis-related capillary leakage could be modulated without adversely affecting leukocyte recruitment. ^, In response to damage- (DAMPs) or pathogen-associated molecular patterns (PAMPs), there is glycocalyx breakdown, EC death and junction protein dysregulation. Endothelial intercellular permeability is regulated by adherens junctions (cadherin–cadherin) and tight junctions (claudin/occludin). During acute inflammation, phosphorylation of the vascular endothelial–cadherin intracellular domain leads to its deconstruction and endocytosis. Claudin proteins, the primary regulators of tight junction permeability are elevated in sepsis, which lead to the disassembly of endothelial tight junctions, contributing to capillary leak. The heightened expression of angiopoietin-2 and lower expression of angiopoietin-1, results in inhibiting of Tie-2 activation and signaling, leading to endothelial permeability and other dysregulations of vascular homeostasis through multiple signaling pathways. The net result of these synergistic maladaptations is the capillary leak syndrome , where plasma and proteins can pass freely into the interstitium, contributing to edema and injury.

ECs can undergo acceleration of programmed cell death following pathogen invasion. PAMPs and DAMPs, in concert with oxidative stress from reactive oxygen species bursts, can trigger programmed cell death pathways in ECs. Such pathways include apoptosis (vesicle formation and DNA/protein fragmentation), necroptosis (cell membrane rupture), pyroptosis (membrane pore formation), and ferroptosis (cell death by iron overload). The loss of cells resulting from these programmed cell death pathways leads to gaps in vessel walls, further contributing to edema-causing processes. Also, the subsequent release of proinflammatory mediators and cellular debris from dead and dying ECs further amplifies the septic process.

In summary, during infection, exogenous PAMPs and endogenous DAMPs can trigger an array of pathophysiological pathways involving the endothelium that can impair its structure and/or function and even result in the death of its constituent cells. The damage to the glycocalyx, loss of vascular patency and EC apoptosis lead to an increase in permeability to proteins and fluids, causing interstitial leakage, tissue edema and resulting organ injury and dysfunction.

As these maladaptive pathways are simply dysfunctional versions of protective, adaptive mechanisms that are essential for resisting pathogen invasion, it is challenging to discriminate between appropriate activation and endothelial dysfunction, especially considering that appropriate responses may differ among organs. ^,

On sensing PAMPs and/or DAMPs, myeloid cells become activated and induce fibrin formation. The resulting fibrin lattices facilitate the detection, containment and elimination of pathogens, acting as a mechanical trap by immobilizing and killing the micro-organisms and preventing their spread into the systemic circulation. The entrapment of pathogens is mediated by the cross-linking of bacteria to fibrin fibers by the action of coagulation factor XIII. Mechanical pressure from clot contracture may tear bacterial capsules and walls, causing the squeezing out of bacterial contents and cell death. The fibrin lattices can also capture significant quantities of lipopolysaccharide, mitigating potential damage from gram negative bacilli.

NETs are complexes of neutrophil DNA and histones causing a multitude of immunothrombotic sequelae resulting from pathogen-induced activation of neutrophils in a process referred to as NETosis. These released webs of DNA, histones, enzymes, and antimicrobial proteins trap bacteria, induce both core coagulation pathways (resulting in additional fibrin formation), and provide a surface around the invading pathogens for further coagulation and immune activities.

Developing blood clots, particularly the fibrin and NET components, can act as immune scaffolding , recruiting immune cells (primarily neutrophils and macrophages) to the sites of infection. Such activity reflects the merging of coagulation and innate immunity pathways to restrict pathogen dissemination by focusing immune antimicrobial activity to the invaded tissue.

In sepsis-associated DIC, inflammatory cytokines are the key mediators of the first phase systemic procoagulable process The extralocal cytokine burst triggers a massive upregulation, expression and release of tissue factor (TF) from circulating and anchored monocytes and monocyte-derived microparticles, which in combination with increased TF exposure at endothelial surfaces that have lost their protective glycocalyx layer, results in a major shift toward a procoagulant state in the normally coagulation-balanced microcirculatory environment. The major increase in TF activity results in the amplified generation of thrombin followed by the conversion of fibrinogen to fibrin, with resulting uncontrolled clot formation at sites far distant from the initial infection site– the sine qua non of DIC.

During sepsis-induced maladaptive coagulation, the function of all 3 physiologic endogenous anticoagulant pathways (the brakes ) are impaired. First, antithrombin (which complexes with and inhibits thrombin and factor Xa) levels are markedly reduced via a combination of processes, including reduced synthesis, increased clearance from the formation of protease–antithrombin complexes, extravascular loss due to increased vascular permeability and direct degradation by neutrophil elastases. Second, the activity of Protein C (a potent inhibitor of factors Va and VIIIa and downregulator of thrombin) is similarly reduced due to a combination of decreased synthesis, reduced substrate affinity, increased consumption, and inhibited activation. The third major anticoagulant system, based on the action of TF pathway inhibitor inhibiting the procoagulant effects of TF VIIa complexes, is also disrupted in sepsis, due at least in part due to cleavage from enzymes released by NETs. These NET enzymes also degrade thrombomodulin, further removing a brake on unchecked thrombin formation.

At the peak of sepsis-induced accelerated thrombus formation and anticoagulation pathway inhibition, endogenous fibrinolysis is almost completely shut down, further cementing microthrombi in place. The initial fibrinolytic reaction to inflammatory mediators is an increase in tissue-type plasminogen activator and urokinase-type plasminogen activator release from the endothelium with the resulting generation of high levels of plasmin, favoring net clot lysis. This is followed by an even greater, and persistent, increase in the levels of plasminogen activator inhibitor 1. The latter results in a sustained suppression of endogenous fibrinolysis, further adding to uncontrolled disseminated thrombus propagation.

In summary, while coagulation pathways form a critical element of innate immunity contributing to pathogen containment, when these pathways become unchecked, they can become major contributors to endothelial damage, microvascular flow compromise, tissue ischemia, and resulting organ damage.