Acute respiratory distress syndrome (ARDS) is an acute respiratory failure that develops in patients of all ages (1,2) and originates from multiple insults that damage directly or indirectly the lungs, such as pneumonia or sepsis (3).
Supportive care to avoid worsening lung injury and improve ARDS outcomes are currently applied, such as mechanical ventilation (4), prone positioning (5) and neuromuscular blockers (6). Nevertheless, morbidity and mortality remain high (35–40%) (2), and new therapies focused in the pathophysiology of ARDS development are required (7).
The lungs of ARDS patients are characterized by inflammation and increased procoagulant factors, no hydrostatic pulmonary edema and the breakage of the alveolar-capillary barrier, increasing proteins permeability (8,9). This produces the activation of pulmonary macrophages towards a proinflammatory phenotype and an increase of intravascular and extravascular neutrophils, platelets and fibrin, as well as endothelial and epithelial injury.
Given the essential role that coagulation plays in ARDS pathophysiology, this review will focus on the coagulation and fibrinolytic pathways and its pharmacological targets to treat ARDS.
Coagulation and fibrinolysis in the alveolar compartment of ARDS
Pulmonary coagulopathy in ARDS pathophysiology is characterized by an activated coagulation and reduced fibrinolysis (10,11), similar to the altered coagulation found systemically in septic patients. Different pathways of the coagulation cascade are involved in the pathophysiology of ARDS: tissue factor (TF) pathway, protein C pathway and the regulation of fibrinolysis by the plasminogen activator (PA) and inhibitor pathway (Figure 1).
Activation of TF is a major initiator of extrinsic coagulation cascade. TF is a transmembrane protein that is activated by the binding of factor VIIa on the cell surface. This complex cleaves factor X producing its activated form, Xa, which brings with it thrombin generation, that is one of the most important procoagulant proteins, and fibrin formation. In normal conditions, there is equilibrium between TF and TF pathway inhibitor (TFPI) which regulates the initiation of extrinsic coagulation cascade via TF pathway. TFPI is a natural anticoagulant inhibitor produced in the vascular endothelium and on the surface of platelets (12). This inhibitor interferes with the complex TF:VIIa:X inhibiting thrombin production and fibrin deposition. TFPI must bind to Xa to become active, so this inhibition process just takes place after the initiation of the coagulation pathway (12). Furthermore, the complex VIIa:Xa has a role on inflammation activating protease-activated receptors (PAR-2) on the cell surface of immune cells, platelets and endothelial cells, producing the expression of molecules of adhesion and promoting an inflammatory process (13).
Independently of ARDS etiology, the inflammatory process is one of the major inducers of the coagulation pathway. It has been proved that alveolar macrophages, alveolar epithelial cells and endothelial cells produce TF after being exposed to a proinflammatory stimulus that causes the activation of the transcription factor nuclear factor-κB (NF-κB) (12,13).
TF in the alveolar space is found in alveolar epithelial cells and alveolar macrophages in human lung tissue from ARDS patients (14) and in mice that received lipopolysaccharide (LPS) directly into the lungs (15). In this line, increased TF procoagulant activity is found in the bronchoalveolar lavage (BAL) of ARDS patients and patients with pneumonia without ARDS (10,16,17) and in plasma of septic patients (18). Increased plasma concentrations of TF in ARDS patients are related with poor clinical outcomes (12). The observed changes in TF indicate a common coagulation mechanism in different ARDS etiologies. In pulmonary edema fluid of ARDS patients the levels of TF protein is more than 100-fold higher than in plasma (14). Shaver et al. found out that the alveolar epithelium is the major source of TF in acute lung injury (ALI), being protective during this disease, as coagulation and the deposition of fibrin are activated producing a barrier and reducing the alveolar-capillary membrane leakage (19). Bastarache et al. proved that intratracheal TF administration in a model lacking murine TF reestablished local coagulant activity and reduced haemorrhage and permeability in an ALI model of LPS (20).
Regarding the natural anticoagulant of TF, TFPI levels are increased in the alveolar compartment of ARDS patients, although it does not compensate TF increment, as procoagulant activity predominates. Levels of TFPI are 7-fold greater in patients at risk and 20-fold more elevated in established ARDS patients (21), and no differences are found in plasma.
Protein C pathway
Protein C pathway is also involved in the regulation of coagulation and fibrinolysis. Protein C is a vitamin K-dependent glycoprotein synthesized by the liver that circulates as a zymogen. Activated protein C (APC) is produced by the thrombin-thrombomodulin (TM) complex on the cell surface. TM is a thrombin receptor that together with thrombin creates a complex that activates protein C, converting thrombin from a procoagulant to an anticoagulant and activating fibrinolysis (22). TM was originally described to be produced by endothelial cells (23) although consequently was either detected in other cell types, including alveolar epithelial cells (24). The endothelial protein C receptor (EPCR) is another cell surface protein that potentiates activation of protein C while binding to TM-thrombin complex.
APC presents anticoagulant properties through proteolytically inactivating factors Va and VIIIa, which suppress thrombin formation, and promotes fibrinolysis by neutralizing PA inhibitor-1 (PAI-1). A link between inflammation and coagulation is produced because of the ability of thrombin to activate PAR-1, 3 and 4, and of factor Xa to activate PAR-2, raising the production of inflammatory genes and increasing the activation and recruitment of neutrophils and platelets into the lung (13). Thus, by suppressing thrombin through APC an anticoagulant and anti-inflammatory effects are produced. On the other hand, APC presents anti-inflammatory functions through the suppression of proinflammatory cytokines released by neutrophils (25,26) and has antiapoptotic functions through p53 inhibition.
In normal conditions, human alveolar epithelial cells are able to activate protein C and express TM and EPCR, which enhances APC. In response to an injurious stimulus, alveolar epithelial cells release TM and EPCR from the cell surface, due to a metalloproteolytic process, reducing the ability of these cells to activate protein C (27) and promoting a procoagulant state and the inhibition of fibrinolysis.
Plasma levels of protein C are reduced in ARDS patients, presenting lower levels in the alveolar compartment (24), especially those patients presenting phenotype 2 (28). In pulmonary edema from ARDS patients, TM is 2-fold higher than in ARDS plasma, and more than 10-fold higher than in normal plasma (24,29). Further, higher plasma levels of soluble TM are related with increased mortality in ARDS (30) and genetic variants in TM and EPCR genes are associated with mortality in ARDS (31). The low protein C levels and high TM levels in the alveolar compartment provide further support to the growing of evidence that the alveolus is a procoagulant, antifibrinolytic environment in ARDS (32). The protein C system may be a potential therapeutic target in patients with ARDS (12).
Plasminogen activator and inhibitor pathway
The activation of coagulation and fibrinolysis drives the deposition of fibrin into the lung. PA, which can be urokinase-type PA (uPA) or tissue-type PA (tPA), drive the conversion of plasminogen to plasmin, a fibrinolytic enzyme. This conversion is neutralized by PAI-1.
Alveolar macrophages, endothelial cells and alveolar epithelial cells are sources of PA and PAI-1. When stimulated with a proinflammatory stimulus, alveolar macrophages express higher levels of PAI-1, and endothelial cells express less tPA, resulting in increased fibrinolysis inhibition (25). In patients with ARDS fibrinolysis is reduced, as the levels of PAI-1 are increased in both plasma and edema fluid, presenting a correlation with mortality (17,33).
Coagulation and fibrinolysis as pharmacological targets for ARDS
Increased procoagulant activity in the alveolar compartment is evident as higher levels of thrombin generation, soluble TF, and factor VIIa are found in BAL fluid from ARDS patients, together with elevated levels of PAI-1, indicating reduced fibrinolysis activity (17). Pharmacological targets for the coagulation cascade and fibrinolytic pathway might be promising candidates for ARDS treatment and prevention.
A treatment for ARDS could be TFPI due to its functions on the coagulant pathway. Neutralize TF activation with TFPI administration diminishes coagulation and cell injury in a septic model in baboons (34) and reduces pulmonary injury and coagulation in a model of LPS through inhibiting leukocytes activation (35). Furthermore, inactivated factor VIIa (VIIai) was developed as an anticoagulant, proving protective effects in a model of sepsis in baboons (36). In a direct and indirect rat model of ALI, nebulized recombinant human TFPI seem feasible and safe (37). It decreased pulmonary and systemic coagulation in both models, although just in the model receiving intratracheal P. aeruginosa the pulmonary inflammation was decreased (37).
A phase III clinical trial of intravenous recombinant TFPI failed in reducing mortality in sepsis (38) and severe community-acquired pneumonia (39). Given the positive results obtained with nebulized recombinant human TFPI in preclinical models, further investigation should focus on this form of delivery.
Nebulized APC administration in animal models of ALI diminishes lung injury (40-42), reduces pulmonary coagulopathy (43,44), stimulates fibrinolysis (45), reduces inflammation (40,45,46) and ameliorates oxygenation (40,43). Systemic coagulation was only decreased in one of the studies with pulmonary infection (43).
In a patient with ARDS that received inhaled APC (Drotrecogin alpha activated), the alveolar compartment resulted with anticoagulant, profibrinolytic and anti-inflammatory effects (26,47). Also, inhaled APC reduced neutrophils recruitment in the alveolar space, and did not produce nor local nor systemic adverse effects. Unfortunately, the negative results obtained in the PROWESS-Shock trial, a phase III trial of 1,967 patients with severe sepsis receiving intravenous recombinant human APC (rhAPC) (48), together with the removal of APC from the market ended with the use of APC (7).
ART-123 is a recombinant human soluble TM that through its anticoagulant and anti-inflammatory effect has been proved to improve disseminated intravascular coagulation in animal models and clinical studies (49-52). Furthermore, in a model of cecal ligation and puncture induced sepsis, ART-123 inhibited proinflammatory cytokines and ameliorated survival. In a model of endotoxemia induced by LPS, intravenous ART-123 reduced HMGB1 plasma levels and mortality (53). Indeed, in a phase II study, intravenously administered ART-123 proved to be safe and effective in patients with sepsis-associated disseminated intravascular coagulation, reducing prothrombin fragment and thrombin-antithrombin (AT) complex concentrations (54). Moreover, in a retrospective study of intravenously combined therapy with sivelestat and recombinant human soluble TM, beneficial effects on survival of patients with ARDS and disseminated intravascular coagulation were suggested (55). At the moment there is an ongoing phase III study of intravenous ART-123 in septic shock patients with disseminated intravascular coagulation and multiorgan failure.
AT, also termed heparin cofactor II or AT III (ATIII) is a broad-spectrum serine protease inhibitor. ATIII neutralizes several enzymes in the coagulation cascade, including thrombin and factor Xa, iXa, Xia and XIIa (56,57).
ATIII contains a heparin-binding domain at its active site. Heparin enhances the inhibitory activity of ATIII of the procoagulant proteins of the coagulation pathway. ATIII also has several indirect anti-inflammatory properties mediated through prostacyclin release (57,58).
Thrombin is increased in the injured lungs of patients with clinical disorders resulting in ALI/ARDS (58-60). Different therapeutic strategies with ATIII have been tested in experimental models and in patients with severe sepsis for restoring the natural anticoagulant cascades. In LPS-induced lung injury, intravenous ATIII has been shown to reduce vascular injury, leukocyte accumulation, and vascular permeability (56-58). Furthermore, in lung injury pneumonia induced by intratracheally S. pneumoniae, the pretreatment of nebulized ATIII attenuated pulmonary coagulopathy and fibrinolysis, reduced bacterial outgrowth, decreased inflammation and did not produce systemic bleeding (46). In models of P. aeruginosa (43) and endotoxemia (44) nebulized ATIII reduced pulmonary coagulation and did not affect systemic coagulation.
Currently, nebulized ATIII has not been administered in any clinical trial. As explained above, preclinical studies with combined ATIII and heparin have also been performed with positive results.
Heparin is a potent natural anticoagulant produced by mast cells in the intestine or lungs, basophils in the blood and endothelial cells (61). This glycosaminoglycan is extensively applied in the clinics for its anticoagulant properties. It potentiates ATIII inhibitory activity in the coagulation pathway and acts through other serine protease inhibitors such as protein C inhibitor and TFPI (56).
In direct and indirect ARDS, previous studies pointed out that heparin diminishes lung injury, although it produces systemic bleedings. Local administration of heparin for example by nebulization might prevent systemic effects and increase its effectiveness (11). Nebulized heparin ameliorated oxygenation in a model of smoke inhalation and sepsis (62). In preclinical and clinical studies inhaled anticoagulants (heparin, heparinoids, ATs, or fibrinolytics such as tissue PA) favored survival (63).
Furthermore, heparin presents anti-inflammatory activities (64). Heparin was found to inhibit the NF-κB pathway and decrease the expression of proinflammatory mediators in human alveolar macrophages treated with LPS (65-67) and reduce NF-kB pathway in alveolar cells (67) in vitro. However, studies in in vivo models of ALI present controversial results about the anti-inflammatory effect of heparin. On the one hand, in an animal model of endotoxemia (43,44) and pneumonia (46) the positive effect of nebulized heparin in coagulopathies was confirmed, although no changes on inflammation were found. On the other hand, the administration of nebulized heparin in an ALI rat model induced by intratracheal LPS diminished procoagulant and proinflammatory markers in lung tissue and the expression of NF-κB and TGF-β effectors in alveolar macrophages (68). Also, heparin reduced the recruitment of neutrophils into the alveolar space and edema, without producing systemic bleedings (68). The difference on these results could be attributed to the different timing and dosage of heparin.
Clinical studies with nebulized heparin administered to ARDS patients, did not present adverse effects, attenuated pulmonary coagulopathy and reduced the days of mechanical ventilation (69-71). A recent multicenter trial, HEPBURN, focused in the safety and efficacy of burn patients receiving nebulized heparin, was stopped due to an elevated systemic clotting time (72,73). No convincing benefit of heparin nebulization was found under mechanical ventilation (74) or for prophylaxis for pneumonia patients receiving mechanical ventilation (75,76). In 16 patients with ventilator-induced lung injury, heparin was nebulized proving safety and increasing the number of ventilator-free days (77).
The safety and efficacy of heparin as a treatment for the different etiologies of ARDS needs further investigation, as data is very limited.
Preclinical models support the use of PA for ARDS (78,79), although clinical studies with trauma or septic patients that received intravenous uPA, tPA or streptokinase presented higher risk of bleeding (80,81). Nebulization of tPA could maintain its properties while avoid systemic adverse effects (81-84).
Until now we have focused on single anticoagulant therapies, but studies were nebulized heparin has been combined with other drugs also proved benefit in ARDS. A preclinical model of combined aerosolized recombinant human AT and heparin in a sheep with burn and smoke inhalation reduced pulmonary pathophysiology (85). Moreover, intravenous recombinant human AT together with aerosolized heparin diminished the lung injury in a model of sheep with burn and smoke inhalation (86). Intravenous AT together with nebulized heparin and tPA in a model of burn smoke inhalation, sheep restored gas exchange but did not produce changes in inflammation (87).
Aerosolized heparin and N-acetylcysteine diminished lung injury in ventilated smoke inhalation ARDS patients (88) and reduced duration of mechanical ventilation in burn inhalation injury (89). No drug incompatibilities were found in a case of a patient with smoke inhalation injury receiving nebulized heparin with N-acetylcysteine and epoprostenol (90). Nebulized heparin in burn patients together with a beta-agonist and a mucolytic diminished duration of mechanical ventilation, was safe and no bleeding events were recorded (91).
New therapies based on the pathophysiological processes of ARDS development are need due to the high morbidity and mortality underlying this disease. Activated coagulation and reduced fibrinolytic activity are intrinsic to ARDS. Preclinical and clinical trials show beneficial effects of anticoagulants in ARDS, although results are controversial. Local treatment in the alveolar compartment, through anticoagulants nebulization, raises its effects and avoids systemic bleedings. Nebulization of tPA or TFPI could maintain its properties while avoid systemic adverse effects, further investigation should focus on this form of delivery. However, we should not forget that animal models mimic human ARDS only in part, and that this could affect the relevance of the data. Furthermore, we should have in mind that the time to initiate a treatment is decisive.
The etiology of ARDS pathophysiology is diverse. Identify subtypes in ARDS heterogeneity might help to predict responsiveness to a specific treatment. The use of intravenous ART-123 in a subtype of ARDS patients should be further investigated. ARDS is a complex disease regarding its pathophysiology, so the unique or combined therapy should face different pathways and processes to ameliorate patient’s outcomes. The nebulization of ATIII and heparin combined or alone in a subtype of patients most likely to respond to the appropriate anticoagulant should be either studied.
This work was partially supported by Fundació Parc Taulí, CIBERES and the Spanish Society of Intensive Care Medicine SEMICYUC. Furthermore, Dr. Artigas received a research grant and award from Grifols.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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