It is now established that tissue injury is associated with disordered fibrin turnover and fibrin deposition in a wide range of diseases (1). A common sequence of events is observed in nearly all forms of tissue injury. First, microvascular permeability is increased with acute inflammation, allowing entry of plasma coagulation substrates into the parenchyma of the injured tissue. Coagulation is next initiated by tissue factor associated with activated factor VII, the so-called extrinsic activation pathway. Activation of this pathway results in formation of a fibrin neomatrix (2). The fibrin neomatrix is next invaded by inflammatory cells, including macrophages, and fibroblasts. Cytokines and selected proteases elaborated in the inflammatory microenvironment induce expression of plasminogen activators (PAs), mainly urokinase (uPA), as well as the plasminogen activator inhibitors (PAIs). The relative expression of uPA and fibrinolytic inhibitors largely determines the extent of local fibrin clearance and remodeling of the transitional fibrin. Ultimately, collagen deposition within the fibrin neomatrix occurs, eventually leading to fibrotic repair.
Interestingly, the same sequence of events also characterizes the desmoplastic response to solid neoplasms and is involved in tumor growth (2). Tumor cells often elaborate these same procoagulants, fibrinolysins, and their inhibitors. As an example, malignant mesothelioma elaborates several of these molecules, so that the tumor itself can thereby regulate local fibrin deposition (3). Fibrin deposition proximate to and within solid tumors is itself an important determinant of neoplastic growth. Apart from control of fibrin clearance, expression of uPA, its receptor (uPAR) and PAIs can all independently influence tumor extension by signaling reactions initiated at the cell surface that, in turn, regulate processes relevant to tumor growth, including cellular proliferation, invasiveness and angiogenesis (4).
Similar changes in systemic fibrin turnover are strongly implicated in the tissue injury and organ dysfunction associated with systemic sepsis. Sepsis is often associated with a systemic coagulopathy associated with increased tissue factor expression. Activation of coagulation is associated with. concurrent impairment of fibrinolysis (5). Tissue fibrin deposition occurs as a result of these concurrent changes, leading to organ dysfunction. Alveolar fibrin deposition, for example, is associated with surfactant dysfunction (6) and fibrinogen, fibrin monomer, and proteolytic cleavage products of fibrinogen can impair surfactant function (7,8) Extensive glomerular and renal vascular fibrin deposition may also contribute to the development of acute renal failure.
PULMONARY FIBRIN DEPOSITION: A CENTRAL EVENT IN ACUTE LUNG INJURY AND ARDS
Alveolar fibrin deposition is extensive in preclinical models of acute exudative alveolitis. For example, florid alveolar fibrin deposition occurs in acute lung injury induced in rats or sheep by intravenous administration of oleic acid (9,10). The exudative alveolitis that occurs during the first 2 weeks after bleomycin-induced lung injury in rats or marmosets is likewise characterized by extensive alveolar fibrin (10,11). In baboons with sepsis-associated ARDS, a fibrinous alveolitis likewise occurs in association with diffuse alveolar damage, the histologic correlate of ARDS in humans (12). Lastly, morphologic analyses have documented that florid fibrin deposition occurs in the lungs of patients with ARDS (13). Fibrin occurs in the alveolar compartment within the first few days of ARDS and persists in association with the organizing alveolar exudate. Rapid organization of the alveolar exudate in ARDS is followed by accelerated intraalveolar fibrosis, sometimes in a few days. The alveolitis of active idiopathic pulmonary fibrosis also exhibits alveolar fibrin (14), further suggesting a link between the alveolar fibrin That accompanies evolving lung injury and pulmonary fibrosis.
Fibrin thrombi also form within the pulmonary vasculature in ARDS. In addition, thrombi occur in the pulmonary arteries in severe ARDS (15). The presence of these pulmonary artery thrombi could be demonstrated by balloon occlusion angiography and correlated with postmortem occlusions and vascular wall thickness. Bedside balloon occlusion can be used to demonstrate the presence of pulmonary artery thrombi and distal filling patterns of the pulmonary microvasculature (16). These perturbations are associated with pulmonary dysfunction, including atelectasis and increased pulmonary vascular resistance. The presence of pulmonary artery thrombi also appears to correlate with increased mortality in one report (16). Intravascular thrombi can also affect acute edematous pulmonary injury (17–19). Disseminated intravascular coagulation has been reported in association with ARDS (20) and may likewise contribute to the parenchymal injury associated with the syndrome.
ABNORMALITIES OF FIBRIN TURNOVER IN ARDS
Over the past few years, the mechanisms of fibrin formation and dissolution that contribute to extravascular fibrin formation in the injured lung have been identified. Bronchoalveolar lavage (BAL) analyses have been used to elucidate these pathways. It now appears that a critical balance between the expression of local procoagulant and fibrinolytic mechanisms determines whether fibrin forms and persists in the injured lung (Figure 1).
Fibrin deposition does not occur in the normal lung. While BAL from normal volunteers contains relatively low levels of tissue factor procoagulant activity, fibrinolytic activity due to uPA is readily detectable (21,22). The uPA is likely derived from different resident lung cells, including alveolar macrophages, lung epithelial cells, and fibroblasts (23). Under normal circumstances, the pulmonary microvasculature is relatively impermeable to coagulation substrates, so that initiation of local coagulation by tissue factor does not occur due to a paucity of distal coagulation substrates. The situation in acute lung injury is entirely different. In oleic acid and bleomycin-induced lung injury, tissue factor-factor VII (or activated factor VIIa) complexes are increased in BAL or in the lung, activating local coagulation (9,11,24). Factor VII and distal coagulation substrates present within the alveolar compartment due to increased microvascular permeability are available to amplify the local procoagulant response. These same responses follow sepsis and nonsepsis-associated ARDS in baboons (12,25). Local fibrin clearance is impaired via the concurrent relative overexpression of plasminogen activator inhibitors and downstream antiplasmins (25) (Figure 1). Similar changes in lower respiratory tract coagulation and fibrinolysis occur in premature baboons with evolving respiratory distress syndrome and diffuse alveolar damage (26).
Identical abnormalities of local fibrin turnover are found in BAL fluids from patients with interstitial lung diseases and ARDS. In patients with sarcoidosis, idiopathic pulmonary fibrosis, and other interstitial lung diseases, BAL procoagulant activity is increased and uPA-related fibrinolytic activity is depressed (22,27–29). Similar abnormalities occur in patients at risk for ARDS by virtue of having systemic sepsis, multiple transfusions, or other predisposing factors (22). In patients undergoing BAL within 3 days of clinical recognition of ARDS, the greatest increment of procoagulant activity is observed. The procoagulant response, mainly attributable to tissue factor associated with factor VII, is temporally associated with a profound defect in local fibrinolytic activity, indicating that fibrin clearance is impaired in the alveolar lining fluids in ARDS (22,30,31). PAI-1 is the major PA inhibitor present in these lower respiratory tract fluids and contributes to the virtually complete inhibition of alveolar fibrinolytic activity in early ARDS. These concurrent changes would be expected to promote pulmonary fibrin deposition. As ARDS progresses over the 2 weeks following recognition, the alveolar procoagulant response is gradually attenuated, whereas the fibrinolytic defect remains profound (32). These persistent abnormalities are likely responsible for the maintenance of alveolar fibrin during the course of evolving ARDS. Presumably, these abnormalities resolve in patients with rapid recovery from ARDS as they do in recovery from acute lung injury in various preclinical models (23). In premature infants with evolving respiratory distress syndrome, BAL procoagulant activity is likewise generally increased and fibrinolytic activity decreased (33,34). Interestingly, the PAI-1 levels in plasma of patients with ARDS are generally higher than those of control critically ill patients, suggesting that local abnormalities of fibrinolysis in ARDS are, at least in part, reflected in the systemic circulation (35).
The changes in BAL procoagulant activity in acute lung injury in general and in ARDS in particular represent the activities derived from the procoagulants, fibrinolysins, and inhibitors expressed by parenchymal lung cells. Cells that express tissue factor include alveolar macrophages and lung epithelial cells and fibroblasts (21,29,36–38). These same cells express uPA, PAI-1, and PAI-2 (39–42). These cells respond to cytokines implicated in the pathogenesis of acute fibrosing lung injury by secreting these molecules in vitro, suggesting that the same secretory processes occur in vivo (23,43). The relative expression of these molecules in alveolar lining fluids in ARDS is attributable to the responses of lung cells to changing patterns of cytokines and other inflammatory stimuli during the course of evolving inflammatory lung injury and repair (44).
PATHOPHYSIOLOGIC CONSEQUENCES OF IMPAIRED FIBRINOLYSIS IN ARDS
The fibrinolytic defect in acute lung injury and ARDS exerts multiple effects (Figure 2). For example, fibrin and its derivatives are all capable of adversely influencing surfactant function (7,8). The interaction between fibrin(ogen) and its derivatives and surfactant could potentiate the microatelectasis associated with pulmonary dysfunction in ARDS. The defect also contributes to the persistence of alveolar fibrin, which promotes the migration of lung fibroblasts, alveolar epithelial cells, and macrophages in the inflammatory microenvironment (2,45,46). Fibrin degradation products formed by the action of plasmin on fibrin can also influence increased vascular permeability via effects on the endothelium (47) (Figure 3) (48). PAs and PAI can also regulate various aspects of tissue remodeling in inflammatory lung injury, as they do in remodeling of the tumor stroma (49,50). These observations suggest that perturbations of the fibrinolytic system can influence the acute inflammatory response and contribute to pulmonary dysfunction in acute lung injury (Figure 2).
Apart from effects on vascular permeability, surfactant dysfunction, or acute inflammation, evidence of a causal relationship between impaired alveolar fibrin clearance and accelerated pulmonary fibrosis has been reported. This relationship is best supported by selective manipulation of the fibrinolytic system in transgenic animals. For example, in bleomycin-treated mice overexpressing PAI-1, fibrinolysis is relatively impaired and accelerated pulmonary fibrosis is increased. In mice deficient in PAI-1, fibrinolysis is conversely potentiated and pulmonary fibrosis relatively attenuated (51). These observations provide compelling evidence that the protracted fibrinolytic defect in ARDS contributes to the development of accelerated pulmonary fibrosis.
INTERVENTIONS THAT TARGET IMPAIRED FIBRINOLYSIS IN ARDS
Limited preclinical evidence supports the feasibility of using profibrinolytic activities to protect the lung against acute injury. In a porcine model of ARDS, intravenous administration of plasminogen activators increased arterial oxygenation and provided a survival advantage (52). Tissue plasminogen activator (tPA)and uPA were effective and provided histologic as well as physiologic protection against acute lung injury. An alternative strategy involving administration of plasminogen or plasmin to increase systemic fibrinolysis, has been used to protect against acute lung injury. In one study, circulating levels of plasminogen were shown to be decreased in experimental animals with acute lung injury, premature infants at risk for respiratory distress syndrome, and patients with ARDS (53). Administration of plasminogen decrease d the incidence of respiratory distress syndrome in treated infants. The mortality rate of infants with established respiratory distress syndrome was also decreased by administration of plasmin.
The postulate that reversal of the fibrinolytic defect associated with acute lung injury could protect against acute lung injury has been tested in several small clinical trials. In one study, five patients with severe ARDS had documented pulmonary thrombi and received infusions of streptokinase (54). Improved hemodynamics, including a fall in pulmonary vascular resistance and improved oxygenation (in three patients) occurred in association with angiographic clearance of the thrombi. Three of the patients were nonsurvivors and there was one documented bleeding episode. Similar improvements were reported in another study of patients with pulmonary thrombi and severe ARDS (55). In a larger study of 19 ARDS patients refractory to supportive measures, treatment with either streptokinase or urokinase resulted in improved arterial oxygenation and no bleeding complications were observed, suggesting that a fibrinolytic strategy could safely be pursued in selected ARDS patients (56).
ABNORMAL PULMONARY FIBRIN TURNOVER AND NEW INTERVENTIONAL APPROACHES FOR PATIENTS WITH SEPSIS
Patients with severe sepsis and those with ARDS are generally at increased risk for bleeding complications. In particular, those with underlying predisposition to gastrointestinal bleeding or coagulopathy are prone to clinically important bleeding complications, so that interventions with anticoagulants or fibrinolysins are properly viewed as potentially hazardous. Recent information suggests that the benefit/risk ratio of these agents for critically ill patients with sepsis merits reexamination. This new information is germane to any consideration of interventional strategies to treat ARDS, as ongoing sepsis is a major risk factor associated with the syndrome.
In septic patients, abnormalities of fibrin turnover are characteristic. Systemic coagulation, sometimes associated with overt disseminated intravascular coagulation and tissue fibrin deposition, occurs in association with depressed systemic fibrinolysis (5,57) and reversal of these defects has been proposed as a promising interventional approach (58,59). Along these lines, an anticoagulant, recombinant activated protein C (APC), has recently been shown to provide benefit in sepsis. APC inhibits factors VIIIa and Va (Figure 4), promotes fibrinolysis by inhibiting PAI-1 and exerts antiinflammatory properties (59) (5,60,61). In a baboon model of lethal sepsis, APC was protective and reduced mortality (62), suggesting the possibility that this agent could provide benefits for patients with sepsis. Recently, APC was, in fact, reported to significantly reduce the relative risk of death (by 19.4%) in a large multicenter trial involving septic patients who received either recombinant APC or placebo (63). Although the risk reduction is not large, the approach offers the prospect of improved outcome in sepsis, which is, again, an important risk factor for ARDS. The study did not determine if APC treatment can reduce the incidence of ARDS in septic patients. There was a small increment in the incidence of serious bleeding in the group that received the recombinant APC, suggesting that careful patient selection may be required to optimize the risk/benefit ratio in clinical practice. This novel approach suggests that anticoagulant interventions can favorably influence the inflammatory response to sepsis. Whether the benefits extend to septic patients with ARDS is currently unclear.
Other anticoagulants have been used to reverse the coagulopathic and lethal effects of sepsis. These agents have been used with varying degrees of success. For example, an inactive form of factor X reversed the coagulopathy of sepsis, but not the hemodynamic effects or tissue injury (64). Other agents have been used to block the extrinsic activation complex, tissue factor associated with factor VII. An inhibitor of the extrinsic activation complex; site-inactivated factor VII, was found to exert antiinflammatory as well as anticoagulant properties in a model of systemic sepsis (65). Another inhibitor of extrinsic coagulation, tissue factor pathway inhibitor (TFPI), was found to reduce the mortality associated with sepsis (66). Early Phase II trials of TFPI have been performed in relatively small numbers of patients with sepsis. The results have yet to be published but preliminary reports presented at national meetings suggest that patients with ARDS could benefit in terms of a survival advantage. Full assessment of the safety and efficacy of this approach must await scrutiny of the full publications derived from this interventional approach.
NOVEL INTERVENTIONS TARGETING FIBRIN TURNOVER: EXTRAPOLATION TO ARDS
Because of the similarities between the systemic derangements of fibrin turnover in sepsis and the local abnormalities of these pathways in acute lung injury (23), similar interventional approaches have recently been attempted in experimental ARDS. Along these lines, site inactivated factor VII and TFPI, have recently been used in a preventive mode to protect against acute lung injury in septic baboons (67). When either of these agents were used by intravenous infusion in baboons with sepsis before ARDS had developed, the coagulopathic response to sepsis was attenuated as were pulmonary fibrin deposition and pulmonary dysfunction. These preliminary studies in a baboon model of sepsis-associated ARDS, indicate that a selective anticoagulant approach can be effective, at least as a preventive intervention. Whether potential antiinflammatory or down-stream profibrinolytic effects attributable to these agents play a role in the observed lung protection has yet to be determined. It also remains to be determined if these anticoagulants would reverse established lung injury if they were administered after the development of ARDS. Studies to address these possibilities and to carefully elucidate the precise effects of these anticoagulants are in progress. However, the interventional data now available, combined with current understanding of the basis of the upregulated procoagulant and diminished fibrinolytic responses in ARDS, suggest that strategies targeting these pathways could be successful.
As described above, preliminary studies have been performed in which fibrinolysins improve d hemodynamics and oxygenation in patients with severe ARDS. The rationale for these interventions was to improve pulmonary vascular perfusion by lysis of pulmonary thrombi. The more recent anticoagulant interventions in sepsis and ARDS suggest that fibrinolytic interventions could likewise be useful to prevent pulmonary fibrin deposition and protect the lungs.
AVAILABLE FIBRINOLYSINS AND CURRENT APPLICATIONS
Fibrinolysins are now commonly used in clinical practice and clinicians are now more familiar with their use. As reviewed recently, several plasminogen activators are currently available (68). Urokinase, streptokinase, and the modified complex anistreplase are relatively less fibrin specific than recombinant tPA and its derivatives. Urokinase in its low molecular weight form is not generally available now owing to manufacturing issues that have yet to be fully resolved.
Plasminogen activators occupy a special niche in specific clinical scenarios in which fibrinolysis has been found to be of clinical benefit. In particular, plasminogen activators are now commonly used in the acute therapy of myocardial infarction (69). Thrombolytic therapy has more recently been advocated for therapy of acute ischemic stroke, within a 3-hour therapeutic window in patients with a clinically meaningful neurologic deficit, no evidence of intracranial bleeding by CT scan, and otherwise meeting rigorous exclusion criteria (70). Thrombolytic therapy can also be of advantage for patients with massive pulmonary embolism and hemodynamic instability. The use of thrombolytic agents for deep venous thrombosis is not routine (71), although this approach may be of value for highly selected patients with limb threatening thrombosis or extensive ileofemoral deep venous thrombosis who are therefore at risk for postphlebitic syndrome. Additionally, plasminogen activators are currently used in cases of organizing pleuritis, such as those associated with complicated parapneumonic pleural effusions. In this situation, the agents are locally instilled in order to promote degradation of pleural loculations in an effort to avoid surgical decortication (72–74). The intrapleural exudate is typically fibrinous early after injury. In a model of fibrosing pleuritis induced by tetracycline (75), either repeated intrapleural instillation of urokinase or heparin can attenuate pleural fibrosis (76).
AVAILABLE FIBRINOLYSINS AND APPLICATION TO ARDS
Modifications of several plasminogen activators have been introduced into clinical use within the past few years. These modifications influence plasma half-life and fibrin specificity. For example, TNK-tPA or tenecteplase is modified at three separate sites and exhibits slightly greater fibrin specificity and a longer plasma half-life versus human recombinant tPA (68). Interestingly, the efficacy of several of these agents, used in the context of acute myocardial infarction, is actually rather similar despite profound differences in cost. For example, single-chain recombinant tPA and streptokinase both yield coronary patency rates of approximately 60%, comparable reocclusion rates of up to 20%, and improvement in survival with comparable rates of bleeding complications, including intracranial bleeding in up to 0.5% of cases (69). The cost of a course of streptokinase, which is associated with allergic reactions, is approximately $500 wholesale, whereas that of recombinant single-chain tPA (Alteplase), which does not elicit allergic reactions, is generally in excess of five times as much (69). Rather than tPA or its congeners, uPA or streptokinase was used in most of the small interventional studies of severely ill ARDS patients noted above. Because the data are preliminary and derive from the analysis of small numbers of patients, it is currently unclear whether there might be any difference in the efficacy or safety of any of the available fibrinolysins when used in the setting of ARDS. Although the available interventional studies suggest the possibility of benefit in cases of severe ARDS, the use of any available agent in this context is not routine and the benefits and risks of this approach in these seriously ill patients are yet to be established. In most of the available reports, the fibrinolysins have been administered intravenously in ARDS patients and it is currently unclear as to whether inhalational administration would be more effective or safer.
NEW INTERVENTIONAL APPROACHES DESIGNED TO OPERATE IN THE INFLAMMATORY MICROENVIRONMENT OF ARDS
The hypothesis that disordered fibrin turnover is central to the pathogenesis of acute lung injury is testable and under study at this time. Interventions with anticoagulants such as site inactivated factor VII and TFPI provide lung protection in baboon sepsis-induced ARDS, supporting the hypothesis (67). Although antiinflammatory properties of these molecules may play a role, a reasonable interpretation of these observations is that interruption of pathologic coagulation and fibrin deposition is integral to the salutary effects. Interventions with fibrinolysins could, in this instance, likewise provide lung protection, by promoting accelerated fibrin clearance in the injured lung. The effects of these interventions on clinical endpoints including accelerated pulmonary fibrosis, ventilator time or the development of nosocomial pneumonia remain to be determined.
Because PAI-1 is a major inhibitor of fibrinolysis in the alveolar compartment in ARDS and uPA is the major endogenous fibrinolysin (22,77), alternative approaches are in development to reverse the fibrinolytic defect in acute lung injury. The strategies now being tested involve the use of modified fibrinolysins to enhance the endogenous uPA-related fibrinolytic activity. These fibrinolysins are designed to resist the effects of local fibrinolytic inhibitors so as to potentiate fibrin clearance. Should this approach prove effective as a rescue strategy in preclinical models of ARDS, it will be important to determine if the lung protective effects of such lysins could be additive to those of selective anticoagulants which exert similar effects.
The fibrinolytic defect in ARDS is predicated on the elaboration of relatively increased levels of inhibitors of plasminogen activators or plasmin in the alveolar compartment. Preclinical studies suggest That administration of plasminogen activators can reverse the defect and improve hemodynamics and gas exchange. Small clinical trials in patients with ARDS suggest That the approach could be beneficial in carefully selected patients, presumably by limiting persistent intravascular and extravascular fibrin deposition in the lung. However, the use of fibrinolysins in patients with ARDS is not routine and validation of the clinical efficacy of this approach will require further study. The risks of this approach need to be carefully defined. Along these lines, preclinical trials are now in progress to determine if novel fibrinolysins that resist local inhibition by PAIs can effectively and safely reverse the acute inflammatory and accelerated fibrotic responses that characterize acute lung injury in ARDS.
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