Anticoagulants for Acute Respiratory Distress Syndrome
Can They Work?

STEVEN IDELL

Department of Specialty Care Services, The University of Texas Health Center at Tyler, Tyler, Texas

	ARTICLE

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Despite years of intensive study and resource allocation, the search for the root causes of acute (or adult) respiratory distress syndrome (ARDS) remains elusive. Although many proinflammatory systems are activated in ARDS, clinical trials of agents designed to selectively block several of these pathways have yet to demonstrate any effective way to reverse the fundamental derangements. Recent and ongoing clinical trials in which new anticoagulants are being used to prevent tissue injury in sepsis could soon change this scenario. Based on presentations at scientific meetings and recent published work, it appears that anticoagulants that block nodal steps in the coagulation cascade are yielding promising results. To many in the pulmonary or critical care community, these reports may be surprising and the approach unfamiliar. The notion that anticoagulants of any stripe could be used to prevent tissue injury and organ failure is still relatively arcane. However, these are among the endpoints by which the efficacy of anticoagulants is now being judged in recent clinical trials.

The molecular basis for the systemic coagulopathy of sepsis and the local derangements of fibrin turnover in the lungs in ARDS are very similar (1). In both circumstances, intravascular and extravascular fibrin deposition appears to contribute to organ dysfunction, including that of the lungs. In the ongoing trials in septic patients, selective anticoagulants, tissue factor pathway inhibitor (TFPI) and activated protein C (APC), are being used to prevent the associated systemic coagulopathy and end-organ injury. These agents appear to exert anti-inflammatory as well as anticoagulant properties. Accordingly, there is good reason to speculate that these anticoagulants might protect against acute lung injury and its sequelae in ARDS. The use of selective anticoagulants to prevent lung injury or remodeling in ARDS is also supported by strong basic and preclinical science.

The hypothesis that disordered fibrin turnover and extravascular fibrin deposition are central to the pathogenesis of tissue injury and remodeling is hardly new. In fact, coagulation and fibrinolysis have long been implicated in the pathogenesis of organ dysfunction in sepsis (2), the healing of wounds (3) as well as the propagation of neoplasms (3). These processes are all unified by similarly deranged coagulation abnormalities and abnormal tissue fibrin deposition, particularly in the lungs in ARDS (3). The literature further implicates coagulation and disordered fibrin turnover in a broad range of pathophysiologic processes that influence acute lung injury and repair in ARDS (6, 7).

The "anticoagulants for ARDS" strategy has evolved by a rather circuitous route. The current preclinical and clinical trials of anticoagulants in sepsis include the subset of patients with sepsis-induced ARDS. These trials extend basic studies that were designed to identify pathways that regulate fibrin deposition in the injured lung. Characterization of these pathways in primates with sepsis or hyperoxia-induced ARDS and in patients with ARDS (7) led to the recognition of putative molecular targets that could be exploited to prevent local coagulation and pulmonary fibrin formation (8). Development of potent, selective inhibitors to these molecular targets was facilitated by technologic advances and promoted by commercial interest. The testing of new anticoagulants accelerated as the interest of pharmaceutical firms intensified, in part because of the search for better ways to prevent restenosis after coronary artery stent placement. Preclinical testing of these anticoagulants was done in disparate scenarios associated with coagulopathy and revealed that some of these selective anticoagulants could prevent organ dysfunction in sepsis, leading to the recent clinical trials.

On what basis should anticoagulants be considered as potential interventions for ARDS? The case for coagulation as a key effector of lung injury in ARDS is first predicated on strong morphologic evidence. While absent in the normal lung, extravascular fibrin deposition is florid in both the alveolar and interstitial compartments in evolving diffuse alveolar damage, which is the histologic hallmark of ARDS (4, 9). Pathologic fibrin deposition also occurs in the vasculature in ARDS and pulmonary artery thrombi are found, implicating anatomic as well as associated vasoconstrictor mechanisms in the occurrence of increased pulmonary vascular resistance in ARDS (10). The distribution of fibrin in the lungs in ARDS demonstrates that coagulation pathways can be pathologically activated in both the extravascular and intravascular compartments.

In the lung parenchyma, formation and remodeling of the transitional fibrin neomatrix during evolving ARDS also recapitulates the events associated with the healing of wounds (3, 7). In both situations, a complex series of responses to injury augments vascular permeability (11) and facilitates the entry of plasmalike fluid into the tissue parenchyma. Coagulation proteases, including thrombin, and fibrin(ogen) derivatives influence this process as well as inflammatory cell traffic (12- 16). Formation of a fibrin neomatrix is initiated by exposure of tissue factor in the inflammatory microenvironment to plasma coagulation substrates, including factor VII. The association of factor VII with tissue factor results in its activation to factor VIIa, thereby amplifying the local procoagulant response, which in the injured lung occurs mainly via this so-called extrinsic coagulation pathway. These interactions can occur at the surface of lung epithelial cells, lung fibroblasts, or lung macrophages, locally promoting extravascular, alveolar-interstitial coagulation in acute pulmonary injury (7). Intravascular coagulation is likewise initiated via tissue factor-VIIa complex formation at the surface of stimulated or injured pulmonary endothelial cells.

Whereas activation of contact or intrinsic coagulation pathway proteases has been demonstrated in the bronchoalveolar lavage fluids (BALF) of patients with ARDS, the major locally expressed procoagulant is clearly tissue factor associated with factor VII (8). This procoagulant complex is present in the alveolar lining fluids of the normal lung (17). The absence of alveolar fibrin in the normal alveolar space appears to be attributable to the paucity of downstream coagulation substrates and the relative abundance of fibrinolytic capacity owing to urokinase plasminogen activator (8, 18). Upregulation of local tissue factor-factor VIIa procoagulant activity likewise occurs in the lungs of patients with pneumonia or interstitial diseases (19, 20), but is uniformly intense in the first 3 d of ARDS (21). Over the first 2 wk of ARDS, there is gradual attenuation of the procoagulant response, but this change is offset by a profound defect of local fibrinolysis, due mainly to the protracted local overexpression of plasminogen activator inhibitor-1 (PAI-1) (8, 18). These concurrent derangements that is, of upregulated coagulation and downregulated fibrinolysispresumably combine to promote persistence of fibrin deposition in the lungs in ARDS.

There is a remarkable uniformity of these same procoagulant and fibrinolytic responses in a broad range of preclinical models (8, 22) and patients with ARDS, pneumonia, or interstitial lung diseases (19, 20, 23). As an example, in models of diffuse alveolar damage in baboons, alveolar fibrin deposition is prominent and temporally correlates with increased expression of tissue factor-factor VIIa procoagulant activity in BALF (7). The same derangements characterize evolving ARDS associated with infection or nonseptic causes of acute lung injury, such as hyperoxia (7). The conserved activation of the extrinsic coagulation pathway strongly supports the thesis that its upregulation is integral to the response of the lung to acute injury.

In ARDS, organization of the fibrin neomatrix appears likely to promote the development of accelerated pulmonary fibrosis that can occur in these patients (4). Remodeling of the transitional fibrin inexorably occurs through invasion of the gel by inflammatory cells, including lung fibroblasts, ultimately leading to collagen deposition and rapid scarification (9, 24). This progression may occur within 1 to 2 wk after clinical recognition of ARDS, providing a temporal link to the rapid development of accelerated pulmonary fibrosis in patients with severe acute lung injury (4). The evidence supporting a progression of early fibrin deposition to subsequent pulmonary fibrosis is strong. In bleomycin-induced lung injury in rats and lower primates such as marmosets, there is a temporal correlation between persistent parenchymal fibrin deposition in the lungs and the development of accelerated pulmonary fibrosis. These events occur over the course of 2 to 3 wk (7). In this situation, the persistence of alveolar fibrin appears to promote subsequent organization and scar formation. On the other hand, transient lung injury induced by oleic acid is characterized by a rapid induction of procoagulant activity and alveolar fibrin, followed by restoration of normal alveolar fibrin turnover, resolution of alveolar fibrin, and the return of normal lung architecture (7). Additional support for a link between disrupted pulmonary fibrin turnover and fibrosis comes from experiments in which fibrinolytic capacity in the lungs was upregulated or downregulated in transgenic mice. Mice deficient in PAI-1 failed to develop intraalveolar fibrin in response to hyperoxic challenge (25). Extending these observations, increased pulmonary fibrosis likewise occurred when PAI-1 was upregulated in bleomycin-treated mice and fibrosis was decreased when PAI-1 was knocked out (26). Although the measured endpoints of these experiments were histologic and biochemical indices of fibrosis, these effects were presumably attributable to manipulation of the capacity of the lung to degrade transitional fibrin.

The idea that disordered fibrin turnover and diffuse fibrin deposition in the acutely injured lung could adversely affect lung function is to some extent intuitive, in that an interposed fibrin neomatrix might seem likely to impair lung function and gas exchange. There is now abundant supporting evidence that the presence of fibrin in ARDS is, at least in part, pathophysiologic. For example, fibrin, its proteolytically derived products and soluble fibrinogen interfere with surfactant function, which may potentiate microatelectasis and intrapulmonary shunting (27). Activation of coagulation can also influence inflammatory cell traffic, either by the local elaboration of procoagulants, such as thrombin, or by altering the density of, or cross-linking of locally deposited fibrin (3). Activation of coagulation pathways can otherwise amplify the local inflammatory response by, in turn, activating alternative inflammatory pathways, including the contact, fibrinolytic, and complement systems and stimulating the expression of inflammatory mediators (7). For example, it was shown that the induction of interleukin-1 (IL-1) could be regulated by fibrinogen, a key substrate of the coagulation system and the precursor of fibrin (28). Thrombin further stimulates expression of a number of cytokines and exerts other proinflammatory effects, including regulation of endothelial cell contraction and permeability, cellular proliferation as well as chemotaxis and aggregation of inflammatory cells. In all, these observations strongly suggest that proinflammatory responses germane to the pathogenesis of ARDS involve coagulation pathway intermediates.

Sepsis is a major risk factor for the development of ARDS and is commonly encountered in clinical practice. It is therefore not surprising that the initial interventional clinical applications of selective anticoagulants have been designed to evaluate these agents as adjunctive treatment for sepsis, rather than for ARDS per se. One anticoagulant, TFPI, has been used to inhibit the coagulopathic responses to endotoxin and was well tolerated in Phase I clinical trials (29). This inhibitor forms a quaternary complex, with TF, factor Xa, and factor VIIa to block the activity of the tissue factor-VIIa procoagulant complex (Figure 1). TFPI is present in bronchoalveolar lavage of patients with ARDS, but endogenous levels are apparently insufficient to block fibrin deposition initiated by tissue factor-VIIa (30). The use of this inhibitor in septic patients is predicated upon the idea that the coagulopathy and end-organ dysfunction of sepsis could be prevented by more effective blockade of extrinsic pathway activation by supplementation with recombinant TFPI (31). Overall and ARDS subgroup analysis of the data from a relatively small Phase 2 clinical trial of septic patients treated with TFPI was recently presented at the last international meeting of the American College of Chest Physicians in San Francisco. The results are encouraging, albeit preliminary. Based on this presentation, it appears that there was a roughly 20% overall survival advantage for all septic patients treated with TFPI. It further appears that the ARDS subgroup benefited from administration of intravenous TFPI in terms of a roughly 35% survival advantage in comparison to vehicle controls. The treated group also exhibited improvement in pulmonary dysfunction scores, raising the possibility that the clinical benefit may derive from improvement of the underlying lung injury. The clinical benefits of TFPI further correlated with indices of its anticoagulant effect, suggesting that the benefits likely at least in part derive from the anticipated effects on hemostasis. Responses of selected cytokines, IL-6 and IL-8, were also abridged, raising the possibility that these effects may also have been of importance. Careful review of the eventual publication will obviously be needed to assess the clinical value of TFPI for patients with ARDS owing to underlying sepsis and to determine how this agent altered the inflammatory response.

View larger version (15K): [in this window] [in a new window]   Figure 1.   "Intrinsic" and "extrinsic" denote the respective coagulation pathways in this simplified diagram. Selected coagulation factors are denoted by roman numerals. The "a" designation indicates the activated form of the coagulation factor. Solid arrows indicate procoagulant steps of the coagulation pathways. Broken arrows indicate inhibitory effects. TAFI = thrombin-activatable fibrinolysis inhibitor. The inhibitory effects of APC on PAI-1 and TAFI promote fibrinolysis. Interventional anticoagulants are denoted in the clear boxes.

In a related vein, a recent report that APC reduces mortality in patients with severe sepsis further suggests that selective anticoagulant molecules can be used to clinical advantage (32). This landmark study has created quite a stir, clearly demonstrating the efficacy of this novel therapeutic approach. APC is a natural anticoagulant that inhibits coagulation factors Va and VIIIa (Figure 1) and exerts anti-inflammatory effects germane to the systemic response to sepsis (33). These include decreasing cytokine production, including that of tumor necrosis factor-alpha (TNF-), IL-1, and IL-6; leukocyte attachment to the endothelium; and neutralization of PAI-1. All of these effects could be beneficial in the lungs in ARDS.

APC is rapidly depleted in septic shock and correlates with progression of shock and increased mortality (33) and can modulate gene expression of several inflammatory mediators, including the cytokines noted previously (34). Based upon such observations and a preceding Phase 2 clinical trial demonstrating that APC reduced markers of coagulation and inflammation, plasma D-dimer and IL-6, in a dose-dependent manner in septic patients, a Phase 3 trial was initiated (32). In this randomized, double-blind, placebo-controlled, multicenter trial involving a total of 1,690 patients, treatment with a 96-h intravenous infusion of recombinant APC significantly reduced overall mortality assessed at 28 d after the start of the infusion. The difference in the rate of death from any cause was reduced from 30.8% in the 840 placebo-treated patients to 24.7% of the 850 APC-treated patients. This difference was highly significant (p = 0.005) and was associated with an absolute reduction in the risk of death by 6.1%. This benefit was achieved at the cost of an increase in the incidence of bleeding; 3.5% in the APC-treated subjects versus 2.0% in placebo-treated control subjects. Some of the patients in this study had respiratory dysfunction as determined by a ratio of PaO₂ to fraction of inspired oxygen (FIO₂) ratio of  250 in the presence of other dysfunctional organs or  200 if the lung was the only dysfunctional organ. Presumably, many of these patients had ARDS but a subgroup analysis of the efficacy of APC in patients with ARDS was not presented in this study and the ability of this agent to protect the lung in ARDS remains to be determined.

However the strategy of anticoagulants for ARDS ultimately fares, our understanding of the pathogenesis of this syndrome should improve as a result of the preclinical and clinical trials that are now being done. Future clinical trials should provide some indication of the value of other anticoagulants, such as TFPI or site-inactivated factor VII, as adjunctive treatments for patients with systemic sepsis. Ongoing preclinical and future clinical trials may also offer proof of principle about the ability of these anticoagulants to protect the lungs in sepsis. If selective anticoagulants improve morbidity or mortality and exert salutary effects on lung function in the subset of patients with ARDS, the trials could provide important leads for future investigation, both at the bench and at the beside. Whether the numbers of patients with ARDS enrolled in the ongoing clinical trials will prove sufficient to draw any firm conclusions about lung protection remains at issue. Trends worthy of further study could be suggested.

At this point, there are certainly more questions than answers about the use of selective anticoagulants as interventions for ARDS. Whether they will ultimately prove clinically useful still remains to be established. Even if they protect the lungs, will the risks, particularly that of serious bleeding, outweigh the potential benefits? Certainly, the use of anticoagulants, with or without ancillary anti-inflammatory properties, could be limited by comorbidities, particularly in trauma patients, in whom an increasingly large proportion of ARDS now seems to occur. If reversal of established lung injury is demonstrated by the recent and ongoing clinical trials, can we apply the same strategy for nonseptic ARDS? The virtual uniformity of procoagulant responses in septic and nonseptic ARDS suggests that we might. Although it would be reasonable to extrapolate from whatever approaches work best in patients with septic ARDS, clinical efficacy in ARDS induced by nonseptic insults would clearly need to be rigorously demonstrated. It is also conceivable that other anticoagulants, such as site-inactivated factor VII for example, might eventually prove more effective than those currently being tested.

Equally important is the question of what proportion of the procoagulant response to acute lung injury is injurious versus that needed for healing. A florid fibrinous exudate in the alveoli may be deleterious, but coagulation, fibrin deposition, and associated inflammatory responses are all natural responses to injury. These responses are likely to be required to some extent for proper repair; defined as restoration of normal lung structure and function. Apart from all these issues, we will still need to understand precisely why these agents work, even if efficacy in patients with septic ARDS is clearly demonstrated in forthcoming publications. Do the effects derive from the anticoagulant properties of the molecules or, rather, are antiinflammatory effects on cellular signaling and gene regulation the factors of prime importance? Anticoagulants such as TFPI or APC inhibit expression of selected cytokines, including TNF-, IL-1, IL-6, and IL-8, effects that could modify the inflammatory response in the injured lung independent of effects on hemostasis. Preclinical studies in primates are now under way to begin to address the mechanisms by which selective anticoagulant molecules protect the lungs in septic and nonseptic models of ARDS (35).

Clearly, the development of effective treatment for ARDS remains a formidable task. The complexity of the problem and paucity of available options invites the investigation of new approaches, including anticoagulant-based strategies. Of the many proinflammatory pathways activated in ARDS, the coagulation cascade is but one interventional target. Whether anticoagulants will eventually prove useful, safe, and cost- effective for patients with ARDS is still uncertain. It is, however, encouraging that selective anticoagulant inhibitors of the extrinsic coagulation pathway, TFPI and site-inactivated factor VII, demonstrate lung protection in primates with septic ARDS (35). Although enthusiasm about "anticoagulants for ARDS" is justifiable at this point, so is due caution. Ongoing preclinical studies and future interventional trials in sepsis patients should help us determine if selective anticoagulants merit further evaluation in those with ARDS.

	Footnotes

Correspondence and requests for reprints should be addressed to Steven Idell, M.D., Ph.D., Chairman, Department of Specialty Care Services, University of Texas Health Center at Tyler, 2 North, 11937 U.S. Hwy 271, Tyler, TX, 75708. E-mail: steven.idell{at}uthct.edu

(Received in original form February 23, 2001 and in revised form May 16, 2001).

Acknowledgments: Supported by Grants NIH RO1s 45018 and 62453 and PO-1HL 42444.

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