Experimental Medicine (TVDP, HTC), Academic Medical. Center, University of Amsterdam, ..... lysis 1998; 9(Suppl 1):S3âS7. 8. ten Cate H, Bauer KA, Levi M, ...
Endothelium: Interface between coagulation and inflammation Marcel Levi, MD; Hugo ten Cate; Tom van der Poll, MD
Objective: To review the involvement of endothelial cells in the pathogenesis of coagulation abnormalities during severe infection, the differential role of proinflammatory cytokines in these mechanisms, and the cross talk between coagulation and inflammation. Data Sources: Published articles on experimental studies of coagulation activation during inflammation and clinical studies of patients with sepsis and associated hemostatic abnormalities. Data Synthesis and Conclusion: The endothelium plays a cen-
I
t has long been known that inflammation can lead to activation of the coagulation system. Acute inflammation, as a response to severe infection or trauma, results in a systemic activation of the coagulation system termed disseminated intravascular coagulation (DIC) (1). It was initially thought that this systemic activation of coagulation was a result of direct activation of the contact system by microorganisms or endotoxin. However, in the 1990s, it became apparent that the principal initiator of inflammation-induced thrombin generation is tissue factor (TF) and that the contact system is not involved (2). Because TF is expressed on cytokine-activated mononuclear cells, which play a pivotal role in the host response to infection, it was hypothesized that microorganism-induced activation of mononuclear cells resulted in TFmediated activation of coagulation. However, other than in severe meningococcemia (3), it has proved difficult to demonstrate ex vivo TF expression on monocytes of septic patients or experimental animals systemically exposed to microorganisms. It has become apparent that cytokines mediate many of the responses triggered
From the Department of Vascular Medicine (ML), Internal Medicine (ML, TVDP), and the Laboratory of Experimental Medicine (TVDP, HTC), Academic Medical Center, University of Amsterdam, The Netherlands. Presented, in part, at the Margaux Conference on Critical Illness, Sedona, AZ, November 14 –18, 2001. Copyright © 2002 by Lippincott Williams & Wilkins
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tral role in all major pathways involved in the pathogenesis of the hemostatic derangement observed during severe inflammation (i.e., initiation and regulation of thrombin generation and inhibition of fibrinolysis). Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross talk in which the endothelium seems to play a pivotal role. (Crit Care Med 2002; 30[Suppl.]:S220 –S224) KEY WORDS: antithrombin; coagulation; cytokine; protein C; sepsis; thrombin; tissue factor; tissue factor pathway inhibitor
by severe inflammation, thereby placing cells other than circulating mononuclear cells in the spotlight (4). Evidence has accumulated to suggest that more complex mechanisms might be involved in the relationship between inflammation and activation of coagulation (5). In addition, it has become clear that this relationship is not unidirectional; instead, a cross talk between the systems occurs by which activation of coagulation will also affect inflammatory activity. In particular, vascular endothelial cells seem to play a pivotal mediatory role in the coagulative response to systemic inflammation and the cross talk between coagulation and inflammation (5, 6). Endothelial cells respond to the cytokines expressed and released by activated leukocytes but can also release cytokines themselves. Furthermore, endothelial cells are able to express adhesion molecules and growth factors that may not only promote the inflammatory response further but also affect the coagulation response. However, it has recently become clear that, in addition to these mostly indirect effects of the endothelium, endothelial cells interfere directly with the initiation and regulation of fibrin formation and removal during severe infection. In fact, endothelial cells play a prominent role in all three major pathogenetic pathways associated with coagulopathy in sepsis: TF-mediated thrombin generation, dysfunctional anticoagulant pathways, and blocked fibrinolysis.
ROLE OF ENDOTHELIAL CELLS IN THE INITIATION OF COAGULATION During severe infection, the initiation of coagulation is primarily mediated by the TF–factor VIIa pathway. TF is a membrane-bound, 4.5 kDa protein that is constitutively expressed on a number of cells throughout the body (7), predominantly in tissues not in direct contact with blood, such as the adventitial layer of larger blood vessels. The subcutaneous tissue also contains substantial amounts of TF, and histologically, TF is localized in a hemostatic “envelope.” TF expressed at the cell surface can interact with factor VII, either in its zymogen or activated form (factor VIIa). On complexing in its zymogen form, factor VII is activated, and the TF–factor VIIa complex catalyzes the conversion of factors IX and X (8). Factors IXa and Xa enhance the activation of factor X and prothrombin, respectively. In cells in contact with blood, TF expression is induced by the action of several compounds, including cytokines, C-reactive protein, and advanced glycosylated end products (9). TF expression at the surface of activated mononuclear cells can be induced in vitro by a number of proinflammatory mediators and is also detectable ex vivo in patients with severe sepsis and in experimental models of endotoxemia in humans (3, 10). However, evidence is emerging that endothelial cells also play an important role in the generation of TF during severe infection. Under in vitro condiCrit Care Med 2002 Vol. 30, No. 5 (Suppl.)
tions, various cytokines (such as tumor necrosis factor [TNF]-␣ and interleukin [IL]-1) have been found to induce TF expression in vascular endothelial cells, and ex vivo observations support the notion of endothelial cell involvement in TF-mediated activation of coagulation during severe infection (9, 11). The demonstration of circulating endothelial cells expressing TF in patients with sickle cell disease also suggests endothelial involvement in TF production (although this has yet to be shown in patients with sepsis) (12). The expression of TF by endothelial cells seems to be confined to certain organs and vascular beds (13), but it is uncertain whether this is genetically controlled in an organ-specific way. Differential activation of endothelial cell TF expression may occur, in particular, during severe infection (13). It is likely that in situations of tissue trauma (such as extensive surgery, brain trauma, or burns) TF expressed constitutively at the site of injury (such as in subcutaneous tissue) contributes to, or is the primary source of, procoagulant stimulation of DIC— although this has not been directly demonstrated. TF has also been localized on polymorphonuclear cells (PMNs) in both whole blood and ex vivo perfusion systems, suggesting an additional source of “blood borne” TF—although it is unlikely that PMNs synthesize TF in detectable quantities (14). Direct interaction between microorganisms and endothelial cells can also occur, especially in the case of viral infections. Endothelial cell perturbation is a common feature of viral infection and can alter hemostasis in both a direct and indirect manner. Endothelial cells can be directly infected by a number of viruses (e.g., herpes simplex virus, adenovirus, parainfluenzavirus, poliovirus, echovirus, measles virus, mumps virus, cytomegalovirus, human T-cell lymphoma virus type I, and HIV [15]). In particular, viral infection of endothelial cells has been demonstrated in hemorrhagic fevers (e.g., Dengue virus, Marburg virus, Ebola virus, Hantaan virus, and Lassa virus [16]). Such infections may result in a procoagulant state, mainly by inducing the expression of TF on the endothelial cell surface, which is probably mediated by cytokines such as IL-1, TNF-␣, and IL-6 (17, 18). Crit Care Med 2002 Vol. 30, No. 5 (Suppl.)
ROLE OF ENDOTHELIAL CELLS IN THE REGULATION OF COAGULATION Thrombin generation is limited by antithrombin, the protein C system, and TF pathway inhibitor (TFPI). During severe infection, all three regulatory systems are defective—primarily as a result of endothelial dysfunction. Antithrombin System. Antithrombin is the main inhibitor of thrombin and factor Xa. During severe infection, antithrombin levels are very low because of consumption, impaired synthesis, and degradation by elastase from activated neutrophils (2). A reduction in glycosaminoglycan availability at the perturbed endothelial surface (because of the influence of cytokines on its synthesis by endothelial cells) may also lead to reduced antithrombin function, because glycosaminoglycans may act as a physiologic heparin-like cofactor of antithrombin (19). Protein C System. The involvement of endothelial dysfunction in the impaired function of the protein C system is even more apparent (20). Under physiologic conditions, protein C is activated by thrombin bound to the endothelial cell membrane–associated molecule, thrombomodulin (21). Endothelial cells, primarily of large blood vessels, express an endothelial protein C receptor that augments the activation of protein C at the cell surface (22, 23). Activated protein C then decelerates the coagulation cascade by inactivating factors Va and VIIIa by proteolytic cleavage. However, in sepsis, in addition to the already low levels of protein C (as a result of consumption and impaired synthesis), the main cause of protein C system dysfunction is the down-regulation of thrombomodulin at the endothelial surface. Proinflammatory cytokines, such as TNF-␣ and IL-1, may significantly down-regulate the expression of thrombomodulin, as suggested by cell culture experiments (24, 25). These data were corroborated by recent observations in patients with severe Gramnegative septicemia, in whom decreased thrombomodulin expression at the endothelial cell surface and impaired activation of protein C were seen (26). In plasma, 60% of the protein C cofactor, protein S, is complexed to a complement regulatory protein, C4b binding protein (C4bBP). The anticoagulant capacity of protein C is enhanced by the free fraction of protein S. Increased plasma
levels of C4bBP—as a consequence of the acute phase reaction in inflammatory disease—may result in a relative protein S deficiency that contributes further to a down-regulation of the protein C system (27). In patient studies, reduced levels of protein C and protein S are associated with increased mortality (28). Blockade of protein C activity by infusion of C4bBP into baboons, in combination with a sublethal dose of Escherichia coli, resulted in a lethal response (27). Blockade of endothelial protein C receptors by a neutralizing monoclonal antibody also increased mortality in the E. coli baboon model (29). In contrast, infusion of activated protein C into baboons administered with lethal doses of E. coli resulted in improved DIC and survival (30). Thus, it seems that the protein C system is of great importance in the host defense against sepsis and DIC, which was further illustrated by the results of the PROWESS trial (31). In this randomized, controlled trial, administration of recombinant human activated protein C (drotrecogin alfa [activated]) resulted in a significant 19.4% relative risk reduction of mortality in patients with severe sepsis. Tissue Factor Pathway Inhibitor. A third inhibitory mechanism of thrombin generation involves TFPI, which exists in several pools— either endothelial cell associated or lipoprotein bound in plasma. This molecule inhibits the TF–factor VIIa complex by forming a quaternary complex in which factor Xa is the fourth component. Clinical studies in septic patients have not provided clues to its importance because in the majority of patients the levels of TFPI are not diminished compared with normal subjects (32). The relevance of TFPI in the coagulopathy of severe inflammation is illustrated by three lines of experimentation: 1. TFPI depletion sensitizes rabbits to DIC induced by TF infusion (33) 2. TFPI infusion protects against the harmful effects of E. coli in primates (34). TFPI not only blocked DIC, but all baboons challenged with lethal doses of E. coli showed a marked improvement in vital functions compared with controls and survived the experiment without apparent complications. The beneficial effects of TFPI may be caused by its attenuating effect on IL-6 generation and by its capacity to bind endotoxin and interfere with its interaction with CD14 S221
3. A recent study in healthy human volunteers confirmed the potential of TFPI to block the procoagulant pathway triggered by endotoxin (35). However, there was no reduction in cytokine levels, in contrast to the apparent antiinflammatory effect of TFPI in the baboon study
coagulation: Administration of recombinant IL-10 to humans completely abrogated endotoxin-induced effects on coagulation (42).
ROLE OF ENDOTHELIAL CELLS IN FIBRINOLYTIC ACTIVITY
Coagulation activation yields proteases that not only interact with coagulation protein zymogens but also with specific cell receptors to induce signaling pathways. In particular, protease interactions that affect inflammatory processes may be important in the development of DIC. Factor Xa, thrombin, and the TF– factor VIIa complex have each been shown to elicit proinflammatory activities (43, 44). Fibrinogen/fibrin is important to the host defense mechanism and probably has an additional role that is not directly related to clotting per se (45). Thrombin has been shown to induce a variety of noncoagulant effects, some of which may influence DIC by affecting cytokine levels in blood. It induces production of monocyte chemotactic protein-1 (MCP-1) and IL-6 in fibroblasts, epithelial cells, and mononuclear cells in vitro (46). Endotoxin-stimulated whole blood produces significant IL-8, which has a procoagulant effect that is TF and thrombin dependent (47). Thrombin also induces IL-6 and IL-8 production in endothelial cells. These effects of thrombin on cell activation are probably mediated by protease-activated receptors 1, 3, and 4 (48). Protease-activated receptors are cellular receptors for activated proteases that may contribute to intracellular signaling. Several studies have indicated that the TF– factor VIIa complex also activates cells by binding to protease-activated receptors, and it seems that protease-activated receptor 2 in particular is involved. Binding of the catalytic TF–factor VIIa complex elicits a variety of inflammatory effects in mononuclear cells that may influence their contribution to coagulation activity (49). A direct indication of the relevance of these phenomena in vivo comes from a recent study showing that infusion of recombinant factor VIIa into healthy human volunteers causes a rise, albeit small, in plasma levels of IL-6 and IL-8 (50). Although the plasma concentrations of factor VIIa in this experiment were much higher than endogenous factor VIIa concentrations in patients with sepsis, it is possible that the mechanism by which VIIa causes cytokine induction (di-
Inhibition of the fibrinolytic system is another key element of the pathogenesis of fibrin deposition during severe inflammation. Major fibrinolytic activators and inhibitors are synthesized and stored in endothelial cells. Although the initial response in bacteremia and endotoxemia is an increase in fibrinolytic activation (mediated by the almost immediate release of plasminogen activators), this is only short-lived and is rapidly shut off by a sustained increase in the main inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (36). Interestingly, a common polymorphism in the plasminogen activator inhibitor-1 gene may also affect the likelihood of patients with a meningococcal infection going on to develop sepsis (37). TNF-␣ and IL-1 increase the plasminogen activator inhibitor-1 synthesis or release from endothelial cells and also decrease plasminogen activator synthesis. TNF-␣ and endotoxin stimulate plasminogen activator inhibitor-1 production in the liver, kidney, lung, and adrenal glands of mice (38). Furthermore, plasminogen activator inhibitor-1– knockout mice challenged with endotoxin do not develop thrombi in the kidney (39). These experiments demonstrate that fibrinolytic action is required to reduce the extent of intravascular fibrin accumulation.
CYTOKINES AND COAGULATION ACTIVATION The derangement of coagulation and fibrinolysis in sepsis is mediated by several proinflammatory cytokines, such as TNF-␣, IL-1, and IL-6 (4). The principal mediator of coagulation activation in sepsis seems to be IL-6 (40). TNF-␣ indirectly influences the activation of coagulation because of its effects on IL-6, and it is the pivotal mediator of the dysregulation of the physiologic anticoagulant pathways and the fibrinolytic defect (4, 41). Antiinflammatory cytokines, such as IL-10, may modulate the activation of S222
CROSS TALK BETWEEN COAGULATION AND INFLAMMATION
T
he endothelium plays a central role in all major
pathways involved in the pathogenesis of hemostatic derangement during severe inflammation.
rect or factor Xa/thrombin-mediated) is of physiologic importance. Another link between inflammation and coagulation is formed by the protein C system. Activated protein C has antiinflammatory effects on mononuclear cells and granulocytes, which may be distinct from its anticoagulant activity (51). The antiinflammatory effect of activated protein C was confirmed in vivo by the demonstration of reduced TNF-␣ production in rats challenged with endotoxin (52). In addition, we have recently shown that mice with a one-allele targeted deletion of the protein C gene (heterozygous protein C– deficient mice) not only develop more severe DIC and increased fibrin deposition on systemic endotoxemia but also have significantly higher circulating levels of proinflammatory cytokines compared with wild-type litter mates (20). These experimental data are corroborated by the observations in the PROWESS trial that recombinant human activated protein C (drotrecogin alfa [activated]) accelerated the decrease in levels of IL-6 in patients with severe sepsis (30). Taken together, a number of coagulation proteases can induce proinflammatory mediators that have procoagulant effects, which may amplify the cascade that leads to DIC. Effects at the cellular level will be determined by the capacity of the coagulation inhibitors to inactivate these enzymes.
CONCLUSION The endothelium plays a central role in all major pathways involved in the pathogenesis of hemostatic derangement during severe inflammation. Endothelial cells seem to be directly involved in the initiation and regulation of thrombin generation and the inhibition of fibrin removal. Proinflammatory cytokines are Crit Care Med 2002 Vol. 30, No. 5 (Suppl.)
crucial in mediating these effects on endothelial cells, which themselves may also express cytokines, thereby amplifying the coagulative response. Rather than being a unidirectional relationship, the interaction between inflammation and coagulation involves significant cross talk between the systems. This could result in inflammation-modifying effects of hemostatic interventions in septic patients.
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