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AB - Abstract Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). Systemic inflammation results in activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Pro-inflammatory cytokines play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice-versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy. The relevance of the cross-talk between inflammation and coagulation is underlined by the promising results in the treatment of severe systemic infection with modulators of coagulation and inflammation. Cytokines, Hemostasis, Infection/inflammation 1. Introduction The relevance of the interaction between coagulation and inflammation as a response to severe infection, in its most extreme form manifesting as disseminated intravascular coagulation (DIC) and multiple organ failure, is becoming increasingly clear [1,2]. In recent years, the various mechanisms that play an important role in this interaction have been elucidated and this knowledge has indeed been demonstrated to be applicable for the improvement of our understanding of the pathogenesis of severe infection or sepsis and, even more importantly, the clinical management of these patients [3]. In this article, the mechanisms that play a role in the interaction between inflammation and coagulation will be reviewed and specific features of infectious disease-mediated effects on the coagulation system will be highlighted. In addition, the cross-talk between activated coagulation and inflammatory mediators will be discussed. 2. Inflammation-induced coagulation modification It 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 [3,4]. It was initially thought that this systemic activation of coagulation was a result of direct activation of the contact system of coagulation by microorganisms or endotoxin. However, in the 1990s, it became apparent that cytokines played a mediatory role in the activation of coagulation and subsequent fibrin deposition and that the point of impact on the coagulation system was rather the tissue factor-factor VIIa (‘extrinsic’) pathway than the contact system (‘intrinsic pathway’) [5,6]. Furthermore, the significance of impaired physiological anticoagulant pathways became increasingly clear [7]. Lastly, it was shown that impaired fibrin removal by a suppressed fibrinolytic system contributed importantly to the microvascular deposition of fibrin. Vascular endothelial cells play a central role in all mechanisms that contribute to inflammation-induced activation of coagulation. Endothelial cells respond to the cytokines expressed and released by activated leukocytes but can also release cytokines themselves [8]. 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 (Fig. 1). 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 [9,10]. Fig. 1 Open in new tabDownload slide Schematic representation of pathogenetic pathways in disseminated intravascular coagulation (DIC). During systemic inflammatory response syndromes, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated by tissue factor expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells will further promote intravascular fibrin deposition. PAI-1 indicates plasminogen activator inhibitor, type 1. Fig. 1 Open in new tabDownload slide Schematic representation of pathogenetic pathways in disseminated intravascular coagulation (DIC). During systemic inflammatory response syndromes, both perturbed endothelial cells and activated mononuclear cells may produce proinflammatory cytokines that mediate coagulation activation. Activation of coagulation is initiated by tissue factor expression on activated mononuclear cells and endothelial cells. In addition, downregulation of physiological anticoagulant mechanisms and inhibition of fibrinolysis by endothelial cells will further promote intravascular fibrin deposition. PAI-1 indicates plasminogen activator inhibitor, type 1. 3. Mechanisms of inflammation-induced coagulation and fibrinolysis activation Inflammation-induced coagulation activation is characterized by widespread intravascular fibrin deposition, which appears to be a result of enhanced fibrin formation and impaired fibrin degradation [1,11]. As outlined in the following paragraphs and schematically represented in Fig. 1, enhanced fibrin formation is caused by tissue factor-mediated thrombin generation and simultaneously occurring depression of inhibitory mechanisms, such as the protein C and S system. The impairment of endogenous thrombolysis is mainly due to high circulating levels of PAI-1, the principal inhibitor of plasminogen activation. These derangements in coagulation and fibrinolysis are mediated by differential effects of various pro-inflammatory cytokines [5]. 3.1. Tissue factor The initiating factors comprise the molecule tissue factor and the plasma protein factor VII(a) [12]. Tissue factor is a membrane-bound 4.5-kDa protein, which is constitutively expressed on a number of cells throughout the body [13]. These cells are mostly 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 appears to be present in all blood tissue barriers [14]. Upon expression at the cell surface, TF can interact with factor VII, either in its zymogen or activated form [15]. Upon complexing, factor VII is activated, and the TF-factor VIIa complex catalyzes the conversion of both factors IX and X [16,17]. Factors IXa and Xa enhance the activation of factors X and prothrombin, respectively (Fig. 1). In cells in contact with the blood circulation, TF is induced by the action of several compounds including cytokines, C reactive protein and advanced glycosilated endproducts [14]. Inducible TF is predominantly expressed by monocytes and macrophages. The expression of TF on monocytes is markedly stimulated by the presence of platelets and granulocytes in a P-selectin dependent reaction [18]. This effect may be the result of nuclear factor kappa B (NFkB) activation induced by binding of activated platelets to neutrophils and mononuclear cells. This cellular interaction also markedly enhances the production of IL-1b, IL-8, MCP-1, and TNFa [19]. Under in vitro conditions, different cytokines such as tumor necrosis factor a (TNFa), and interleukin (IL) 1, induce TF by vascular endothelial cells, but its relevance for in vivo coagulation is uncertain [14,20]. TF has also been localized on polymorphonuclear cells (PMN) in whole blood and ex vivo perfusion systems, suggesting an additional pool of ‘blood borne’ TF [21], but it is unlikely that PMN actually synthesize TF in detectable quantities [22]. Finally, TF and associated procoagulant activity in vitro has been detected on microvesicles derived from predominantly platelets and granulocytes in patients with meningococcal sepsis [23]. The localization on microvesicles may imply a highly efficient pool of procoagulant material assembling not only the initiating TF-factor VIIa complex but also the phospholipid surface facilitating the development of the tenase and prothrombinase complexes. In addition, a soluble form of TF is detectable in plasma from humans, and its levels are elevated in DIC [24]. The significance of soluble TF is unknown. It is likely the result of membrane cleavage by metalloproteinases produced under inflammatory conditions, and it circulates in free as well as complexed forms. Whether soluble TF is catalytically active and involved in inducing coagulation remains to be investigated. In addition to its effect on the haemostatic system, tissue factor also has cell signalling and mitogenic effects. These effects are probably mediated by the protease-activated receptors (PARs) 1 and 2. Other examples of such effects are described below in the paragraph describing the cross-talk between coagulation and inflammation. In humans with infection and an activated coagulation system, monocytes expressing enhanced levels of TF and procoagulant activity have been demonstrated. The tissue expression of TF appears to be confined to certain organs and vascular beds, but it is uncertain whether its expression is genetically controlled in an organ specific way [9]. 3.2. The contact system Whether in humans with severe infection the contact route plays any role remains unknown. Negatively charged substances including phospholipids and glycosaminoglycans, are a theoretically relevant source of contact activation. Recent studies suggest that intact cell surfaces mediate the assembly of contact factor proteins that may initiate this route of activation [25]. The assembly of kininogens on a multiprotein receptor leads to controlled prekallikein activation. In the case of endothelial cells a complex between high molecular weight kininogen (HK) and prekallikrein or factor XI binds to a multiprotein receptor on these cells. This receptor consists of cytokeratin 1, uPAR and gC1qR [25]. Cytokeratin 1 was also demonstrated on platelets and granulocytes, which may allow the interaction of HK with these cells as well. On endothelial cells, PK activation leads to factor XII conversion amplifying PK activation. The activation of PK causes the cleavage of HK and liberation of bradykinin. Bradykinin induces tPA and this is one of the potential direct effects of the contact system on fibrinolysis [26,27,27]. Several lines of evidence support the important role of the contact system in activating fibrinolysis. Additional studies indicate that kininogens contain a peptide fragment that interferes with thrombin binding to platelets through preventing peptide liberation from PAR1 by thrombin [28]. Taken together, a profibrinolytic and anticoagulant function of the contact system is more likely than a procoagulant role in vivo. Studies in patients with a clinical suspicion of DIC showed elevated levels of markers of activation of the contact system. Kaufmann et al. measured elevated concentrations of kininogen-a 1 anti-trypsin complexes [29], however studies with similar methods for coagulation activation markers have hardly ever detected elevated levels of contact activation [30]. A study in patients with meningococcal septicemia showed a negative correlation between plasma factor XII levels and factor XIIa-C1 inhibitor complexes [31]. Although this would suggest consumption of factor XII, and subsequent activation of factor XI downstream, a possible alternative explanation is a negative acute phase effect with reduced synthesis of factor XII, in conjunction with thrombin-mediated activation of factor XI [32]. Experimental studies suggested that blockade of the contact route in an E. coli sepsis model in primates with a monoclonal antibody against factor XIIa failed to protect animals from the coagulation derangement, but diminished development of lethal hypotension [33]. This latter study provided reasonable support for the current view that the contact activation pathway does not contribute to coagulation activation. The contact route may play important roles in pro-inflammatory mechanisms related to vascular permeability, vascular proliferative processes (role of kininogen in smooth muscle cell proliferation) and stimulation of fibrinolysis [34]. 3.3. Physiological anticoagulant pathways Systemic activation of coagulation upon inflammation is counteracted by several mechanisms. First, coagulation inhibitors are present to slow down the coagulation mechanism (Fig. 2). Soluble inhibitors constitute antithrombin (AT), proteins C and S, and tissue factor pathway inhibitor (TFPI) [35]. Antithrombin inhibits coagulation proteases by 1:1 complex formation, which, in the case of thrombin–antithrombin complexes, can be detected by immunoassay in plasma from patients with DIC [24,36]. AT is thought to be one of the most important inhibitors of the activated coagulation system, and markedly lowered plasma levels are found in sepsis [37,38]. In the course of DIC the function of AT may be influenced in several ways. First, a reduced absolute amount of the inhibitor may occur due to reduced protein synthesis on the one hand and clearance on the other hand. Clearance may be either in the form of protease-inhibitor complex, or due to proteolytic cleavage by proteolytic enzymes including granulocyte elastase [39]. Second, the function of AT may be impaired due to the possibly reduced availability of glycosaminoglycans which may act as the physiological heparin-like cofactor of AT [40]. Under the influence of cytokines the synthesis of glycosaminoglycans by endothelial cells may be reduced, impairing the inhibitory potential of AT [41]. In animal models of experimental bacteremia, an antithrombin concentrate prolonged survival and reduced the severity of DIC [42]. This protective effect may have been distinct from the anticoagulant effect as such because in one of these models, an active site blocked factor Xa preparation reduced the severity of DIC, but did not protect the animals from dying due to sepsis [43]. The protective effect of antithrombin may have resulted from an anti-inflammatory effect. Infusion of recombinant antithrombin at very high concentrations (about 10-fold higher than the basal plasma concentration) markedly reduced mortality due to lethal E. coli infusion, but also caused a significant reduction in the plasma levels of IL-6 and IL-8 [44]. In spite of significantly higher levels of TNFa and lower levels of IL-10, the overall effect on DIC was apparently favourable because the reduction in fibrinogen level was less pronounced in the AT-treated animals. An unexpected finding was that tPA levels, after an initial small rise in both groups, were markedly lower in the E. coli challenged baboons given antithrombin. As a result there was no increment in the levels of plasmin–antiplasmin complexes (PAP), whereas the increase in PAI-1 levels was somewhat increased in AT-treated animals. Fig. 2 Open in new tabDownload slide Point of impact of the three major physiological anticoagulant pathways. Antithrombin is the most important inhibitor of thrombin and factor Xa, activated protein C is able to degrade the essential cofactors Va and VIIIa, and TFPI inhibits the tissue factor/factor VIIa complex. Abbreviation: TFPI, tissue factor pathway inhibitor. Fig. 2 Open in new tabDownload slide Point of impact of the three major physiological anticoagulant pathways. Antithrombin is the most important inhibitor of thrombin and factor Xa, activated protein C is able to degrade the essential cofactors Va and VIIIa, and TFPI inhibits the tissue factor/factor VIIa complex. Abbreviation: TFPI, tissue factor pathway inhibitor. Since TNFa is a critical mediator of fibrinolysis in primates given a low-dose endotoxin [45], and given the elevated levels of TNF-α in baboons given antithrombin, a marked increase in tPA and PAP complexes would have been expected in the baboon model after AT infusion. The absence thereof suggests that TNF-α is not the single most important cytokine influencing fibrinolysis in sepsis. Potentially, the rise of PAI-1 sufficiently blunts fibrinolysis, but an alternative explanation may be a direct effect of antithrombin at tPA release by the endothelium, caused by AT binding to glycosaminoglycans at the endothelial surface. Given the net negative effect on fibrinolysis, the incomplete protection only achieved at very high doses of antithrombin, the therapeutic potential of antithrombin may be limited. Protein C and its cofactor protein S form a second line of defense. Thrombin binds to the endothelial cell membrane associated molecule thrombomodulin, and this complex converts protein C to its active form, protein Ca (PCa) (Fig. 3) [46]. In addition, the thrombin–thrombomodulin complex accelerates the conversion of the thrombin activatable fibrinolytic inhibitor (TAFI) [47]. PCa inactivates factors Va and VIIIa by proteolytic cleavage, thus slowing down the coagulation cascade. Endothelial cells, primarily of large blood vessels, express an endothelial protein C receptor (EPCR), which augments the activation of protein C at the cell surface [48–50]. Activated protein C has anti-inflammatory effects on mononuclear cells and granulocytes, which may be distinct from its anticoagulant activity. Administration of PCa prevented thrombin-induced thromboembolism in mice, mainly through its antithrombotic effect [51]. An anti-inflammatory effect of PCa was demonstrated by Hancock et al. [52], showing reduced TNFα production in rats challenged with endotoxin. Activated PC reduced the severity of spinal cord injury in rats, probably due to inhibition of leukocyte activity [53]. In the latter model, soluble thrombomodulin had a similar anti-inflammatory effect, but this was also mediated by PCa. In a pulmonary inflammatory model induced by endotoxin, thrombomodulin also reduced vascular permeability through a protein C-dependent mechanism [54]. Fig. 3 Open in new tabDownload slide Dysfunction of the protein C system in disseminated intravascular coagulation (DIC) is due to low levels of zymogen protein C, downregulation of thrombomodulin and the endothelial protein C receptor and low levels of free protein S due to acute phase-induced high levels of its binding protein (i.e. C4b-binding protein). Fig. 3 Open in new tabDownload slide Dysfunction of the protein C system in disseminated intravascular coagulation (DIC) is due to low levels of zymogen protein C, downregulation of thrombomodulin and the endothelial protein C receptor and low levels of free protein S due to acute phase-induced high levels of its binding protein (i.e. C4b-binding protein). In contrast, defects in the protein C mechanism enhance the vulnerability to inflammatory reactions and the ensuing activation of coagulation. In patient studies, lowered levels of protein C and protein S are associated with increased mortality. Blockade of the activity of protein C by infusion of C4 binding protein turns a sublethal model of E. coli in baboons into a lethal model [55]. Blockade of EPCR by a neutralizing monoclonal antibody also increased mortality in the E. coli baboon model [56]. Vice versa, infusion of PC in the same model, protected against DIC and dying [57]. Thus, it appears that the protein C mechanism is of great importance in the host defense against sepsis and coagulation activation. In situations, associated with DIC and systemic inflammation, TNFa and interleukin-1 may significantly down-regulate the cellular expression of thrombomodulin, as suggested by cell culture experiments [58–60]. The formation of thrombin may induce the shedding of EPCR by the endothelium, due to activation of metalloproteinases by thrombin. It is presently unknown whether thrombomodulin is also cleaved by similar mechanisms. A third inhibitory mechanism constitutes TFPI. This molecule, which exists in several pools either endothelial cell associated, or lipoprotein bound in plasma, inhibits the TF-factor VIIa complex by forming a quaternary complex in which factor Xa is the fourth component [61]. Clinical studies in septic patients have not provided clues as to its importance, because in the majority of patients the levels of TFPI are not diminished compared to normals [62]. This may be explained by the lack of downregulatory effects of inflammatory mediators on cultured endothelial cells [63]. The relevance of TFPI in sepsis-induced coagulation activation is illustrated by two lines of experimentation. First, depletion of TFPI sensitized rabbits to DIC induced with tissue factor infusion sensitizes the animals to develop a more severe DIC [64]. Second, TFPI infusion protected against the harmful effects of E. coli in primates. In this study, TFPI not only blocked DIC but all baboons challenged with lethal amounts of E. coli showed a marked improvement in vital functions and survived the experiment without apparent complications [65]. The beneficial effects of TFPI may in part be due to its capacity to bind endotoxin and to interfere with its interaction with CD14 [66], and to its attenuating effect on IL-6 generation. A recent study in volunteers confirmed the potential of TFPI to block the procoagulant pathway triggered by endotoxin [67]. However, in this study in healthy subjects, there was no reduction in cytokine levels, in contrast to the apparent anti-inflammatory effect of TFPI in the baboon study. There are several possible explanations for this discrepancy, which all relate to the marked differences between the endotoxin and E. coli sepsis models in which the effects of TFPI were investigated. In the beneficial effects of TFPI on survival, anti-inflammatory effects rather than antithrombotic activity may be prominent [65]. In general, the presence of intact function and normal plasma levels of inhibitors appears to be important in the defense against DIC. It should be noted however, that there are no strong indications that individuals with congenital deficiencies of inhibitors would suffer a greater chance of developing DIC, but this issue remains to be explored. In addition, the influence of inhibitors in modifying the interaction between coagulation and inflammation deserves further attention. 3.4. Fibrinolysis In experimental models of severe infection, fibrinolysis is activated, demonstrated by an initial activation of plasminogen activation, followed by a marked impairment caused by the release in blood of plasminogen activator inhibitor, type 1 (PAI-1) [45,68,69]. The latter inhibitor strongly inhibits fibrinolysis causing a net procoagulant situation. The molecular basis is cytokine-mediated activation of vascular endothelial cells; TNFα and IL-1 decreased free tPA and increased PAI-1 production, TNFa increased total uPA production in endothelial cells [70,71]. Endotoxin and TNFα stimulated PAI-1 production in liver, kidney, lung and adrenals of mice. The net procoagulant state is illustrated by a late rise in fibrin breakdown fragments after E. coli challenge of baboons. Experimental data also indicate that the fibrinolytic mechanism is active in clearing fibrin from organs and circulation. Endotoxin-induced fibrin formation in kidneys and adrenals was most dependent on a decrease in urokinase type plasminogen activator (uPA) [72]. PAI-1 knockout mice challenged with endotoxin did not develop thrombi in the kidney in contrast to wild-type animals [71]. Endotoxin administration to mice with a functionally inactive thrombomodulin gene (TMProArg mutation) and defective protein C activator cofactor function caused fibrin plugs in the pulmonary circulation, while wild-type animals did not develop macroscopic fibrin [73]. This phenomenon proved to be temporary, with detectable thrombi at 4 h after endotoxin, and disappearance of clots at 24 h in animals sacrificed at that timepoint. These experiments demonstrate that fibrinolytic action is required to reduce the extent of intravascular fibrin formation. Fibrinolytic activity is markedly regulated by PAI-1, the principal inhibitor of this system. Recent studies have shown that a functional mutation in the PAI-1 gene, the 4G/5G polymorphism, not only influenced the plasma levels of PAI-1, but was also linked to clinical outcome of meningococcal septicemia. Patients with the 4G/4G genotype had significantly higher PAI-1 concentrations in plasma and an increased risk of death [74]. Further investigations demonstrated that the PAI-1 polymorphism did not influence the risk of contracting meningitis as such, but probably increased the likelihood of developing septic shock from meningococcal infection [75]. These studies are the first evidence that genetically determined differences in the level of fibrinolysis influences the risk of developing complications of a Gram-negative infection. In other clinical studies in cohorts of patients with DIC, high plasma levels of PAI-1 were one of the best predictors of mortality [76,77]. These data suggest that activation of coagulation contributes to mortality in this situation, but as indicated earlier, the fact that PAI-1 is an acute phase protein, a higher plasma concentration may also be a marker of disease rather than a causal factor. Interestingly, platelet α-granules contain large quantities of PAI-1 and release PAI-1 upon their activation. Since platelets become activated in case of severe inflammation and infection, this may further increase the levels of PAI-1 and contribute to the fibrinolytic shut-off. 3.5. Platelets In addition to the mechanisms described above, platelets may play a role in the pathogenesis of inflammation-induced coagulation activation as well. Endotoxin can directly activate platelets and many pro-inflammatory cytokines are capable of inducing platelet activation through the sphingosine pathway and platelet activating factor (PAF) and its receptor. The importance of platelet activation for the activation of coagulation in severe infection is probably related to the provision of a suitable phospholipid surface on the activated platelet membrane for assembly of complexes of activated coagulation factors, such as the prothrombinase complex, consisting of activated factors X and V, prothrombin and calcium. The presence of such a surface may catalyze several-fold the generation of thrombin and render the coagulation system less susceptible to fluid-phase protease inhibitors. 4. Cytokines and other mediatory factors Activation of blood coagulation requires a number of cofactors. In particular, to develop coagulation activation, a number of interacting surfaces from cell remnants or intact cells, inflammatory mediators and coagulation proteins is required. The stimulus is presented by the underlying disease and can thus be diverse: a bacterial cell compound such as endotoxin, a protease induced by a malignant cell type, tissue damage exposing catalytic surfaces and constitutively expressed TF, a substance that might directly activate coagulation (fat, amniotic fluid) by unknown pathways, or others. Each of these triggers interact with other mediators: TF assembles on phospholipids, cells provide catalytic surfaces by exposure of phosphatidyl serine, cytokines interact with receptors and induce signalling pathways that induce TF and other proinflammatory components via the NFκB complex. To illustrate this situation, we will describe in greater detail the mechanisms that lead to endotoxin-induced activation of the coagulation mechanism. This model provides the best studied model of the complex network of interactions that involves activated coagulation in a DIC like fashion [78]. Endotoxin is the lipopolysaccharide compound from Gram-negative bacteria inducing the sepsis syndrome and DIC. Gram-negative bacteria liberate endotoxins from their membrane which interact with cell surfaces by different pathways. In blood, endotoxin directly binds to CD 14 at monocytes, and binds to endothelial cells after complexing with lipopolysaccharide binding protein (LBP) and the Toll-like receptor 4 complex [79]. By these interactions, endotoxin induces a number of signalling pathways leading to the activation of the NFkB system, which starts the transcription of genes of proinflammatory cytokines, TF and others. These mechanisms are further reviewed elsewhere [80]. Except for a direct positive effect of endotoxin on TF synthesis, the formation of the cytokines IL-1, TNFα, and IL-6 stimulates TF formation [14]. Ex vivo, this was directly demonstrated by showing that the production of TF mRNA was rapidly induced in blood cells after injection of endotoxin to human volunteers [81]. In vitro, whole blood cells generate TF upon incubation with endotoxin or IL-1, TNFα and IL-6. In vitro, cultured human endothelial cells also induce TF after incubation with TNFα and IL-1, but their role in DIC remains unknown. Thus far, the only direct evidence for endothelial involvement in TF production has been the demonstration of TF expressing circulating endothelial cells in patients with sickle cell disease (a possible DIC associated condition) [82]. Studies in primates have revealed the molecular mechanism underlying endotoxin induced activation of coagulation [68]. After intravenous endotoxin challenge, a rapid production and liberation of proinflammatory cytokines is observed. Among those, TNFa [69] and IL-6 [83] are important for inducing fibrinolytic and procoagulant changes in the blood. Specifically, a rapid increase in the plasma levels of tissue plasminogen activator (tPA) and the prothrombin fragment F1+2 as well as thrombin–antithrombin complexes (TAT) occurs. Fibrinolytic activity indicated by plasmin–antiplasmin complexes is impaired by a subsequent rise in plasminogen activator inhibitor 1 (PAI-1), and a net procoagulant state results [5]. Studies in baboons challenged with lethal amounts of E. coli (a model of Gram-negative septicemia) have underscored the importance of cytokines in mediating the sepsis syndrome, and demonstrated the prolonged proinflammatory course in which the actual formation of fibrin is particularly evident at >24 h after E. coli challenge [84]. In fact most fibrin appears in blood, when thrombin generation is already declining, and evidence of endothelial cell activation becomes apparent indicated by elevated levels of soluble thrombomodulin. Both in the chimpanzee endotoxin model and the E. coli model, TF is essential for inducing coagulation activity, and inhibition of the TF pathway abolishes clotting activation [85]. IL-6 is an important mediator of procoagulant effects, while TNFa is particularly involved in the fibrinolytic response to endotoxin [86]. Vice versa, inhibition of TF by TFPI reduced IL-6 in blood in the baboon model [87], suggesting that a more extensive crosstalk between inflammatory mediators and coagulation exists (see further). These effects may be more obvious in the sepsis model, than in the endotoxin model [88]. Recent experiments in humans challenged with endotoxin did not reveal any effect of TFPI on IL-6 nor any of the other cytokines measured in blood [67]. Thus the strength of the trigger may determine the degree of involvement of the cytokine network and its interactions with the coagulation system. Monocytes expressing TF directly bind factor VII(a), shed TF, or become associated with the damaged vessel wall, a process probably occurring when macrophages expressing TF invade the vessel wall and play a procoagulant role in atherosclerosis [89]. Circulating monocytes may trigger DIC, after interacting with platelets. Microvesicles may accelerate this process, and the complex interaction between cells, membrane fragments, soluble mediators and proteins may cause the full blown DIC syndrome. In the endotoxin model thrombin is an important feedback activator of the coagulation mechanism, because the thrombin-specific inhibitor hirudin reduces the procoagulant response in human volunteers [90]. The extent of catalysis and exhaustion of coagulation proteins and cellular elements is primarily determined by the strength of the triggers and the potential of the inhibitory mechanisms. 5. Cross-talk between coagulation and inflammation 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 tissue factor–factor VIIa complex have each been shown to elicit pro-inflammatory activities [91,92]. Fibrinogen/fibrin is important to the host defense mechanism, and probably has an additional role that is not directly related to clotting per se [93]. Thrombin has been shown to induce a variety of non-coagulant 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 [94]. Endotoxin-stimulated whole blood produces significant IL-8, which has a procoagulant effect that is tissue factor- and thrombin-dependent [95]. 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 (PARs) 1, 3 and 4 [96]. PARs are cellular receptors for activated proteases that may contribute to intracellular signaling. Several studies have indicated that the tissue factor–factor VIIa complex also activates cells by binding to PARs, and it appears that PAR2 in particular is involved. Binding of the catalytic tissue factor–factor VIIa complex elicits a variety of inflammatory effects in mononuclear cells that may influence their contribution to coagulation activity [97]. 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 [98]. 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 (direct 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 anti-inflammatory effects on mononuclear cells and granulocytes, which may be distinct from its anticoagulant activity [99]. The anti-inflammatory effect of activated Protein C was confirmed in vivo by the demonstration of reduced TNF-α 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 upon systemic endotoxemia, but also have significantly higher circulating levels of pro-inflammatory cytokines compared with wild-type littermates [100]. 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 [101]. For high doses of antithrombin, similar interactions with the inflammatory cascades were seen [44]. Taken together, a number of coagulation proteases can induce pro-inflammatory 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. 6. Relevance of the cross-talk between inflammation and coagulation for organ failure There is ample evidence that inflammatory activation in concert with microvascular thrombosis contributes to multiple organ failure in patients with severe infection and DIC. Firstly, extensive data have been reported on post-mortem findings of patients with DIC [102,103]. These autopsy findings include diffuse bleeding at various sites, hemorraghic necrosis of tissue, microthrombi in small blood vessels and thrombi in mid-size and larger arteries and veins. The demonstration of ischemia and necrosis was invariably due to fibrin deposition in small and mid-size vessels of various organs [104]. Importantly, the presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Secondly, experimental animal studies of DIC show fibrin deposition in various organs. Experimental bacteremia or endotoxemia causes intra- and extravascular fibrin deposition in kidneys, lungs, liver, brain and various other organs. Amelioration of the hemostatic defect by various interventions in these experimental models appears to improve organ failure and, in some but not all cases, mortality [42,87]. Lastly, clinical studies support the notion of coagulation as an important denominator of clinical outcome. DIC has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma [1,105]. 7. Coagulation and vascular complications in infectious diseases Apart from the generalized response upon systemic inflammation as discussed above, specific infections may result in thrombohemorrhagic syndromes, hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) or vasculitis. Symptoms and signs may be dominated by bleeding, thrombosis, or both [1,79,106]. Clinically overt infection-induced activation of coagulation may occur in 30–50% of patients with Gram-negative sepsis [107–110]. Contrary to widely held belief, this may appear as common in patients with Gram-positive sepsis as in those with Gram-negative sepsis [111]. Activation of the coagulation system has also been documented for non-bacterial pathogens, i.e. viruses [112,113], protozoa (Malaria) [114,115], fungi [116] and spirochetes [117]. 7.1. Thrombosis and bleeding Viral and bacterial infections may result in an enhanced risk for local thromboembolic disease, i.e. deep venous thrombosis or pulmonary embolism. In a thromboembolic prevention study of low-dose subcutaneous standard heparin for hospitalized patients with infectious diseases, morbidity due to thromboembolic disease was significantly reduced in the heparin group compared to the group receiving no prophylaxis. There was however no beneficial effect of prophylaxis on mortality due to thromboembolic complications [118]. In chronic viral diseases, such as CMV or HIV infection, the risk of thromboembolic complications is relatively low [119–121]. Viral hemorrhagic fever is complicated by DIC in the most severe cases [122–126]. DIC is not frequently encountered in other viral infections but has been reported in cases of infection with Rotavirus [127,128], Varicella, Rubella, Rubeola and Influenza [129–136]. TTP and HUS, triggered by a viral or bacterial infection [137,138], frequently lead to bleeding symptoms, but also platelet and fibrin thrombi may be generated in various organs, leading to prominent symptoms with organ dysfunction. In specific infections, such as viral hemorrhagic fever, bleeding complications are prominent [122,123]. In other viral and bacterial infections associated with TTP or HUS, bleeding also is often the prominent and presenting symptom (Table 1) [139–141]. Table 1 Viral hemorrhagic fevers Virus . Geographic distribution . Source of infection . Dengue HF Southeast Asia, Mid/South America, China Mosquito Chikungunya Southeast Asia Mosquito Ebola Zaire, Sudan Unknown Marburg HF Zimbabwe, Kenya, Uganda Unknown Lassa fever West Africa Rodent Yellow fever South America, Africa Mosquito Omsk HF Former Soviet Union Tick Hantaan Central Europe, former Soviet Union, Asia Rodent Virus . Geographic distribution . Source of infection . Dengue HF Southeast Asia, Mid/South America, China Mosquito Chikungunya Southeast Asia Mosquito Ebola Zaire, Sudan Unknown Marburg HF Zimbabwe, Kenya, Uganda Unknown Lassa fever West Africa Rodent Yellow fever South America, Africa Mosquito Omsk HF Former Soviet Union Tick Hantaan Central Europe, former Soviet Union, Asia Rodent Open in new tab Table 1 Viral hemorrhagic fevers Virus . Geographic distribution . Source of infection . Dengue HF Southeast Asia, Mid/South America, China Mosquito Chikungunya Southeast Asia Mosquito Ebola Zaire, Sudan Unknown Marburg HF Zimbabwe, Kenya, Uganda Unknown Lassa fever West Africa Rodent Yellow fever South America, Africa Mosquito Omsk HF Former Soviet Union Tick Hantaan Central Europe, former Soviet Union, Asia Rodent Virus . Geographic distribution . Source of infection . Dengue HF Southeast Asia, Mid/South America, China Mosquito Chikungunya Southeast Asia Mosquito Ebola Zaire, Sudan Unknown Marburg HF Zimbabwe, Kenya, Uganda Unknown Lassa fever West Africa Rodent Yellow fever South America, Africa Mosquito Omsk HF Former Soviet Union Tick Hantaan Central Europe, former Soviet Union, Asia Rodent Open in new tab 7.2. Vasculitis Bacterial and viral infections may result in a vasculitis-like syndrome with either bleeding manifestations or ischemic injury [142–144]. Vasculitis is a well-documented phenomenon in CMV infection [145,146], occurring predominantly in the vasculature of the gastrointestinal tract where it causes colitis [147,148], the central nervous system where it causes cerebral infarction [149,150], and the skin where it results in petechiae, purpura papules, localized ulcers or a diffuse maculopapular eruption [151]. HIV (human immunodeficiency virus) infection may be accompanied by vasculitis syndromes, e.g. polyarteriitis nodosa, Henoch Schönlein purpura and leukocytoclastic vasculitis [152–154]. Hepatitis B and C infection may cause polyarteritis-like vasculitis [155,156]. Parvovirus B19 has been suggested to be associated with vasculitis-like syndromes including Kawasaki disease, polyarteritis nodosa and Wegener's granulomatosis [157–159]. 8. Specific features of the pathogenesis of coagulation disorders in infectious disease Much of our knowledge on the mechanisms that play a role in infection-associated activation of coagulation comes from observations in clinical and experimental infectious disease. Essentially, and as outlined in detail in the preceding paragraphs, several pathways appear to play a role, including tissue factor-mediated generation of thrombin, impairment of physiological anticoagulant mechanisms, and a depression of the fibrinolytic system, due to elevated levels of PAI-1. In addition, specific features of coagulation activation in patients with infectious disease may be appreciated: 8.1. Endothelial cell activation Endothelial cells may turn into a procoagulant state either by stimulation of cytokines in concert with circulating blood cells, such as lymphocytes or platelets, or by direct infection (viruses) of endothelial cells. The role of endothelial cells seems to be crucial in the development of shock and activation of coagulation [160,161]. Endothelial cell injury is a common feature of viral infection and can alter hemostasis in a direct or indirect manner. The endothelial cell can be directly infected by different viruses, e.g. HSV, Adenovirus, Parainfluenzavirus, Poliovirus, Echovirus, Measles virus, Mumps virus, Cytomegalovirus, HTLV-1 and HIV [162–165]. The ability to infect endothelial cells has also been demonstrated in hemorrhagic fevers due to Dengue virus, Marburg virus, Ebola virus, Hantaan virus and Lassa virus [166]. Such infections may result in a procoagulant state, mainly by inducing tissue factor expression on the endothelial surface, probably mediated by cytokines such as IL-1, TNFα, and IL-6 [167–170]. However not all viral infections affecting endothelial cells result in activation of coagulation, which may indicate that activation of endothelium is one factor in a multifactorial process. The change in the endothelial cell from a resting to a procoagulant state may be associated with expression of endothelial surface adhesion molecules [171]. These molecules, i.e. ICAM, VCAM, E Selectin and von Willebrand factor (vWF), play an essential role in the binding of leukocytes, resulting in a local inflammatory response, endothelial cell damage and subsequent plasma leakage and shock [172,173]. The finding of increased plasma concentrations of these endothelial surface adhesion molecules is thought to be a reflection of the level of activation and perhaps damage of the endothelial cell [121]. 8.2. Alterations in the protein C and S system During sepsis, the protein C/S system is downregulated, as described earlier. Some viruses have the ability to induce specific changes in the coagulation inhibitory system. In the course of HIV infection, the protein C/S system may be impaired as a result of an acquired protein S deficiency, the pathogenesis of which is not yet clarified [174,175]. Increased plasma concentrations of the C4b-binding protein, an acute phase protein which binds protein S, may result in decreased levels of free protein S. Antiphospholipid antibodies, which may be present in HIV patients, might interfere with the protein C/protein S complex and diminish its activity [176]. In patients with Dengue hemorrhagic fever, we also found decreased levels of both protein C and protein S activity [177]. As in Dengue, HIV can affect the endothelial cell; hypothetically this could lead to decreased production of protein S. 8.3. Thrombocytopenia Thrombocytopenia is seen in the course of many viral infections but is only occasionally serious enough to lead to hemostatic impairment and bleeding complications. It is assumed that thrombocytopenia is mainly immune-mediated [178]. Alternative mechanisms are decreased thrombopoiesis, increased platelet consumption, or a combination of both [179]. Direct interaction of the virus with platelets may lead to thrombocytopenia and/or thrombocytopathy [180,181]. Endothelial injury by the virus may lead to increased adherence and consumption of platelets [182]. Viral infections that have been associated with thrombocytopenia are Mumps, Rubella, Rubeola, Varicella, disseminated Herpes simplex, CMV, infectious mononucleosis, Hantaan virus infection, Dengue hemorrhagic fever, Crimean-congo hemorrhagic fever and Marburg hemorrhagic fever [183–188]. 9. Inflammation-induced coagulation as a point of impact for (supportive) treatment of severe infection and sepsis Based on the assumption that defective physiological anticoagulant mechanisms play a pivotal role in the pathogenesis of coagulation derangement in sepsis, restoration of these pathways may be a logical approach in the (supportive) treatment of patients with severe sepsis. In fact, for all three anticoagulant pathways, such treatment options are available or are at an advanced stage of development. Restoration of the antithrombin pathway may be achieved by administration of antithrombin concentrates. The use of antithrombin concentrates in patients with DIC has been studied relatively intensively. Most of these trials concern patients with sepsis and/or septic shock. All trials show some beneficial effect in terms of improvement of laboratory parameters, shortening of the duration of DIC, or even improvement in organ function. In the more recent clinical trials, very high doses of antithrombin concentrate were used to attain supraphysiological plasma levels and the beneficial results in these trials seem to be more distinct [3,189]. Some trials showed a modest reduction in mortality in antithrombin-treated patients, however, the effect never reached statistical significance. A large-scale multicenter randomized controlled trial to directly address this issue has very recently been completed [190]. Preliminary results seem to indicate that there is no significant reduction in mortality of septic patients who were treated with antithrombin concentrate. A subgroup analysis indicates that patients not receiving concomitant heparin may experience some benefit of antithrombin treatment but this hypothesis remains to be confirmed in a prospective study. A beneficial effect of recombinant human activated protein C was demonstrated in two randomized controlled trials. Firstly, in a dose-ranging clinical trial, 131 patients with sepsis were enrolled [101]. Included patients received activated protein C by continuous infusion at doses ranging from 12 to 30 μg/kg per h, or placebo. In these patients, a 40% reduction in the relative risk of mortality was shown, although this was not statistically significant (due to the size of the trial). Based on these encouraging results in the phase II trial, a large multicenter efficacy trial was carried out [101]. This trial was prematurely stopped at the second interim analysis because of a significant reduction in mortality in the activated protein C-treated patients. Mortality was 24.7% in the activated protein C group compared with 30.8% in the placebo group (relative risk reduction 19.4%, 95% confidence interval, 6.6–30.5). The relative insufficiency of endogenous TFPI in sepsis and DIC may be overcome by the administration of pharmacological doses of recombinant TFPI. In a rat model of DIC, the infusion of recombinant tissue factor pathway inhibitor (TFPI) immediately after endotoxin administration significantly inhibited the consumption of coagulation factors and platelets [191]. Furthermore, a reduced number of fibrin thrombi was formed in liver, lungs, kidney and spleen. Similar effects were found in a rabbit model of DIC [64]. In human endotoxemia, recombinant TFPI was shown to dose-dependently reduce thrombin generation [67]. Clinical phase II trials on the use of TFPI in patients with sepsis have yielded promising results but a large multicenter phase III trial turned out to be negative, although published results are not yet available. 10. Conclusion A bi-directional relationship between coagulation and inflammation appears to play a pivotal role in the mechanisms leading to organ failure in patients with severe infection or sepsis. The endothelium plays a central role in all major pathways involved in the pathogenesis of hemostatic derangement during severe inflammation. Endothelial cells appear to be directly involved in the initiation and regulation of thrombin generation and the inhibition of fibrin removal. Pro-inflammatory cytokines are crucial in mediating these effects on endothelial cells, which themselves may also express cytokines, thereby amplifying the coagulative response. The interaction between inflammation and coagulation involves significant cross-talk between the systems. At all levels in the activated coagulation system in sepsis, natural anticoagulant pathways are defective and as a consequence incapable of containing the ongoing thrombin formation. Pharmacological restoration of these anticoagulant mechanisms may be a logical action in the (supportive) treatment of septic patients with coagulation abnormalities. Indeed, experimental and (initial) clinical studies show beneficial results of this type of treatment, not only confined to improvement of the coagulation status but also on clinically relevant outcome parameters such as organ function and survival. References [1] Levi M. ten Cate H. Disseminated intravascular coagulation N Engl J Med 1999 341 586 592 Google Scholar Crossref Search ADS PubMed WorldCat [2] Wheeler A.P. Bernard G.R. Treating patients with severe sepsis N Engl J Med 1999 340 207 214 Google Scholar Crossref Search ADS PubMed WorldCat [3] Levi M. ten Cate H. van der Poll T. Disseminated intravascular coagulation: State of the art Thromb Haemost 1999 82 695 705 Google Scholar PubMed OpenURL Placeholder Text WorldCat [4] Esmon C.T. et al. Inflammation, sepsis, and coagulation Haematologica 1999 84 254 259 Google Scholar PubMed OpenURL Placeholder Text WorldCat [5] Levi M. et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia Eur J Clin Invest 1997 27 3 9 Google Scholar Crossref Search ADS PubMed WorldCat [6] Osterud B. Bjorklid E. The tissue factor pathway in disseminated intravascular coagulation Semin Thromb Hemost 2001 27 605 617 Google Scholar Crossref Search ADS PubMed WorldCat [7] Taylor F.B. Jr. Response of anticoagulant pathways in disseminated intravascular coagulation Semin Thromb Hemost 2001 27 619 631 Google Scholar Crossref Search ADS PubMed WorldCat [8] ten Cate J.W. et al. Cytokines: triggers of clinical thrombotic disease Thromb Haemost 1997 78 415 419 Google Scholar PubMed OpenURL Placeholder Text WorldCat [9] Aird W.C. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis Crit Care Med 2001 29 S28 S34 Google Scholar Crossref Search ADS PubMed WorldCat [10] Levi M. ten Cate H. van der Poll T. Endothelium: interface between coagulation and inflammation Crit Care Med 2002 30 S220 S224 Google Scholar Crossref Search ADS PubMed WorldCat [11] Vallet B. Microthrombosis in sepsis Minerva Anestesiol 2001 67 298 301 Google Scholar PubMed OpenURL Placeholder Text WorldCat [12] Ruf W. Edgington T.S. Structural biology of tissue factor, the initiator of thrombogenesis in vivo FASEB J 1994 8 385 390 Google Scholar PubMed OpenURL Placeholder Text WorldCat [13] Mann K.G. et al. The role of the tissue factor pathway in initiation of coagulation Blood Coagul Fibrinolysis 1998 9 Suppl 1 S3 S7 Google Scholar PubMed OpenURL Placeholder Text WorldCat [14] Camerer E. Kolsto A.B. Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation Thromb Res 1996 81 1 41 Google Scholar Crossref Search ADS PubMed WorldCat [15] Banner D.W. et al. The crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor Nature 1996 380 41 46 Google Scholar Crossref Search ADS PubMed WorldCat [16] ten C.H. et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor J Clin Invest 1993 92 1207 1212 Google Scholar Crossref Search ADS PubMed WorldCat [17] Bauer K.A. et al. Factor IX is activated in vivo by the tissue factor mechanism Blood 1990 76 731 736 Google Scholar PubMed OpenURL Placeholder Text WorldCat [18] Osterud B. Tissue factor expression by monocytes: regulation and pathophysiological roles Blood Coagul Fibrinolysis 1998 9 Suppl 1 S9 S14 Google Scholar PubMed OpenURL Placeholder Text WorldCat [19] Neumann F.J. et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets Circulation 1997 95 2387 2394 Google Scholar Crossref Search ADS PubMed WorldCat [20] Edgington T.S. et al. Cellular immune and cytokine pathways resulting in tissue factor expression and relevance to septic shock Nouv Rev Fr Hematol 1992 34 Suppl S15 S27 Google Scholar PubMed OpenURL Placeholder Text WorldCat [21] Giesen P.L. et al. Blood-borne tissue factor: another view of thrombosis Proc Natl Acad Sci USA 1999 96 2311 2315 Google Scholar Crossref Search ADS PubMed WorldCat [22] Osterud B. Rao L.V. Olsen J.O. Induction of tissue factor expression in whole blood—lack of evidence for the presence of tissue factor expression on granulocytes Thromb Haemost 2000 83 861 867 Google Scholar PubMed OpenURL Placeholder Text WorldCat [23] Nieuwland R. et al. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis Blood 2000 95 930 935 Google Scholar PubMed OpenURL Placeholder Text WorldCat [24] Koyama T. et al. Determination of plasma tissue factor antigen and its clinical significance Br J Haematol 1994 87 343 347 Google Scholar Crossref Search ADS PubMed WorldCat [25] Schmaier A.H. Rojkjaer R. Shariat-Madar Z. Activation of the plasma kallikrein/kinin system on cells: a revised hypothesis Thromb Haemost 1999 82 226 233 Google Scholar PubMed OpenURL Placeholder Text WorldCat [26] Smith D. Gilbert M. Owen W.G. Tissue plasminogen activator release in vivo in response to vasoactive agents Blood 1985 66 835 839 Google Scholar PubMed OpenURL Placeholder Text WorldCat [27] Brown N.J. Nadeau J.H. Vaughan D.E. Selective stimulation of tissue-type plasminogen activator (t-PA) in vivo by infusion of bradykinin Thromb Haemost 1997 77 522 525 Google Scholar PubMed OpenURL Placeholder Text WorldCat [28] Hasan A.A. Amenta S. Schmaier A.H. Bradykinin and its metabolite, Arg-Pro-Pro-Gly-Phe, are selective inhibitors of alpha-thrombin-induced platelet activation Circulation 1996 94 517 528 Google Scholar Crossref Search ADS PubMed WorldCat [29] Kaufman N. et al. Alpha 2-macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis Blood 1991 77 2660 2667 Google Scholar PubMed OpenURL Placeholder Text WorldCat [30] Nuijens J.H. et al. Quantification of plasma factor XIIa-Cl(−)-inhibitor and kallikrein-Cl(−)-inhibitor complexes in sepsis Blood 1988 72 1841 1848 Google Scholar PubMed OpenURL Placeholder Text WorldCat [31] Wuillemin W.A. et al. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock Thromb Haemost 1995 74 1436 1441 Google Scholar PubMed OpenURL Placeholder Text WorldCat [32] Minnema M.C. et al. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia Blood 1998 92 3294 3301 Google Scholar PubMed OpenURL Placeholder Text WorldCat [33] Pixley R.A. et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons J Clin Invest 1993 91 61 68 Google Scholar Crossref Search ADS PubMed WorldCat [34] Levi M. Keep in contact: The role of the contact system in infection and sepsis Crit Care Med 2000 23 3765 3766 Google Scholar Crossref Search ADS WorldCat [35] Mann K.G. Biochemistry and physiology of blood coagulation Thromb Haemost 1999 82 165 174 Google Scholar PubMed OpenURL Placeholder Text WorldCat [36] Kario K. et al. Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio Haemostasis 1992 22 179 186 Google Scholar PubMed OpenURL Placeholder Text WorldCat [37] Mesters R.M. et al. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients Blood 1996 88 881 886 Google Scholar PubMed OpenURL Placeholder Text WorldCat [38] Alpert L.I. Benisch B. Hemangioendothelioma of the liver associated with microangiopathic hemolytic anemia. Report of four cases Am Med 1970 48 624 628 Google Scholar Crossref Search ADS WorldCat [39] Jochum M. et al. Effect of human granulocytic elastase on isolated human antithrombin III Hoppe Seylers Z Physiol Chem 1981 362 103 112 Google Scholar Crossref Search ADS PubMed WorldCat [40] Bourin M.C. Lindahl U. Glycosaminoglycans and the regulation of blood coagulation Biochem J 1993 289 313 330 Google Scholar Crossref Search ADS PubMed WorldCat [41] Kobayashi M. Shimada K. Ozawa T. Human recombinant interleukin-1 beta- and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells J Cell Physiol 1990 144 383 390 Google Scholar Crossref Search ADS PubMed WorldCat [42] Kessler C.M. et al. The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity Blood 1997 89 4393 4401 Google Scholar PubMed OpenURL Placeholder Text WorldCat [43] Taylor F.B.J. et al. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage Blood 1991 78 364 368 Google Scholar PubMed OpenURL Placeholder Text WorldCat [44] Minnema M.C. et al. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli Blood 2000 95 1117 1123 Google Scholar PubMed OpenURL Placeholder Text WorldCat [45] Biemond B.J. et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades Clin Sci 1995 88 587 594 Google Scholar Crossref Search ADS PubMed WorldCat [46] Esmon C.T. The roles of protein C and thrombomodulin in the regulation of blood coagulation J Biol Chem 1989 264 4743 4746 Google Scholar PubMed OpenURL Placeholder Text WorldCat [47] Bouma B.N. Meijers J.C. Fibrinolysis and the contact system: a role for factor XI in the down-regulation of fibrinolysis Thromb Haemost 1999 82 243 250 Google Scholar PubMed OpenURL Placeholder Text WorldCat [48] Fukudome K. Esmon C.T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor J Biol Chem 1994 269 26486 26491 Google Scholar PubMed OpenURL Placeholder Text WorldCat [49] Laszik Z. et al. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway Circulation 1997 96 3633 3640 Google Scholar Crossref Search ADS PubMed WorldCat [50] Esmon C.T. et al. Endothelial protein C receptor Thromb Haemost 1999 82 251 258 Google Scholar PubMed OpenURL Placeholder Text WorldCat [51] Gresele P. et al. Activated human protein C prevents thrombin-induced thromboembolism in mice. Evidence that activated protein c reduces intravascular fibrin accumulation through the inhibition of additional thrombin generation J Clin Invest 1998 101 667 676 Google Scholar Crossref Search ADS PubMed WorldCat [52] Hancock W.W. et al. The anticoagulants protein C and protein S display potent antiinflammatory and immunosuppressive effects relevant to transplant biology and therapy Transplant Proc 1992 24 2302 2303 Google Scholar PubMed OpenURL Placeholder Text WorldCat [53] Taoka Y. et al. Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes J Neurosci 1998 18 1393 1398 Google Scholar PubMed OpenURL Placeholder Text WorldCat [54] Uchiba M. et al. rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation Am J Physiol 1997 273 L889 L894 Google Scholar PubMed OpenURL Placeholder Text WorldCat [55] Taylor F.B.J. et al. Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli Blood 1995 86 2642 2652 Google Scholar PubMed OpenURL Placeholder Text WorldCat [56] Taylor F.B.J. et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis Blood 2000 95 1680 1686 Google Scholar PubMed OpenURL Placeholder Text WorldCat [57] Taylor F.B.J. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon J Clin Invest 1987 79 918 925 Google Scholar Crossref Search ADS PubMed WorldCat [58] Nawroth P.P. Stern D.M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor J Exp Med 1986 163 740 745 Google Scholar Crossref Search ADS PubMed WorldCat [59] Moore K.L. Esmon C.T. Esmon N.L. Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture Blood 1989 73 159 165 Google Scholar PubMed OpenURL Placeholder Text WorldCat [60] Furlan M. et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome N Engl J Med 1998 339 1578 1584 Google Scholar Crossref Search ADS PubMed WorldCat [61] Broze G.J. Jr. Tissue factor pathway inhibitor and the revised theory of coagulation Annu Rev Med 1995 46 103 112 Google Scholar Crossref Search ADS PubMed WorldCat [62] Novotny W.F. et al. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples Blood 1991 78 387 393 Google Scholar PubMed OpenURL Placeholder Text WorldCat [63] Ameri A. et al. Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators Blood 1992 79 3219 3226 Google Scholar PubMed OpenURL Placeholder Text WorldCat [64] Sandset P.M. et al. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant Proc Natl Acad Sci USA 1991 88 708 712 Google Scholar Crossref Search ADS PubMed WorldCat [65] Randolph M.M. et al. Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli—a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli Thromb Haemost 1998 79 1048 1053 Google Scholar PubMed OpenURL Placeholder Text WorldCat [66] Park C.T. Creasey A.A. Wright S.D. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14 Blood 1997 89 4268 4274 Google Scholar PubMed OpenURL Placeholder Text WorldCat [67] de Jonge E. et al. Tissue factor pathway inhibitor (TFPI) dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia Blood 2000 95 1124 1129 Google Scholar PubMed OpenURL Placeholder Text WorldCat [68] Levi M. et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees J Clin Invest 1994 93 114 120 Google Scholar Crossref Search ADS PubMed WorldCat [69] Biemond B.J. et al. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo Circulation 1997 96 1612 1615 Google Scholar Crossref Search ADS PubMed WorldCat [70] Schleef R.R. et al. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor J Biol Chem 1988 263 5797 5803 Google Scholar PubMed OpenURL Placeholder Text WorldCat [71] Sawdey M.S. Loskutoff D.J. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta J Clin Invest 1991 88 1346 1353 Google Scholar Crossref Search ADS PubMed WorldCat [72] Yamamoto K. Loskutoff D.J. Fibrin deposition in tissues from endotoxin-treated mice correlates with decreases in the expression of urokinase-type but not tissue-type plasminogen activator J Clin Invest 1996 97 2440 2451 Google Scholar Crossref Search ADS PubMed WorldCat [73] ten Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis Crit Care Med 2000 29 S9 S11 Google Scholar Crossref Search ADS WorldCat [74] Hermans P.W. et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group Lancet 1999 354 556 560 Google Scholar Crossref Search ADS PubMed WorldCat [75] Westendorp R.G. Hottenga J.J. Slagboom P.E. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock Lancet 1999 354 561 563 Google Scholar Crossref Search ADS PubMed WorldCat [76] Brandtzaeg P. et al. Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease Thromb Res 1990 57 271 278 Google Scholar Crossref Search ADS PubMed WorldCat [77] Mesters R.M. et al. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis Thromb Haemost 1996 75 902 907 Google Scholar PubMed OpenURL Placeholder Text WorldCat [78] van D.S. et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways Blood 1990 76 2520 2526 Google Scholar PubMed OpenURL Placeholder Text WorldCat [79] Aderem A. Ulevitch R.J. Toll-like receptors in the induction of the innate immune response Nature 2000 406 782 787 Google Scholar Crossref Search ADS PubMed WorldCat [80] Bohrer H. et al. Role of NFkappaB in the mortality of sepsis J Clin Invest 1997 100 972 985 Google Scholar Crossref Search ADS PubMed WorldCat [81] Franco R.F. et al. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation Blood 2000 96 554 559 Google Scholar PubMed OpenURL Placeholder Text WorldCat [82] Solovey A. et al. Tissue factor expression by endothelial cells in sickle cell anemia J Clin Invest 1998 101 1899 1904 Google Scholar Crossref Search ADS PubMed WorldCat [83] McClanahan T.B. et al. Antithrombotic effects of BCH 2763, a new direct thrombin inhibitor, in a canine model of venous thrombosis J Thromb Thrombolysis 1999 7 301 306 Google Scholar Crossref Search ADS PubMed WorldCat [84] Taylor F.B.J. Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor Prog Clin Biol Res 1994 388 175 194 Google Scholar PubMed OpenURL Placeholder Text WorldCat [85] Aguejouf O. et al. The arterial antithrombotic activity of thioxylosides in a rat model of laser-induced thrombosis Semin Thromb Hemost 1996 22 327 333 Google Scholar Crossref Search ADS PubMed WorldCat [86] van der Poll T. et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees J Exp Med 1994 179 1253 1259 Google Scholar Crossref Search ADS PubMed WorldCat [87] Creasey A.A. et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock J Clin Invest 1993 91 2850 2856 Google Scholar Crossref Search ADS PubMed WorldCat [88] Esmon C.T. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin? Blood 2000 95 1113 1116 Google Scholar PubMed OpenURL Placeholder Text WorldCat [89] Annex B.H. et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes Circulation 1995 91 619 622 Google Scholar Crossref Search ADS PubMed WorldCat [90] Pernerstorfer T. et al. Lepirudin blunts endotoxin-induced coagulation activation Blood 2000 95 1729 1734 Google Scholar PubMed OpenURL Placeholder Text WorldCat [91] Altieri D.C. Molecular cloning of effector cell protease receptor-1, a novel cell surface receptor for the protease factor Xa J Biol Chem 1994 269 3139 3142 Google Scholar PubMed OpenURL Placeholder Text WorldCat [92] Camerer E. Huang W. Coughlin S.R. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa Proc Natl Acad Sci USA 2000 97 5255 5260 Google Scholar Crossref Search ADS PubMed WorldCat [93] Degen J.L. Hemostatic factors and inflammatory disease Thromb Haemost 1999 82 858 864 Google Scholar PubMed OpenURL Placeholder Text WorldCat [94] Johnson K. et al. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation J Immunol 1998 160 5130 5135 Google Scholar PubMed OpenURL Placeholder Text WorldCat [95] Johnson K. et al. The proinflammatory cytokine response to coagulation and endotoxin in whole blood Blood 1996 87 5051 5060 Google Scholar PubMed OpenURL Placeholder Text WorldCat [96] Kahn M.L. et al. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin J Clin Invest 1999 103 879 887 Google Scholar Crossref Search ADS PubMed WorldCat [97] Cunningham M.A. et al. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages Blood 1999 94 3413 3420 Google Scholar PubMed OpenURL Placeholder Text WorldCat [98] de Jonge E et al. Activation of coagulation by administration of recombinant factor VIIa elicits interleukin-6 and interleukin-8 release in healthy human subjects. J. of Clin. Lab. Immunol., 2003, in press. [99] Esmon C.T. Does inflammation contribute to thrombotic events? Haemostasis 2000 30 Suppl 2 34 40 Google Scholar PubMed OpenURL Placeholder Text WorldCat [100] Levi M. de Jonge E. van der Poll T. Rationale for restoration of physiological anticoagulant pathways in patients with sepsis and disseminated intravascular coagulation Crit Care Med 2001 7 Suppl S90 S94 Google Scholar Crossref Search ADS WorldCat [101] Bernard G.R. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis N Engl J Med 2001 344 699 709 Google Scholar Crossref Search ADS PubMed WorldCat [102] Robboy S.J. et al. Pathology of disseminated intravascular coagulation (DIC). Analysis of 26 cases Hum Pathol 1972 3 327 343 Google Scholar Crossref Search ADS PubMed WorldCat [103] Shimamura K. et al. Distribution patterns of microthrombi in disseminated intravascular coagulation Arch Pathol Lab Med 1983 107 543 547 Google Scholar PubMed OpenURL Placeholder Text WorldCat [104] Coalson J.J. Pathology of sepsis, septic shock, and multiple organ failure. Perspective on sepsis and septic shock 1986 Fullerton, CA Society of Critical Care Medicine pp. 27–59 [105] Fourrier F. et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies Chest 1992 101 816 823 Google Scholar Crossref Search ADS PubMed WorldCat [106] van Gorp E. et al. Review: infectious diseases and coagulation disorders J Infect Dis 1999 180 176 186 Google Scholar Crossref Search ADS PubMed WorldCat [107] Gando S. et al. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome Thromb Haemost 1996 75 224 228 Google Scholar PubMed OpenURL Placeholder Text WorldCat [108] Thijs L.G. et al. Coagulation disorders in septic shock Intensive Care Med 1993 19 Suppl 1 S8 S15 Google Scholar Crossref Search ADS PubMed WorldCat [109] Baglin T. Disseminated intravascular coagulation: diagnosis and treatment Br Med J 1996 312 683 687 Google Scholar Crossref Search ADS WorldCat [110] Gando S. Nakanishi Y. Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome Crit Care Med 1995 23 1835 1842 Google Scholar Crossref Search ADS PubMed WorldCat [111] Bone R.C. Gram-positive organisms and sepsis Arch Intern Med 1994 154 26 34 Google Scholar Crossref Search ADS PubMed WorldCat [112] Bhamarapravati N. Hemostatic defects in dengue hemorrhagic fever Rev Infect Dis 1989 11 Suppl 4 S826 S829 Google Scholar Crossref Search ADS PubMed WorldCat [113] Heller M.V. et al. Early markers of blood coagulation and fibrinolysis activation in Argentine hemorrhagic fever Thromb Haemost 1995 73 368 373 Google Scholar PubMed OpenURL Placeholder Text WorldCat [114] Mohanty D. et al. Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria Am J Hematol 1997 54 23 29 Google Scholar Crossref Search ADS PubMed WorldCat [115] Chuttani K. et al. Diagnosis of cardiac tamponade after cardiac surgery: relative value of clinical, echocardiographic, and hemodynamic signs Am Heart J 1994 127 913 918 Google Scholar Crossref Search ADS PubMed WorldCat [116] Fera G. et al. Disseminated intravascular coagulation associated with disseminated cryptococcosis in a patient with acquired immunodeficiency syndrome Infection 1993 21 171 173 Google Scholar Crossref Search ADS PubMed WorldCat [117] Schroder S. et al. Thrombotic thrombocytopenic purpura (TTP) associated with a Borrelia burgdorferi infection Am J Hematol 1995 50 72 73 Google Scholar Crossref Search ADS PubMed WorldCat [118] Gardlund B. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group Lancet 1996 347 1357 1361 Google Scholar Crossref Search ADS PubMed WorldCat [119] Laing R.B. Brettle R.P. Leen C.L. Venous thrombosis in HIV infection Int J STD AIDS 1996 7 82 85 Google Scholar Crossref Search ADS PubMed WorldCat [120] Jenkins R.E. Peters B.S. Pinching A.J. Thromboembolic disease in AIDS is associated with cytomegalovirus disease AIDS 1991 5 1540 1542 Google Scholar Crossref Search ADS PubMed WorldCat [121] Drancourt M. et al. Diagnosis of Mediterranean spotted fever by indirect immunofluorescence of Rickettsia conorii in circulating endothelial cells isolated with monoclonal antibody-coated immunomagnetic beads J Infect Dis 1992 166 660 663 Google Scholar Crossref Search ADS PubMed WorldCat [122] Hayes E.B. Gubler D.J. Dengue and dengue hemorrhagic fever. [Review] [83 refs] Pediatr Infect Dis J 1992 11 311 317 Google Scholar Crossref Search ADS PubMed WorldCat [123] Sumarmo T. et al. Clinical observations on virologically confirmed fatal dengue infections in Jakarta Indonesia. Bull WHO 1983 61 693 701 OpenURL Placeholder Text WorldCat [124] Kuberski T. et al. Clinical and laboratory observations on patients with primary and secondary dengue type 1 infections with hemorrhagic manifestations in Fiji Am Trop Med Hyg 1977 26 775 783 OpenURL Placeholder Text WorldCat [125] Egbring R. Slenczka W. Baltzer G. Clinical manifestations and mechanism of the haemorrhagic diathesis in Marburg viral disease Martini G.A. Siegert R. Marburg virus disease 1971 New York Springer 41 48 [126] Gear J.S. et al. Outbreak of Marburg virus disease in Johannesburg Br Med J 1975 4 489 493 Google Scholar Crossref Search ADS PubMed WorldCat [127] Limbos M.A. Lieberman J.M. Disseminated intravascular coagulation associated with rotavirus gastroenteritis: report of two cases Clin Infect Dis 1996 22 834 836 Google Scholar Crossref Search ADS PubMed WorldCat [128] Anderson D.R. Harrison L. Hirsh J. Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy Arch Intern Med 1993 153 1441 1447 Google Scholar Crossref Search ADS PubMed WorldCat [129] McKay D.G. Margaretten W. Disseminated intravascular coagulation in virus diseases Arch Intern Med 1967 120 129 152 Google Scholar Crossref Search ADS PubMed WorldCat [130] Linder M. et al. Virus infection and blood coagulation Thromb Diath Haemorrh 1970 23 1 11 Google Scholar PubMed OpenURL Placeholder Text WorldCat [131] Talley N.A. Assumpcao C.A. Disseminated intravascular clotting complicating viral pneumonia due to influenza Med J Aust 1971 2 763 766 Google Scholar PubMed OpenURL Placeholder Text WorldCat [132] Whitaker A.N. Bunce I. Graeme E.R. Disseminated intravascular coagulation and acute renal failure in influenza A2 infection Med J Aust 1974 2 196 201 Google Scholar PubMed OpenURL Placeholder Text WorldCat [133] Settle H. Glueck H.I. Disseminated intravascular coagulation associated with influenza Ohio State Med J 1900 71 541 543 OpenURL Placeholder Text WorldCat [134] Anderson D.R. et al. Varicella hepatitis: a fatal case in a previously healthy, immunocompetent adult. Report of a case, autopsy, and review of the literature Arch Intern Med 1994 154 2101 2106 Google Scholar Crossref Search ADS PubMed WorldCat [135] Cumming A.D. et al. Significance of urinary C3 excretion in glomerulonephritis J Clin Pathol 1976 29 601 607 Google Scholar Crossref Search ADS PubMed WorldCat [136] Clemens R. et al. Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway Br J Haematol 1994 87 100 105 Google Scholar Crossref Search ADS PubMed WorldCat [137] Badesha P.S. Saklayen M.G. Hemolytic uremic syndrome as a presenting form of HIV infection Nephron 1996 72 472 475 Google Scholar Crossref Search ADS PubMed WorldCat [138] Chu Q.D. et al. Thrombotic thrombocytopenic purpura and HIV infection [see comments] South Med J 1995 88 82 86 Google Scholar Crossref Search ADS PubMed WorldCat [139] Levi M. van Gorp E. ten Cate H. Disseminated intravascular coagulation Handin R.I. Lux S.E. Stossel T.P. Blood: principles and practice of hematology 2002 Philadelphia J.B. Lippincott [140] Qadri S.M. Kayali S. Enterohemorrhagic Escherichia coli. A dangerous food-borne pathogen Postgrad Med 1900 103 179 180 Google Scholar Crossref Search ADS WorldCat [141] Laing R.W. Teh C. Toh C.H. Thrombotic thrombocytopenic purpura (TTP) complicating leptospirosis: a previously undescribed association J Clin Pathol 1990 43 961 962 Google Scholar Crossref Search ADS PubMed WorldCat [142] Ackerman A.B. et al. Inflammatory diseases. Histologic diagnosis of inflammatory skin diseases 1997 Williams and Wilkins pp. 170–186 [143] Lie J.T. Vasculitis associated with infectious agents Curr Opin Rheumatol 1996 8 26 29 Google Scholar Crossref Search ADS PubMed WorldCat [144] Guillevin L. Lhote F. Gherardi R. The spectrum and treatment of virus-associated vasculitides Curr Opin Rheumatol 1997 9 31 36 Google Scholar Crossref Search ADS PubMed WorldCat [145] Golden M.P. et al. Cytomegalovirus vasculitis. Case reports and review of the literature Medicine 1994 73 246 255 Google Scholar Crossref Search ADS PubMed WorldCat [146] Ho D.D. et al. Replication of human cytomegalovirus in endothelial cells J Infect Dis 1984 150 956 957 Google Scholar Crossref Search ADS PubMed WorldCat [147] Goodman M.D. Porter D.D. Cytomegalovirus vasculitis with fatal colonic hemorrhage Arch Pathol Lab Med 1973 96 281 284 OpenURL Placeholder Text WorldCat [148] Foucar E. et al. Colon ulceration in lethal cytomegalovirus infection Am Clin Pathol 1981 76 788 801 Google Scholar Crossref Search ADS WorldCat [149] Booss J. et al. Mechanisms of injury to the central nervous system following experimental cytomegalovirus infection Am Otolaryngol 1990 11 313 317 Google Scholar Crossref Search ADS WorldCat [150] Koeppen A.H. et al. Central nervous system vasculitis in cytomegalovirus infection J Neurol Sci 1981 51 395 410 Google Scholar Crossref Search ADS PubMed WorldCat [151] Lin C.S. et al. Cytomegalic inclusion disease of the skin Arch Dermatol 1981 117 282 284 Google Scholar Crossref Search ADS PubMed WorldCat [152] Libman B.S. Quismorio F.P.J. Stimmler M.M. Polyarteritis nodosa-like vasculitis in human immunodeficiency virus infection J Rheumatol 1995 22 351 355 Google Scholar PubMed OpenURL Placeholder Text WorldCat [153] Calabrese L.H. Vasculitis and infection with the human immunodeficiency virus Rheum Dis Clin North Am 1991 17 131 147 Google Scholar PubMed OpenURL Placeholder Text WorldCat [154] Gherardi R. et al. The spectrum of vasculitis in human immunodeficiency virus-infected patients. A clinicopathologic evaluation Arthritis Rheum 1993 36 1164 1174 Google Scholar Crossref Search ADS PubMed WorldCat [155] Sergent J.S. et al. Vasculitis with hepatitis B antigenemia: long-term observation in nine patients Medicine 1976 55 1 18 Google Scholar Crossref Search ADS PubMed WorldCat [156] Carson C.W. et al. Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa J Rheumatol 1993 20 304 309 Google Scholar PubMed OpenURL Placeholder Text WorldCat [157] Leruez-Ville M. et al. Polyarteritis nodosa and parvovirus B19 Lancet 1994 344 263 264 Google Scholar Crossref Search ADS PubMed WorldCat [158] Nikkari S. et al. Wegener's granulomatosis and parvovirus B19 infection Arthritis Rheum 1994 37 1707 1708 Google Scholar Crossref Search ADS PubMed WorldCat [159] Yoto Y. et al. Human parvovirus B19 infection in Kawasaki disease Lancet 1994 344 58 59 Google Scholar Crossref Search ADS PubMed WorldCat [160] Stemerman M.B. Colton C. Morell E. Perturbations of the endothelium Prog Hemostasis Thromb 1984 7 289 324 OpenURL Placeholder Text WorldCat [161] Kaiser L. Sparks H.V. Jr. Endothelial cells. Not just a cellophane wrapper Arch Intern Med 1987 147 569 573 Google Scholar Crossref Search ADS PubMed WorldCat [162] Friedman H.M. Infection of endothelial cells by common human viruses Rev Infect Dis 1989 11 Suppl 4 S700 S704 Google Scholar Crossref Search ADS PubMed WorldCat [163] Friedman H.M. et al. Susceptibility of endothelial cells derived from different blood vessels to common viruses In Vitro Cell Dev Biol 1986 22 397 401 Google Scholar Crossref Search ADS PubMed WorldCat [164] Hoxie J.A. Matthews D.M. Cines D.B. Infection of human endothelial cells by human T-cell leukemia virus type I Proc Natl Acad Sci USA 1984 81 7591 7595 Google Scholar Crossref Search ADS PubMed WorldCat [165] Wiley C.A. et al. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients Proc Natl Acad Sci USA 1986 83 7089 7093 Google Scholar Crossref Search ADS PubMed WorldCat [166] Butthep P. Bunyaratvej A. Bhamarapravati N. Dengue virus and endothelial cell: a related phenomenon to thrombocytopenia and granulocytopenia in dengue hemorrhagic fever Southeast Asian J Trop Med Public Health 1993 24 Suppl 1 246 249 Google Scholar PubMed OpenURL Placeholder Text WorldCat [167] van Dam-Mieras M.C. et al. The procoagulant response of cytomegalovirus infected endothelial cells Thromb Haemost 1992 68 364 370 Google Scholar PubMed OpenURL Placeholder Text WorldCat [168] Etingin O.R. et al. Viral activation of the coagulation cascade: molecular interactions at the surface of infected endothelial cells Cell 1990 61 657 662 Google Scholar Crossref Search ADS PubMed WorldCat [169] Dudding L. et al. Cytomegalovirus infection stimulates expression of monocyte-associated mediator genes J Immunol 1989 143 3343 3352 Google Scholar PubMed OpenURL Placeholder Text WorldCat [170] Smith P.D. et al. Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages J Clin Invest 1992 90 1642 1648 Google Scholar Crossref Search ADS PubMed WorldCat [171] McEver R.P. GMP-140: a receptor for neutrophils and monocytes on activated platelets and endothelium J Cell Biochem 1991 45 156 161 Google Scholar Crossref Search ADS PubMed WorldCat [172] Anderson R. et al. Activation of endothelial cells via antibody-enhanced dengue virus infection of peripheral blood monocytes J Virol 1997 71 4226 4232 Google Scholar PubMed OpenURL Placeholder Text WorldCat [173] Takahashi M. et al. Monocyte-endothelial cell interaction induces expression of adhesion molecules on human umbilical cord endothelial cells Cardiovasc Res 1996 32 422 429 Google Scholar Crossref Search ADS PubMed WorldCat [174] Sugerman R.W. et al. Acquired protein S deficiency in children infected with human immunodeficiency virus Pediatr Infect Dis J 1996 15 106 111 Google Scholar Crossref Search ADS PubMed WorldCat [175] Stahl C.P. et al. Protein S deficiency in men with long-term human immunodeficiency virus infection Blood 1993 81 1801 1807 Google Scholar PubMed OpenURL Placeholder Text WorldCat [176] Hassell K.L. et al. Correlation of antiphospholipid antibodies and protein S deficiency with thrombosis in HIV-infected men Blood Coagul Fibrinolysis 1994 5 455 462 Google Scholar PubMed OpenURL Placeholder Text WorldCat [177] Van Gorp E.C. et al. Activation of coagulation factor XI, without detectable contact activation in dengue haemorrhagic fever Br J Haematol 2001 113 94 99 Google Scholar Crossref Search ADS PubMed WorldCat [178] Levin J. Bleeding with infectious disease Ratnoff O.D. Forbes C.D. Disorders of hemostasis 1984 Grune and Stratton 367 378 [179] Nakao S. Lai C.J. Young N.S. Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines Blood 1989 74 1235 1240 Google Scholar PubMed OpenURL Placeholder Text WorldCat [180] Halstead S.B. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade Rev Infect Dis 1989 11 Suppl 4 S830 S839 Google Scholar Crossref Search ADS PubMed WorldCat [181] Terada H. et al. Interaction of influenza virus with blood platelets Blood 1966 28 213 228 Google Scholar PubMed OpenURL Placeholder Text WorldCat [182] Curwen K.D. Gimbrone M.A.J. Handin R.I. In vitro studies of thromboresistance: the role of prostacyclin (PGI2) in platelet adhesion to cultured normal and virally transformed human vascular endothelial cells Lab Invest 1980 42 366 374 Google Scholar PubMed OpenURL Placeholder Text WorldCat [183] Myllyla G. et al. Interaction between human blood platelets, viruses and antibodies. IV. Post-Rubella thrombocytopenic purpura and platelet aggregation by Rubella antigen–antibody interaction Clin Exp Immunol 1969 4 323 332 Google Scholar PubMed OpenURL Placeholder Text WorldCat [184] Morse E.E. Zinkham W.H. Jackson D.P. Thrombocytopenic purpura following rubella infection in children and adults Arch Intern Med 1966 117 573 579 Google Scholar Crossref Search ADS PubMed WorldCat [185] Charkes N.D. Purpuric chickenpox: report of a case, review of the literature and classification by clinical features Ann Intern Med 1961 54 745 759 Google Scholar Crossref Search ADS PubMed WorldCat [186] Tobin J.D.J. Ten B.R. Varicella with thrombocytopenia causing fatal intracerebral hemorrhage Am Dis Child 1972 124 577 578 OpenURL Placeholder Text WorldCat [187] Brook I. Disseminated varicella with pneumonia, meningoencephalitis, thrombocytopenia, and fatal intracranial hemorrhage South Med J 1979 72 756 757 Google Scholar Crossref Search ADS PubMed WorldCat [188] Chanarin I. Walford D.M. Thrombocytopenic purpura in cytomegalovirus mononucleosis Lancet 1973 2 238 239 Google Scholar Crossref Search ADS PubMed WorldCat [189] Fourrier F. et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation Chest 1993 104 882 888 Google Scholar Crossref Search ADS PubMed WorldCat [190] Warren B.L. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial J Am Med Assoc 2001 286 1869 1878 Google Scholar Crossref Search ADS WorldCat [191] Elsayed Y.A. et al. Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model Am Clin Pathol 1996 106 574 583 Google Scholar Crossref Search ADS WorldCat Author notes * For this manuscript Dr. F. Calabrese acted as Guest Editor. Time for primary review 28 days. Copyright © 2003, European Society of Cardiology
TI - Infection and inflammation and the coagulation system
JF - Cardiovascular Research
DO - 10.1016/S0008-6363(02)00857-X
DA - 2003-10-15
UR - https://www.deepdyve.com/lp/oxford-university-press/infection-and-inflammation-and-the-coagulation-system-e7ht9ZDiL5
SP - 26
EP - 39
VL - 60
IS - 1
DP - DeepDyve
ER -