REVIEW ARTICLE

Modulation of hemostatic mechanisms in bacterial infectious diseases

From the Department of Cell and Molecular Biology, Section for Molecular Pathogenesis, Lund University, Lund, Sweden.

	Introduction

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Life-threatening complications from bacterial infections are a major and growing clinical problem, aggravated by the emergence and spread of antibiotic resistance in bacterial pathogens and by an increase in the number of immunocompromised patients.^1-3 During bacterial infection, the host responds to invading microbes with a number of different defense mechanisms. Some bacteria or bacterial products, however, can modulate the host response and cause serious complications from the disease. In severe infections, such as sepsis and septic shock, the coagulation and fibrinolytic systems are targets for such modulation. These cascades are normally activated upon tissue injury and/or blood vessel damage. During infection, inflammatory mediators of the parasite and/or host can manipulate the procoagulant/anticoagulant equilibrium and cause severe bleeding disorders.^4,5 Although such effects induced by pathogenic bacteria often lead to similar clinical pictures, different microbes seem to interfere at different stages of the coagulation and fibrinolytic systems. This review aims to provide an overview of how pathogenic bacteria can manipulate the coagulation and fibrinolytic cascades in infectious diseases.

	Current view on hemostasis

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

The coagulation cascade can be divided into an extrinsic and an intrinsic pathway (Figure 1). The extrinsic pathway is triggered upon complex formation of exposed tissue factor (TF) with coagulation factor VII (F VII). This is followed by an activation of factor IX (F IX) and/or factor X (F X) by the TF-F VII complex and subsequent conversion of prothrombin to thrombin, which finally induces the formation of fibrin from fibrinogen.⁶ The intrinsic pathway is initiated after activation of the contact system, a process involving F XI, factor XII (F XII), plasma kallikrein (PK), and high molecular weight kininogen (HK).^7,8 In addition to its procoagulative functions, activation of the contact system also leads to the release of bradykinin, which is generated by cleavage of HK by PK. Kinins are considered to be important pro-inflammatory mediators.⁹

View larger version (36K): [in this window] [in a new window]   Figure 1. The blood coagulation cascade. The coagulation cascade is divided into an intrinsic and an extrinsic pathway. Coagulation factors are represented in blue and are designated by an "a" upon activation. Arrows symbolize the proteolytic conversion. Cofactors are marked in red and coagulation inhibitors in green. Proteins that participate in fibrinolysis have a brown color. The following abbreviations are used: F, factor; HK, high molecular weight kininogen; PAI-1, plasminogen activator inhibitor; PK, plasma kallikrein; TAFI, thrombin activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; tPA, tissue plasminogen activator; and uPA, urokinase-type plasminogen activator. Strong and weak interactions are indicated by solid and dotted lines.

At present, it is generally accepted that coagulation is driven mainly by the extrinsic pathway.⁶ This notion is based on the observation that patients with deficiencies in the contact factors F XII, HK, and PK do not suffer from any bleeding disorders.⁸ It therefore seems likely that these proteins play only a secondary role in hemostasis. However, F XI deficiency leads to minor bleeding abnormalities, a dysfunction explained by the ability of thrombin to activate F XI by a mechanism that is independent of the contact system.¹⁰ Thrombin-activated F XI triggers an augmentation stage of coagulation and allows continuation of clotting after down-regulation of TF activity by TF-pathway inhibitor (TFPI).^11,12 Work published to date indicates that activation of F XI by thrombin also attenuates fibrinolysis inside a fibrin clot.^13,14

Coagulation is controlled at 3 levels. First, thrombin changes to an anticoagulant factor upon binding to thrombomodulin (TM), a glycoprotein bound to the endothelium.¹⁵ The formation of the thrombin/TM complex allows a rapid cleavage and activation of the anticoagulant protein C. Activated protein C then down-regulates further formation of thrombin by proteolytically inactivating the coagulation cofactors factor V (F V) and factor VIII (F VIII). Additionally, thrombin, in complex with TM, loses its ability to clot fibrinogen. Second, in order to prevent an expansion of clotting in the periphery of the damaged tissue, coagulation factors are inactivated by circulating proteinase inhibitors such as TFPI, C1 inhibitor (C1 INH), and antithrombin III (AT III).^16-18 Finally, fibrinolysis is hindered inside the clot by a thrombin-dependent activation of the plasma protein thrombin-activatable fibrinolysis inhibitor (TAFI). TAFI exhibits carboxypeptidase-B-like activity and suppresses fibrinolysis, most likely by removing carboxy-terminal lysine residues. Since plasmin binds to carboxy-terminal lysines of progressively degraded fibrin, this mechanism might protect the clot from degradation.¹⁹

At the site of tissue injury, fibrinolysis is initiated by the conversion of plasminogen to plasmin.²⁰ Plasmin has multiple functions, such as degradation of fibrin, inactivation of the cofactors F V and F VIII, and activation of metalloproteinases, which play an important role in wound healing and tissue-remodeling processes.^21-23 Plasminogen is activated by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA),²⁴ proteins released from endothelial cells in response to thrombin and upon cell damage.²⁵ Plasminogen activity is regulated by plasmin inhibitors such as ₂-antiplasmin and ₂-macroglobulin and also attenuated by plasminogen activator inhibitor 1 (PAI-1), the primary physiological inhibitor of tPA and uPA.^26,27

Lately, the connection between hemostasis and inflammation has attracted much interest.²⁸ This link was established by recent work showing that the coagulation factors thrombin, F X, and F VII trigger intracellular signal cascades by binding to specific cell-membrane-spanning receptors, which have no known role in hemostasis.^29-32 The receptors for thrombin (protease-activated receptors [PARs]) are the best characterized. PARs belong to the family of G-protein-coupled receptors, which are activated upon binding to a protease that cleaves the exodomain of the receptor. This manipulation unmasks a tethered peptide ligand that then stimulates its own receptor.³³ So far, 4 receptors that are triggered by this mechanism have been identified. Thrombin activates PAR-1, PAR-3, and PAR-4, whereas PAR-2 is activated by trypsin, mast cell tryptase, and a cysteine proteinase from Porphyromonas gingivalis.^34-37 The receptors for F X (effector cell protease receptor-1 [EPR-1]) and F VII (TF) do not belong to the family of G-protein-coupled receptors and are activated by different mechanisms.^38,39 Additionally, a receptor for protein C (endothelial cell protein C [EPCR]) has been described.⁴⁰ Whether this receptor triggers intracellular signaling is currently under investigation.^41-43 Patients with sepsis have significantly increased levels of a soluble form of EPCR in plasma, indicating that EPCR can be used as a marker protein in infectious diseases.⁴⁴ The binding of coagulation factors to these receptors and their subsequent activation trigger inflammatory reactions such as leukocyte recruitment, release of cytokines and nitric oxide, and the production of reactive oxygen species.^30,39,45-47

	Bacteria and the extrinsic pathway

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

As mentioned above, the coagulation cascade is initiated mainly by binding of F VII to cell-surface-bound TF. The physiological importance of TF was demonstrated by experiments in transgenic mice, which show that interruption of the gene for TF is associated with lethal embryonic bleeding and impaired vascular development.^48,49 TF is expressed in many tissues, including brain, lung, placenta, and kidney.⁵⁰ Cells that constitutively produce TF are usually not in contact with blood, but are found in perivascular tissues and stroma.¹¹ Peripheral blood cells and endothelium do not normally produce TF. However, TF activity in these cells is increased after stimulation with such substances as endotoxin, tumor necrosis factor  (TNF-), phorbol esters, serum, or vascular endothelial growth factor (VEGF). Inflammatory mediators such as endotoxin and TNF- regulate TF-gene induction by using a promoter region containing DNA-binding motifs for nuclear factor B and activator protein 1, whereas TF expression induced by serum, phorbol esters, and VEGF is controlled by a promoter region containing overlapping Sp1/endothelial growth factor 1 sites.^6,51-53 Recently, Giesen et al⁵⁴ provided evidence that small amounts of thrombogenic TF are also found in plasma.

Recently, Gando et al⁵⁵ reported that TF values from sepsis patients are significantly higher than from trauma patients, indicating an important role for TF-triggered coagulation complications during septic conditions. The observation that TF activity is enhanced during infection is in accordance with the finding that several bacterial species, such as Mycobacterium leprae, Neisseria meningitidis, Rickettsia conorii, Rickettsia rickettsii, Staphylococcus aureus, and Streptococcus sanguis, are able to trigger TF expression in monocytes and endothelial cells.^56-64 It seems likely, therefore, that the onset of coagulation in sepsis results partially from induction of TF expression in endothelial cells and monocytes by bacterial products. The finding that Gram-positive microorganisms also trigger TF activity indicates that bacterial products other than endotoxin could be involved in the up-regulation of procoagulant activity. Gram-positive bacteria may induce this indirectly, as various exotoxins and peptidoglycans have been shown to trigger the induction of pro-inflammatory cytokines.^6,65-69 Notably, cytokines such as interferon , interleukin 1 (IL-1), and TNF-, are strong inducers of TF expression.⁷⁰ These observations indicate that TF activity is increased in response to products from both Gram-positive and Gram-negative bacteria and that this can be one of the initial steps for inducing coagulation disorders in infectious diseases.

	Bacteria and the contact system

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Numerous studies provide accumulating evidence that the contact system is activated during sepsis.⁷¹ It was demonstrated as early as 1970 that patients with hypotensive septicemia have significantly decreased levels of contact factors.⁷² More recently, it has been reported that activation of the contact system occurs in children with meningococcal septic shock and that low levels of F XII and HK in systemic inflammatory response syndrome (SIRS) patients correlate with a fatal outcome of the disease.^73-75 In one of the more recent studies, it was also shown that levels of PK-₂-macroglobulin complexes are increased in SIRS patients, indicating an activation of the contact system.⁷⁴ The ₂-macroglobulin binds to activated PK followed by a removal of the complex by a receptor-mediated mechanism in the reticuloendothelial system. These findings are in accordance with experiments in baboons demonstrating that irreversible hypotension induced by infusion of Escherichia coli correlates with a decline in levels of HK and an increase of PK-₂-macroglobulin complexes.⁷⁶ The administration of an inhibitory monoclonal antibody to F XII, which blocks contact activation, prevented the development of irreversible hypotension and led to an extension of the survival time in infected animals.⁷⁷ These observations suggest an important role for the contact system in the hemodynamic derangements of septic patients.⁷⁸

In 1996, Ben Nasr et al⁷⁹ reported that contact factors bind to the surface of E coli and Salmonella spp bacteria that express curli organelles or thin aggregative fimbriae. Subsequent studies demonstrated that the contact system is activated as a consequence of the assembly of contact factors on the bacterial surface. This is followed by the release of bradykinin, a potent inducer of fever, pain, and hypotension.⁸⁰ Moreover, the absorption of contact system proteins and fibrinogen by these surface organelles led to a depletion of relevant coagulation factors and caused a hypocoagulatory state in mice.⁸⁰ Apart from Gram-negative bacteria, cell-wall peptidoglycan products from Streptococcus pyogenes have been shown to trigger the contact system.⁸¹ In fact, most streptococcal serotypes bind kininogens by their M proteins,⁸² which are considered to be important virulence factors on the outer membrane of the microorganism.⁸³ Once HK is absorbed on the bacterial surface, it is susceptible to proteolytic cleavage by PK, leading to the formation of bradykinin.⁸⁴

In addition to bacterial-surface molecules, secreted microbial products have been demonstrated to activate the contact system. Early observations identified bacterial endotoxin as a potent activator of F XII.⁸⁵ Recently, with the use of a low-grade endotoxemia model in humans, it has become apparent that F XI is also activated by a contact-system-independent mechanism.⁸⁶ Apart from endotoxin, many bacterial proteinases that are able to trigger the release of kinins have been isolated (Table 1).^87-93 In order to generate bioactive kinins from HK, bacterial proteinases act on kininogens directly^92,93 or activate the contact factors F XII and PK, which in turn cleave HK, causing the release of bradykinin.^87,91 As kinins increase vascular permeability, the generation of these pro-inflammatory peptides in infectious foci might be a bacterial strategy that facilitates penetration and spreading of the pathogen into the tissue.

View this table: [in this window] [in a new window]   Table 1. Generation of kinins by bacterial proteinases

	Bacteria and fibrinogen/fibrin

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

The systemic activation of coagulation during infection results in the cleavage of fibrinogen by thrombin. The fibrin monomers generated can then become deposited in various organs, leading to microvascular and macrovascular thrombosis. The concomitant stimulation and aggregation of platelets, either by thrombin or by bacterial substances, may also cause thrombocytopenia.⁹⁴ As a result of widespread thrombus formation, tissue ischemia and organ failure may occur. At the same time, fibrinogen degradation products can trigger the release of monocyte/macrophage-derived IL-1, IL-6, and PAI-1. Whereas IL-1 and IL-6 induce additional vascular endothelial damage, PAI-1 inhibits fibrinolysis, which accelerates further thrombus formation.⁹⁵ Apart from these functions, fibrinogen is an important factor that regulates cellular interactions in the vasculature, such as the binding of leukocytes to the endothelial cells.⁹⁶

As shown for intra-abdominal infections, fibrinous exudates can incorporate large numbers of bacteria, viz E coli and Bacteroides fragilis. Once bacteria are sequestered within the fibrin deposit, they are protected from phagocytosis, which might be a microbial strategy for avoiding the host defense machinery. Inside the clot, the microorganism can continue to proliferate, leading to the formation of abscesses. However, the host can also benefit from the encapsulation of the microorganism, since the entrapment of bacteria in a fibrin deposit might act to diminish the magnitude of bacterial dissemination, thus preventing host mortality.⁹⁷

Fibrinogen-binding proteins (FgBPs) have been studied mostly in staphylococci and streptococci. To date, 5 different FgBPs have been characterized in S aureus.^98-102 Three of them are secreted: (1) an 87-kd coagulase, which binds to prothrombin and forms a complex that has thrombinlike activity and converts fibrinogen to fibrin,¹⁰³ (2) a 60-kd FgBP, which binds to fibrinogen and prothrombin,⁹⁸ and (3) a 16-kd FgBP, which binds to the -chain of fibrinogen.⁹⁹ The last-named protein has been shown to contribute to bacterial virulence in wound infections owing to its ability to delay healing processes.¹⁰⁴ Additionally, 2 surface-associated clumping factors (ClfA and ClfB) of S aureus have been found to adhere to fibrinogen-containing substrates.¹⁰² ClfA was shown to play an important role in the pathogenesis of S aureus endocarditis,¹⁰⁵ whereas the function of ClfB is not completely understood.¹⁰⁶ The ability of staphylococcal surface proteins to bind to fibrinogen is believed to be important in promoting bacterial adherence to host tissues during an infection and may serve as a mechanism for colonization of the cardiac tissue in infective endocarditis. A membrane-bound FgBP in Staphylococcus epidermidis, designated Fbe, which shares sequence homology with ClfA, has been identified recently.¹⁰⁷ However, unlike ClfA, Fbe seems to mediate the binding of the microorganism to fibrinogen-coated surfaces.¹⁰⁸ A recent serological study showed that antibody levels to the FgBPs, ClfA and Fbe, were significantly risen in convalescent-phase sera from patients with S aureus septicemia, indicating that these 2 proteins are expressed during infection.¹⁰⁹

Most group A streptococcal serotypes (S pyogenes) express FgBPs on their surface.⁸² Apart from fibrinogen-mediated adherence of these bacteria to endothelial and epithelial cells, streptococcal FgBPs seem to have an important antiphagocytic function owing to their ability to impair deposition of complement.^110-113

	Bacteria and fibrinolysis

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Plasmin(ogen) plays a central role in fibrinolysis as it dissolves insoluble fibrin matrices.¹¹⁴ In addition to its fibrinolytic properties, plasmin degrades extracellular matrix proteins such as laminin and fibronectin and activates metalloproteinases.^23,115 Studies with plasminogen-deficient mice have shown an effect of the enzyme on cell migration and tissue remodeling.¹¹⁶ In addition to plasmin(ogen), plasminogen activators have been demonstrated to be crucial factors in fibrinolysis. Transgenic mice deficient in tPA and uPA showed impaired clot lysis and suffered extensive spontaneous fibrin deposition.¹¹⁷ Also, these mice developed venous thrombosis upon endotoxin administration to a higher extent than wild-type animals.

In sepsis, progressive failure of multiple organs is often accompanied by fibrin deposition and formation of microthrombi. Clinical studies have provided evidence that plasminogen concentrations in septic patients are significantly decreased.¹¹⁸ Moreover, plasminogen levels or the ratio of plasminogen to ₂-antiplasmin have been demonstrated to be good markers for survival from septicemia.¹¹⁸ Recently, Aiuto et al¹¹⁹ reported that infusion of recombinant tPA in a patient suffering from meningococcal purpura fulminans resulted in a dramatic improvement in hemodynamics and an increase in skin perfusion. This effect might be explained by the observation that PAI-1 levels in sepsis patients are significantly increased, leading to the consumption of plasminogen activators, which in turn down-regulates plasmin activity.^118,120,121 Taken together, these studies indicate that disturbance of the fibrinolytic process in infectious diseases, either by low plasmin levels in blood or by the lack of plasminogen activation, can lead to enhanced fibrin deposition, causing life-threatening sequelae.

As shown in Table 2, many bacterial species have been demonstrated to interact with human plasmin(ogen).¹²² Interestingly, the mode of interaction varies for different species.¹²³ For example, most group A streptococci secrete the nonenzymatic plasminogen activator streptokinase. Binding of streptokinase to plasminogen converts the zymogen into an active enzyme by inducing a conformational change without hydrolyzing a peptide bond, which is normally required to activate plasminogen.¹²⁴ Also, staphylococci secrete a nonenzymatic plasminogen activator, staphylokinase. The mechanism of plasminogen activation by staphylokinase differs from its activation by streptokinase, however, in that small amounts of active plasmin are required for an efficient activation.¹²⁵ The crystal structures of the catalytic domain of human plasmin in complex with streptokinase or staphylokinase have been solved recently.^126,127 In contrast to nonenzymatic activators, a surface-bound plasminogen-binding protein (Pla) that exhibits protease activity has been found in Yersinia pestis.¹²⁸ Bacterially bound plasmin is thought to trigger dissemination of Y pestis from a peripheral site and/or to facilitate the escape of the microorganism from fibrin-mediated entrapment.¹²⁹ In addition to microbial plasminogen activators, many pathogenic bacteria express nonactivating plasminogen-binding molecules on their surface (Table 2). Once plasminogen is bound to the bacterial surface, the zymogen can be activated by different mechanisms. Whereas streptococci and staphylococci produce their own activators, Borrelia burgdorferi, Salmonella enteritidis, and E coli can activate bound plasminogen by recruited tPA or uPA.^130,131 Studies with B burgdorferi, S aureus, and S pyogenes have demonstrated that plasmin, mobilized to the bacterial surface, is protected from inhibition by host proteinase inhibitors, in particular ₂-antiplasmin, resulting in a long-lasting surface-associated enzymatic activity.^132-134 An important advantage for bacteria, which bind and activate plasminogen, was demonstrated by Coleman et al,¹³⁵ who used plasminogen-deficient mice to show that the active enzyme gives rise to enhanced dissemination of B burgdorferi. Recently, Svensson et al¹³⁶ reported that plasminogen-binding serotypes of S pyogenes have a strong tendency to cause impetigo lesions, suggesting a central role for bacterially activated plasmin during localized infection in the epidermis. These studies indicate once more that the interaction of bacteria with plasmin(ogen) might have an important role in bacterial pathogenesis.

View this table: [in this window] [in a new window]   Table 2. Interaction of bacteria or bacterial products with plasmin(ogen)

	Treatments using coagulation inhibitors

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Blood coagulation is normally limited to a site of vascular injury, indicating that clotting is regulated in a highly controlled manner. The mechanism requires, apart from procoagulative factors, a number of specific proteinase inhibitors or enzymes that down-regulate clotting activity.¹³⁷ It is important to stress that the correct ratio of procoagulative enzymes and their inhibitors is necessary to ensure that clotting is restricted to a damaged site. Once this delicate balance is disturbed, an efficient wound-healing process is hindered either by the inability to form a fibrin network, by uncontrolled coagulation, or by impaired fibrinolysis. In patients with sepsis, severe sepsis, or septic shock, the levels of many natural inhibitors are markedly lowered, and this may result in an unfavorable outcome for the disease.^138-140 In several animal models and clinical trials, therapeutic substitution of coagulation inhibitors has been demonstrated to improve survival in cases of severe infection. In what follows, some of these treatments are described.

	Tissue factor pathway inhibitor

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Expression of TFPI is, under normal conditions, restricted to megakaryocytes, to endothelium of the small capillaries, and to macrophages. TFPI levels in plasma are increased under inflammatory conditions.⁵⁰ However, despite the elevated levels of plasma TFPI in sepsis patients, efficacy studies indicate that in addition, administration of a 10-fold higher concentration of recombinant TFPI might be needed to compensate for an uncontrolled activation of the extrinsic pathway of coagulation.¹⁴¹ Treatments with recombinantly expressed variants of TFPI showed improved survival rates in several rabbit and baboon sepsis models,^142-145 whereas, in pigs, TFPI treatment attenuated the response of the inflammatory mediators TNF- and IL-8, but did not provide significant survival benefit.¹⁴⁶ The anti-inflammatory effect of TFPI can be explained by recent observations made by Park et al,¹⁴⁷ who showed that TFPI binds to endotoxin, suggesting that this interaction can depress cellular responses to the bacterial component. Infusion of TFPI in humans who received an intravenous injection of endotoxin resulted in an attenuation of thrombin generation. However, endotoxin-induced initiation of the fibrinolytic system and release of cytokines (TNF- and IL-6) was not affected by TFPI treatment.¹⁴⁸ Currently, a phase 2 clinical trial of recombinantly expressed TFPI in patients with sepsis is in progress.¹⁴¹

	Antithrombin III

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

AT III is the main inhibitor of thrombin and F X, but other serine proteinases, including F IX, F XI, F XII, PK, uPA, tPA, and plasmin, are also inactivated by AT III.¹⁴⁹ In septic shock, AT III levels drop drastically in plasma, and low AT III levels are predictive of a fatal outcome for the disease.¹³⁹ Several mechanisms can cause low AT III levels, such as consumption of AT III, degradation by elastase released from neutrophils, and extravascular leakage due to increased vascular permeability.¹⁵⁰ Experiments with baboons infected with a lethal dose of E coli showed that treatment with AT III increased the formation of thrombin-AT III complexes and diminished fibrinogen consumption as compared with a nontreated control group. The analysis of the cytokine response to the AT III administration revealed that levels of IL-6, IL-8, and IL-10 in plasma were significantly reduced in the AT III-treated group, whereas TNF- concentrations were enhanced.¹⁵¹ The finding that survival was improved in the group of infected baboons treated with AT III indicates that the anticoagulant and anti-inflammatory effects of an AT III treatment may improve the outcome in severe infectious diseases.¹⁵¹ Application of AT III has also been tested in humans suffering from severe sepsis or septic shock in several studies.¹⁵⁰ Generally, high doses are required to maintain supranormal antithrombin levels and to overcome the problem of antithrombin consumption.¹⁴⁹ Recently, Baudo et al¹⁵² published a double-blind, randomized, multicenter study of 120 patients receiving AT III or placebo treatment. They concluded from their study that AT III reduces mortality only in a subgroup of septic shock patients. Other studies by Inthorn et al¹⁵³ showed that long-term treatment with AT III attenuates the systemic inflammatory response and leads to a down-regulation of IL-6 in patients with severe sepsis. A double-blind placebo-controlled study involving 120 patients was carried out in Italy in 1999. Within the first 30 days, this trial showed that AT III therapy had a favorable effect on the survival of patients suffering from severe sepsis and/or post-surgery complications. However, this effect was not significant in terms of the overall survival.³

	C1 inhibitor

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

C1 INH, the major plasma inhibitor of activated complement C1-esterase, PK, and F XII, is an acute-phase protein, and its levels can increase up to 2-fold during uncomplicated sepsis.¹⁵⁴ However, the ratio between functional and total levels of C1 INH is lower in patients with sepsis than in healthy volunteers.¹⁵⁵ It has been assumed that degradation of the active inhibitor, probably by neutrophil elastase, is the cause of this phenomenon.¹⁵⁴ Administration of C1 INH to baboons suffering from lethal E coli sepsis results in a reduction of circulating cytokine levels, such as TNF-, IL-6, IL-8, and IL-10. Anatomical examination of C1 INH-treated animals revealed less severe damage to various organs than in control animals. However, the C1 INH therapy failed to result in a significant increase in survival.¹⁵⁶ The effect of a combined C1 INH and AT III treatment after intravenous injection of endotoxin in rabbits was investigated by Giebler et al.¹⁵⁷ This study found that the treatment significantly decreased clot formation in lungs and livers and resulted in an improved cardiovascular stability. There have also been reports that C1 INH treatment improves the clinical outcome in patients suffering from septic shock or streptococcal toxic shock syndrome. However, no controlled double-blind study of the effect of C1 INH in severe sepsis or septic shock has been evaluated so far.^158,159

	Thrombomodulin, protein C, protein S, and C4b-binding protein

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

TM is a cofactor expressed on endothelial cell surfaces, which modifies the activity of thrombin, leading to an activation of protein C and subsequent initiation of the anticoagulative pathway. The expression of TM is down-regulated by endotoxin and cytokines such as IL-1.¹⁶⁰ Several animal studies provide evidence that application of a recombinantly produced soluble variant of TM prevents fatal acute thromboembolism and diminishes glomerular fibrin deposition in endotoxin-induced disseminated intravascular coagulation (DIC).¹⁶¹ A double-blind study to evaluate the effect of recombinant soluble TM in DIC is in progress.¹⁶¹

Protein C and its cofactor protein S function as important regulatory factors of the blood coagulation cascade.¹⁶² Protein S is found in 2 forms, as free protein or in a noncovalent bimolecular complex with C4b-binding protein (C4BP).¹⁶³ The latter protein is a regulatory protein in the complement system that down-regulates the classical pathway of complement activation. C4BP binds approximately 60% of the circulating protein S and inactivates its anticoagulant properties.¹⁶² During sepsis, protein C levels are lowered, and especially in meningococcal septic shock, severely reduced protein C levels contribute to mortality and morbidity.^94,164,165 Levels of C4BP and protein S, however, are within normal range, indicating that it is mainly the deficiency of protein C that determines the severity of meningococcal septic shock.¹⁶⁵ In animal models, the administration of protein C had favorable effects on the hemodynamic parameters of endotoxin-treated animals and led to an improved survival.^166,167 Smith and White¹⁶⁸ recently published a clinical study involving 30 patients with meningococcaemia and severe protein C deficiency. Treatment of the patients with protein C resulted in a significant improvement of the host response to meniningococcal infection. Protein C and activated protein C are currently being investigated in clinical trials for septic shock.¹⁶⁹ The receptor for protein C (EPCR) seems to play an important role in regulating the activity of protein C in infectious diseases. As shown in baboons that were challenged with a sublethal dose of E coli, the administration of a monoclonal antibody that blocks protein-C binding to EPCR converts the response to sublethal concentrations of bacteria into a lethal challenge.¹⁶⁹ Interestingly, C4BP has been shown to bind to most strains of the species S pyogenes and Bordetella pertussis.^170,171 Functional studies indicate that the bacteria could interact with C4BP in order to protect themselves from a complement-mediated attack. However, any possible effect on the coagulation cascade was not studied.

	Concluding remarks

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

Despite an improved intensive care system, morbidity and mortality associated with severe bacterial infections constitute an increasing problem. This dilemma is caused by, among other factors, the ability of bacteria to develop antibiotic resistance and by an increasing number of immunocompromised patients. In order to develop novel therapeutic strategies that can successfully fight severe diseases caused by bacteria, it is necessary to have a thorough understanding of the molecular mechanisms involved in their interactions with host effector systems. Much knowledge about sepsis and septic shock has been achieved by studying the effect of endotoxin in different in vitro and in vivo models. However, Gram-positive bacteria are increasing in prevalence in sepsis patients, and not all complications that occur in Gram-negative sepsis can be explained by the effect of endotoxin.^172-175 An increasing knowledge of the role of microbial products in hemostasis may lead to novel treatments in life-threatening infectious diseases.

	Footnotes

Submitted March 27, 2000; accepted May 22, 2000.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.

Reprints: Heiko Herwald, Department of Cell and Molecular Biology, Section for Molecular Pathogenesis, Lund University, PO Box 94, S-221 00 Lund, Sweden; e-mail: heiko.herwald@medkem.lu.se .

	References

Top Introduction Current view on hemostasis Bacteria and the extrinsic... Bacteria and the contact... Bacteria and fibrinogen/fibrin Bacteria and fibrinolysis Treatments using coagulation... Tissue factor pathway inhibitor Antithrombin III C1 inhibitor Thrombomodulin, protein C,... Concluding remarks References

1. Tenover FC, Hughes JM. The challenges of emerging infectious diseases: development and spread of multiply-resistant bacterial pathogens. JAMA. 1996;275:300-304[Abstract].

2. Bax RP, Anderson R, Crew J, et al. Antibiotic resistance: what can we do? Nat Med. 1998;4:545-546[Medline] [Order article via Infotrieve].

3. Giudici D, Baudo F, Palareti G, Ravizza A, Ridolfi L, D' Angelo A. Antithrombin replacement in patients with sepsis and septic shock. Haematologica. 1999;84:452-460[Medline] [Order article via Infotrieve].

4. Cicala C, Cirino G. Linkage between inflammation and coagulation: an update on the molecular basis of the crosstalk. Life Sci. 1998;62:1817-1824[Medline] [Order article via Infotrieve].

5. van Gorp EC, Suharti C, ten Cate H, et al. Review: infectious diseases and coagulation disorders. J Infect Dis. 1999;180:176-186[Medline] [Order article via Infotrieve].

6. Camerer E, Kolstø AB, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation. Thromb Res. 1996;81:1-41[Medline] [Order article via Infotrieve].

7. Furie B, Furie BC. The molecular basis of blood coagulation. Cell. 1988;53:505-518[Medline] [Order article via Infotrieve].

8. Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood. 1997;90:3819-3843[Free Full Text].

9. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev. 1992;44:1-80[Medline] [Order article via Infotrieve].

10. Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII: factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem. 1991;266:7353-7368[Abstract/Free Full Text].

11. Carson SD, Johnson DR, Tracy SM. Tissue factor and the extrinsic pathway of coagulation during infection and vascular inflammation. Eur Heart J. 1993;14(suppl K):98-104[Medline] [Order article via Infotrieve].

12. Walsh PN. Platelets and factor XI bypass the contact system of blood coagulation. Thromb Haemost. 1999;82:234-242[Medline] [Order article via Infotrieve].

13. Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost. 1997;78:386-391[Medline] [Order article via Infotrieve].

14. Bouma BN, Meijers JC. Fibrinolysis and the contact system: a role for factor XI in the down-regulation of fibrinolysis. Thromb Haemost. 1999;82:243-250[Medline] [Order article via Infotrieve].

15. Sadler JE, Lentz SR, Sheehan JP, Tsiang M, Wu Q. Structure-function relationships of the thrombin-thrombomodulin interaction. Haemostasis. 1993;23(suppl 1):183-193[Medline] [Order article via Infotrieve].

16. Bauer KA, Rosenberg RD. Role of antithrombin III as a regulator of in vivo coagulation. Semin Hematol. 1991;28:10-18[Medline] [Order article via Infotrieve].

17. Davis AE III. Structure and function of C1 inhibitor. Behring Inst Mitt.; 1989:142-150.

18. Broze GJ Jr. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu Rev Med. 1995;46:103-112[Medline] [Order article via Infotrieve].

19. Von dem Borne PA, Bajzar L, Meijers JC, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest. 1997;99:2323-2327[Abstract/Free Full Text].

20. Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest. 1991;88:1067-1072[Medline] [Order article via Infotrieve].

21. Holmberg L, Ljung R, Nilsson IM. The effects of plasmin and protein Ca on factor VIII:C and VIII:CAg. Thromb Res. 1983;31:41-50[Medline] [Order article via Infotrieve].

22. Omar MN, Mann KG. Inactivation of factor Va by plasmin. J Biol Chem. 1987;262:9750-9755[Abstract/Free Full Text].

23. Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost. 1999;82:259-270[Medline] [Order article via Infotrieve].

24. Weitz JI, Stewart RJ, Fredenburgh JC. Mechanism of action of plasminogen activators. Thromb Haemost. 1999;82:974-982[Medline] [Order article via Infotrieve].

25. Mayer M. Biochemical and biological aspects of the plasminogen activation system. Clin Biochem. 1990;23:197-211[Medline] [Order article via Infotrieve].

26. Anonick PK, Wolf B, Gonias SL. Regulation of plasmin, miniplasmin, and streptokinase-plasmin complex by alpha 2-antiplasmin, alpha 2-macroglobulin, and antithrombin III in the presence of heparin. Thromb Res. 1990;59:449-462[Medline] [Order article via Infotrieve].

27. Schleef RR, Loskutoff DJ. Fibrinolytic system of vascular endothelial cells: role of plasminogen activator inhibitors. Haemostasis. 1988;18:328-341[Medline] [Order article via Infotrieve].

28. Esmon CT. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin? Blood. 2000;95:1113-1116[Free Full Text].

29. Ellis CA, Malik AB, Gilchrist A, et al. Thrombin induces proteinase-activated receptor-1 gene expression in endothelial cells via activation of Gi-linked Ras/mitogen-activated protein kinase pathway. J Biol Chem. 1999;274:13718-13727[Abstract/Free Full Text].

30. Papapetropoulos A, Piccardoni P, Cirino G, et al. Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling. Proc Natl Acad Sci U S A. 1998;95:4738-4742[Abstract/Free Full Text].

31. Røttingen JA, Enden T, Camerer E, Iversen JG, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor. J Biol Chem. 1995;270:4650-4660[Abstract/Free Full Text].

32. Ruf W, Mueller BM. Tissue factor signaling. Thromb Haemost. 1999;82:175-182[Medline] [Order article via Infotrieve].

33. Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci U S A. 1999;96:11023-11027[Abstract/Free Full Text].

34. Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A. 1994;91:9208-9212[Abstract/Free Full Text].

35. Akers IA, Parsons M, Hill MR, et al. Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am J Physiol Lung Cell Mol Physiol. 2000;278:L193-L201[Abstract/Free Full Text].

36. Steinhoff M, Vergnolle N, Young SH, et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000;6:151-158[Medline] [Order article via Infotrieve].

37. Lourbakos A, Chinni C, Thompson P, et al. Cleavage and activation of proteinase-activated receptor-2 on human neutrophils by gingipain-R from Porphyromonas gingivalis. FEBS Lett. 1998;435:45-48[Medline] [Order article via Infotrieve].

38. Nicholson AC, Nachman RL, Altieri DC, et al. Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa. J Biol Chem. 1996;271:28407-28413[Abstract/Free Full Text].

39. Cunningham MA, Romas P, Hutchinson P, Holdsworth SR, Tipping PG. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood. 1999;94:3413-3420[Abstract/Free Full Text].

40. Esmon CT, Xu J, Gu JM, et al. Endothelial protein C receptor. Thromb Haemost. 1999;82:251-258[Medline] [Order article via Infotrieve].

41. Kurosawa S, Stearns-Kurosawa DJ, Hidari N, Esmon CT. Identification of functional endothelial protein C receptor in human plasma. J Clin Invest. 1997;100:411-418[Abstract/Free Full Text].

42. Simmonds RE, Lane DA. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. Blood. 1999;94:632-641[Abstract/Free Full Text].

43. Esmon CT, Fukudome K, Mather T, et al. Inflammation, sepsis, and coagulation. Haematologica. 1999;84:254-259[Medline] [Order article via Infotrieve].

44. Kurosawa S, Stearns-Kurosawa DJ, Carson CW, D'Angelo A, Della Valle P, Esmon CT. Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood. 1998;91:725-727[Free Full Text].

45. Vergnolle N. Proteinase-activated receptor-2-activating peptides induce leukocyte rolling, adhesion, and extravasation in vivo. J Immunol. 1999;163:5064-5069[Abstract/Free Full Text].

46. Cirino G, Cicala C, Bucci M, et al. Factor Xa as an interface between coagulation and inflammation: molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo. J Clin Invest. 1997;99:2446-2451[Abstract/Free Full Text].

47. Duchosal MA, Rothermel AL, McConahey PJ, Dixon FJ, Altieri DC. In vivo immunosuppression by targeting a novel protease receptor. Nature. 1996;380:352-356[Medline] [Order article via Infotrieve].

48. Bugge TH, Xiao Q, Kombrinck KW, et al. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation. Proc Natl Acad Sci U S A. 1996;93:6258-6263[Abstract/Free Full Text].

49. Toomey JR, Kratzer KE, Lasky NM, Stanton JJ, Broze GJ Jr. Targeted disruption of the murine tissue factor gene results in embryonic lethality. Blood. 1996;88:1583-1587[Abstract/Free Full Text].

50. Østerud B, Bajaj MS, Bajaj SP. Sites of tissue factor pathway inhibitor (TFPI) and tissue factor expression under physiologic and pathologic conditions. On behalf of the Subcommittee on Tissue Factor Pathway Inhibitor (TFPI) of the Scientific and Standardization Committee of the ISTH. Thromb Haemost. 1995;73:873-875[Medline] [Order article via Infotrieve].

51. Moll T, Czyz M, Holzmüller H, et al. Regulation of the tissue factor promoter in endothelial cells: binding of NF kappa B-, AP-1-, and Sp1-like transcription factors. J Biol Chem. 1995;270:3849-3857[Abstract/Free Full Text].

52. Cui MZ, Parry GC, Oeth P, et al. Transcriptional regulation of the tissue factor gene in human epithelial cells is mediated by Sp1 and EGR-1. J Biol Chem. 1996;271:2731-2739[Abstract/Free Full Text].

53. Mechtcheriakova D, Wlachos A, Holzmüller H, Binder BR, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1. Blood. 1999;93:3811-3823[Abstract/Free Full Text].

54. Giesen PL, Rauch U, Bohrmann B, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A. 1999;96:2311-2315[Abstract/Free Full Text].

55. Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost. 1998;79:1111-1115[Medline] [Order article via Infotrieve].

56. Lyberg T, Closs O, Prydz H. Effect of purified protein derivative and sonicates of Mycobacterium leprae and Mycobacterium bovis BCG on thromboplastin response in human monocytes in vitro. Infect Immun. 1982;38:855-859[Medline] [Order article via Infotrieve].

57. Heyderman RS, Klein NJ, Daramola OA, et al. Induction of human endothelial tissue factor expression by Neisseria meningitidis: the influence of bacterial killing and adherence to the endothelium. Microb Pathog. 1997;22:265-274[Medline] [Order article via Infotrieve].

58. Schlichting E, Lyberg T, Solberg O, Andersen BM. Endotoxin liberation from Neisseria meningitidis correlates to their ability to induce procoagulant and fibrinolytic factors in human monocytes. Scand J Infect Dis. 1993;25:585-594[Medline] [Order article via Infotrieve].

59. Teysseire N, Arnoux D, George F, Sampol J, Raoult D. von Willebrand factor release and thrombomodulin and tissue factor expression in Rickettsia conorii-infected endothelial cells. Infect Immun. 1992;60:4388-4393[Abstract].

60. Shi RJ, Simpson-Haidaris PJ, Lerner NB, Marder VJ, Silverman DJ, Sporn LA. Transcriptional regulation of endothelial cell tissue factor expression during Rickettsia rickettsii infection: involvement of the transcription factor NF-kappaB. Infect Immun. 1998;66:1070-1075[Abstract/Free Full Text].

61. Sporn LA, Haidaris PJ, Shi RJ, Nemerson Y, Silverman DJ, Marder VJ. Rickettsia rickettsii infection of cultured human endothelial cells induces tissue factor expression. Blood. 1994;83:1527-1534[Abstract/Free Full Text].

62. Veltrop MH, Beekhuizen H, Thompson J. Bacterial species- and strain-dependent induction of tissue factor in human vascular endothelial cells. Infect Immun. 1999;67:6130-6138[Abstract/Free Full Text].

63. Bancsi MJ, Thompson J, Bertina RM. Stimulation of monocyte tissue factor expression in an in vitro model of bacterial endocarditis. Infect Immun. 1994;62:5669-5672[Abstract].

64. Bancsi MJ, Veltrop MH, Bertina RM, Thompson J. Influence of monocytes and antibiotic treatment on tissue factor activity of endocardial vegetations in rabbits infected with Streptococcus sanguis. Infect Immun. 1996;64:448-451[Abstract].

65. Mattsson E, Rollof J, Verhoef J, Van Dijk H, Fleer A. Serum-induced potentiation of tumor necrosis factor alpha production by human monocytes in response to staphylococcal peptidoglycan: involvement of different serum factors. Infect Immun. 1994;62:3837-3843[Abstract].

66. Norrby-Teglund A, Norgren M, Holm SE, Andersson U, Andersson J. Similar cytokine induction profiles of a novel streptococcal exotoxin, MF, and pyrogenic exotoxins A and B. Infect Immun. 1994;62:3731-3738[Abstract].

67. Ferrante A, Staugas RE, Rowan-Kelly B, et al. Production of tumor necrosis factors alpha and beta by human mononuclear leukocytes stimulated with mitogens, bacteria, and malarial parasites. Infect Immun. 1990;58:3996-4003[Medline] [Order article via Infotrieve].

68. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin-6 (IL- 6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990;75:40-47[Abstract].

69. Bayston K, Tomlinson M, Cohen J. In-vitro stimulation of TNF-alpha from human whole blood by cell-free supernatants of gram-positive bacteria. Cytokine. 1992;4:397-402[Medline] [Order article via Infotrieve].

70. Schwager I, Jungi TW. Effect of human recombinant cytokines on the induction of macrophage procoagulant activity. Blood. 1994;83:152-160[Abstract/Free Full Text].

71. Lottenberg R. Contact activation proteins and the bacterial surface. Trends Microbiol. 1996;4:413-414[Medline] [Order article via Infotrieve].

72. Mason JW, Kleeberg U, Dolan P, Colman RW. Plasma kallikrein and Hageman factor in Gram-negative bacteremia. Ann Intern Med. 1970;73:545-551[Medline] [Order article via Infotrieve].

73. Wuillemin WA, Fijnvandraat K, Derkx BH, et al. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost. 1995;74:1436-1441[Medline] [Order article via Infotrieve].

74. Pixley RA, Zellis S, Bankes P, et al. Prognostic value of assessing contact system activation and factor V in systemic inflammatory response syndrome. Crit Care Med. 1995;23:41-51[Medline] [Order article via Infotrieve].

75. van Deuren M, Brandtzaeg P, van der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev. 2000;13:144-166[Abstract/Free Full Text].

76. Pixley RA, DeLa Cadena RA, Page JD, et al. Activation of the contact system in lethal hypotensive bacteremia in a baboon model. Am J Pathol. 1992;140:897-906[Abstract].

77. Pixley RA, De La Cadena R, Page JD, et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia: in vivo use of a monoclonal antifactor XII antibody to block contact activation in baboons. J Clin Invest. 1993;91:61-68[Medline] [Order article via Infotrieve].

78. Levi M, ten Cate H, van der Poll T, van Deventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975-979[Abstract].

79. Ben Nasr AB, Olsén A, Sjöbring U, Müller-Esterl W, Björck L. Assembly of human contact phase factors and release of bradykinin at the surface of curli-expressing Escherichia coli. Mol Microbiol. 1996;20:927-935[Medline] [Order article via Infotrieve].

80. Herwald H, Mörgelin M, Olsén A, et al. Activation of the contact-phase system on bacterial surfaces: a clue to serious complications in infectious diseases. Nat Med. 1998;4:298-302[Medline] [Order article via Infotrieve].

81. DeLa Cadena RA, Laskin KJ, Pixley RA, et al. Role of kallikrein-kinin system in pathogenesis of bacterial cell wall-induced inflammation. Am J Physiol. 1991;260:G213-G219[Abstract/Free Full Text].

82. Ben Nasr AB, Herwald H, Müller-Esterl W, Björck L. Human kininogens interact with M protein, a bacterial surface protein and virulence determinant. Biochem J. 1995;305:173-180[Medline] [Order article via Infotrieve].

83. Fischetti VA. Streptococcal M protein: molecular design and biological behaviour. Clin Microbiol Rev. 1989;2:285-314[Medline] [Order article via Infotrieve].

84. Ben Nasr AB, Herwald H, Renné T, Müller-Esterl W, Björck L. Absorption of kininogen from human plasma by Streptococcus pyogenes is followed by the release of bradykinin. Biochem J. 1997;326:657-660[Medline] [Order article via Infotrieve].

85. Morrison DC, Roser JF, Henson PM, Cochrane CG. Activation of rat mast cells by low molecular weight stimuli. J Immunol. 1974;112:573-582[Medline] [Order article via Infotrieve].

86. Minnema MC, Pajkrt D, Wuillemin WA, et al. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood. 1998;92:3294-3301[Abstract/Free Full Text].

87. Molla A, Yamamoto T, Akaike T, Miyoshi S, Maeda H. Activation of Hageman factor and prekallikrein and generation of kinin by various microbial proteinases. J Biol Chem. 1989;264:10589-10594[Abstract/Free Full Text].

88. Sakata Y, Akaike T, Suga M, Ijiri S, Ando M, Maeda H. Bradykinin generation triggered by Pseudomonas proteases facilitates invasion of the systemic circulation by Pseudomonas aeruginosa. Microbiol Immunol. 1996;40:415-423[Medline] [Order article via Infotrieve].

89. Maruo K, Akaike T, Inada Y, Ohkubo I, Ono T, Maeda H. Effect of microbial and mite proteases on low and high molecular weight kininogens: generation of kinin and inactivation of thiol protease inhibitory activity. J Biol Chem. 1993;268:17711-17715[Abstract/Free Full Text].

90. Kadowaki T, Yoneda M, Okamoto K, Maeda K, Yamamoto K. Purification and characterization of a novel arginine-specific cysteine proteinase (argingipain) involved in the pathogenesis of periodontal disease from the culture supernatant of Porphyromonas gingivalis. J Biol Chem. 1994;269:21371-21378[Abstract/Free Full Text].

91. Imamura T, Pike RN, Potempa J, Travis J. Pathogenesis of periodontitis: a major arginine-specific cysteine proteinase from Porphyromonas gingivalis induces vascular permeability enhancement through activation of the kallikrein/kinin pathway. J Clin Invest. 1994;94:361-367[Medline] [Order article via Infotrieve].

92. Scott CF, Whitaker EJ, Hammond BF, Colman RW. Purification and characterization of a potent 70-kDa thiol lysyl-proteinase (Lys-gingivain) from Porphyromonas gingivalis that cleaves kininogens and fibrinogen. J Biol Chem. 1993;268:7935-7942[Abstract/Free Full Text].

93. Herwald H, Collin M, Müller-Esterl W, Björck L. Streptococcal cysteine proteinase releases kinins: a novel virulence mechanism. J Exp Med. 1996;184:665-673[Abstract].

94. de Jonge E, Levi M, Stoutenbeek CP, van Deventer SJ. Current drug treatment strategies for disseminated intravascular coagulation. Drugs. 1998;55:767-777[Medline] [Order article via Infotrieve].

95. Bick RL. Disseminated intravascular coagulation: pathophysiological mechanisms and manifestations. Semin Thromb Hemost. 1998;24:3-18[Medline] [Order article via Infotrieve].

96. Altieri DC. Regulation of leukocyte-endothelium interaction by fibrinogen. Thromb Haemost. 1999;82:781-786[Medline] [Order article via Infotrieve].

97. Rotstein OD. Role of fibrin deposition in the pathogenesis of intraabdominal infection. Eur J Clin Microbiol Infect Dis. 1992;11:1064-1068[Medline] [Order article via Infotrieve].

98. Bodén MK, Flock JI. Evidence for three different fibrinogen-binding proteins with unique properties from Staphylococcus aureus strain Newman. Microb Pathog. 1992;12:289-298[Medline] [Order article via Infotrieve].

99. Bodén MK, Flock JI. Cloning and characterization of a gene for a 19 kDa fibrinogen-binding protein from Staphylococcus aureus. Mol Microbiol. 1994;12:599-606[Medline] [Order article via Infotrieve].

100. McDevitt D, Francois P, Vaudaux P, Foster TJ. Molecular characterization of the clumping factor (fibrinogen receptor) of Staphylococcus aureus. Mol Microbiol. 1994;11:237-248[Medline] [Order article via Infotrieve].

101. Cheung AI, Projan SJ, Edelstein RE, Fischetti VA. Cloning, expression, and nucleotide sequence of a Staphylococcus aureus gene (fbpA) encoding a fibrinogen-binding protein. Infect Immun. 1995;63:1914-1920[Abstract].

102. Foster TJ, Höök M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol. 1998;6:484-488[Medline] [Order article via Infotrieve].

103. McDevitt D, Vaudaux P, Foster TJ. Genetic evidence that bound coagulase of Staphylococcus aureus is not clumping factor. Infect Immun. 1992;60:1514-1523[Abstract].

104. Palma M, Nozohoor S, Schennings T, Heimdahl A, Flock JI. Lack of the extracellular 19-kilodalton fibrinogen-binding protein from Staphylococcus aureus decreases virulence in experimental wound infection. Infect Immun. 1996;64:5284-5289[Abstract].

105. Moreillon P, Entenza JM, Francioli P, et al. Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis of experimental endocarditis. Infect Immun. 1995;63:4738-4743[Abstract].

106. Ni Eidhin D, Perkins S, Francois P, Vaudaux P, Hook M, Foster TJ. Clumping factor B (ClfB), a new surface-located fibrinogen-binding adhesin of Staphylococcus aureus. Mol Microbiol. 1998;30:245-257[Medline] [Order article via Infotrieve].

107. Nilsson M, Frykberg L, Flock JI, Pei L, Lindberg M, Guss B. A fibrinogen-binding protein of Staphylococcus epidermidis. Infect Immun. 1998;66:2666-2673[Abstract/Free Full Text].

108. Pei L, Palma M, Nilsson M, Guss B, Flock JI. Functional studies of a fibrinogen binding protein from Staphylococcus epidermidis. Infect Immun. 1999;67:4525-4530[Abstract/Free Full Text].

109. Colque-Navarro P, Palma M, Söderquist B, Flock JI, Mollby R. Antibody responses in patients with staphylococcal septicemia against two Staphylococcus aureus fibrinogen binding proteins: clumping factor and an extracellular fibrinogen binding protein. Clin Diagn Lab Immunol. 2000;7:14-20[Abstract/Free Full Text].

110. Poirier TP, Kehoe MA, Whitnack E, Dockter ME, Beachey EH. Fibrinogen binding and resistance to phagocytosis of Streptococcus sanguis expressing cloned M protein of Streptococcus pyogenes. Infect Immun. 1989;57:29-35[Medline] [Order article via Infotrieve].

111. Schmidt KH, Mann K, Cooney J, Köhler W. Multiple binding of type 3 streptococcal M protein to human fibrinogen, albumin and fibronectin. FEMS Immunol Med Microbiol. 1993;7:135-143[Medline] [Order article via Infotrieve].

112. Ryc M, Beachey EH, Whitnack E. Ultrastructural localization of the fibrinogen-binding domain of streptococcal M protein. Infect Immun. 1989;57:2397-2404[Medline] [Order article via Infotrieve].

113. Dale JB, Washburn RG, Marques MB, Wessels MR. Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci. Infect Immun. 1996;64:1495-1501[Abstract].

114. Parry MA, Zhang XC, Bode I. Molecular mechanisms of plasminogen activation: bacterial cofactors provide clues. Trends Biochem Sci. 2000;25:53-59[Medline] [Order article via Infotrieve].

115. Liotta LA, Goldfarb RH, Brundage R, Siegal GP, Terranova V, Garbisa S. Effect of plasminogen activator (urokinase), plasmin, and thrombin on glycoprotein and collagenous components of basement membrane. Cancer Res. 1981;41:4629-4636[Abstract].

116. Rømer J, Bugge TH, Pyke C, et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med. 1996;2:287-292[Medline] [Order article via Infotrieve].

117. Carmeliet P, Schoonjans L, Kieckens L, et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368:419-424[Medline] [Order article via Infotrieve].

118. Duboscq C, Quintana I, Bassilotta E, et al. Plasminogen: an important hemostatic parameter in septic patients. Thromb Haemost. 1997;77:1090-1095[Medline] [Order article via Infotrieve].

119. Aiuto LT, Barone SR, Cohen PS, Boxer RA. Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med. 1997;25:1079-1082[Medline] [Order article via Infotrieve].

120. Pralong G, Calandra T, Glauser MP, et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost. 1989;61:459-462[Medline] [Order article via Infotrieve].

121. Engebretsen LF, Kierulf P, Brandtzaeg P. Extreme plasminogen activator inhibitor and endotoxin values in patients with meningococcal disease. Thromb Res. 1986;42:713-716[Medline] [Order article via Infotrieve].

122. Boyle MD, Lottenberg R. Plasminogen activation by invasive human pathogens. Thromb Haemost. 1997;77:1-10[Medline] [Order article via Infotrieve].

123. Coleman JL, Benach JL. Use of the plasminogen activation system by microorganisms. J Lab Clin Med. 1999;134:567-576[Medline] [Order article via Infotrieve].

124. Davidson DJ, Higgins DL, Castellino FJ. Plasminogen activator activities of equimolar complexes of streptokinase with variant recombinant plasminogens. Biochemistry. 1990;29:3585-3590[Medline] [Order article via Infotrieve].

125. Grella DK, Castellino FJ. Activation of human plasminogen by staphylokinase: direct evidence that preformed plasmin is necessary for activation to occur. Blood. 1997;89:1585-1589[Abstract/Free Full Text].

126. Wang X, Lin X, Loy JA, Tang J, Zhang XC. Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science. 1998;281:1662-1665[Abstract/Free Full Text].

127. Parry MA, Fernandez-Catalan C, Bergner A, et al. The ternary microplasmin-staphylokinase-microplasmin complex is a proteinase-cofactor-substrate complex in action. Nat Struct Biol. 1998;5:917-923[Medline] [Order article via Infotrieve].

128. Sodeinde OA, Sample AK, Brubaker RR, Goguen JD. Plasminogen activator/coagulase gene of Yersinia pestis is responsible for degradation of plasmid-encoded outer membrane proteins. Infect Immun. 1988;56:2749-2752[Medline] [Order article via Infotrieve].

129. Welkos SL, Friedlander AM, Davis KJ. Studies on the role of plasminogen activator in systemic infection by virulent Yersinia pestis strain C092. Microb Pathog. 1997;23:211-223[Medline] [Order article via Infotrieve].

130. Klempner MS, Noring R, Epstein MP, et al. Binding of human plasminogen and urokinase-type plasminogen activator to the Lyme disease spirochete, Borrelia burgdorferi. J Infect Dis. 1995;171:1258-1265[Medline] [Order article via Infotrieve].

131. Sjöbring U, Pohl G, Olsén A. Plasminogen, absorbed by Escherichia coli expressing curli or by Salmonella enteritidis expressing thin aggregative fimbriae, can be activated by simultaneously captured tissue-type plasminogen activator (t-PA). Mol Microbiol. 1994;14:443-452[Medline] [Order article via Infotrieve].

132. Fuchs H, Wallich R, Simon MM, Kramer MD. The outer surface protein A of the spirochete Borrelia burgdorferi is a plasmin(ogen) receptor. Proc Natl Acad Sci U S A. 1994;91:12594-12598[Abstract/Free Full Text].

133. Santala A, Saarinen J, Kovanen P, Kuusela P. Activation of interstitial collagenase, MMP-1, by Staphylococcus aureus cells having surface-bound plasmin: a novel role of plasminogen receptors of bacteria. FEBS Lett. 1999;461:153-156[Medline] [Order article via Infotrieve].

134. Lottenberg R, Broder CC, Boyle MD. Identification of a specific receptor for plasmin on a group A streptococcus. Infect Immun. 1987;55:1914-1918[Medline] [Order article via Infotrieve].

135. Coleman JL, Gebbia JA, Piesman J, Degen JL, Bugge TH, Benach JL. Plasminogen is required for efficient dissemination of B. burgdorferi in ticks and for enhancement of spirochetemia in mice. Cell. 1997;89:1111-1119[Medline] [Order article via Infotrieve].

136. Svensson MD, Sjöbring U, Bessen DE. Selective distribution of a high-affinity plasminogen-binding site among group A streptococci associated with impetigo. Infect Immun. 1999;67:3915-3920[Abstract/Free Full Text].

137. Sala N, Fontcuberta J, Rutllant ML. New biological concepts on coagulation inhibitors. Intensive Care Med. 1993;19(suppl 1):S3-S7[Medline] [Order article via Infotrieve].

138. Lämmle B, Tran TH, Ritz R, Duckert F. Plasma prekallikrein, factor XII, antithrombin III, C1(-)-inhibitor and alpha 2-macroglobulin in critically ill patients with suspected disseminated intravascular coagulation (DIC). Am J Clin Pathol. 1984;82:396-404[Medline] [Order article via Infotrieve].

139. Fourrier F, Chopin C, Goudemand J, 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[Abstract].

140. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost. 1998;24:33-44[Medline] [Order article via Infotrieve].

141. Bajaj MS, Bajaj SP. Tissue factor pathway inhibitor: potential therapeutic applications. Thromb Haemost. 1997;78:471-477[Medline] [Order article via Infotrieve].

142. Bregengard C, Nordfang O, Wildgoose P, Svendsen O, Hedner U, Diness V. The effect of two-domain tissue factor pathway inhibitor on endotoxin-induced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis. 1993;4:699-706[Medline] [Order article via Infotrieve].

143. Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FB Jr, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest. 1993;91:2850-2856[Medline] [Order article via Infotrieve].

144. Carr C, Bild GS, Chang AC, et al. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circ Shock. 1994;44:126-137[Medline] [Order article via Infotrieve].

145. Camerota AJ, Creasey AA, Patla V, Larkin VA, Fink MP. Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. J Infect Dis. 1998;177:668-676[Medline] [Order article via Infotrieve].

146. Goldfarb RD, Glock D, Johnson K, et al. Randomized, blinded, placebo-controlled trial of tissue factor pathway inhibitor in porcine septic shock. Shock. 1998;10:258-264[Medline] [Order article via Infotrieve].

147. Park CT, Creasey AA, Wright SD. Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. Blood. 1997;89:4268-4274[Abstract/Free Full Text].

148. de Jonge E, Dekkers PE, Creasey AA, et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood. 2000;95:1124-1129[Abstract/Free Full Text].

149. Fourrier F, Jourdain M, Tournois A, Caron C, Goudemand J, Chopin C. Coagulation inhibitor substitution during sepsis. Intensive Care Med. 1995;21(suppl 2):S264-S268[Medline] [Order article via Infotrieve].

150. Fourrier F. Therapeutic applications of antithrombin concentrates in systemic inflammatory disorders. Blood Coagul Fibrinolysis. 1998;9(suppl 2):S39-S45[Medline] [Order article via Infotrieve].

151. Minnema MC, Chang AC, Jansen PM, et al. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood. 2000;95:1117-1123[Abstract/Free Full Text].

152. Baudo F, Caimi TM, de Cataldo F, et al. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study. Intensive Care Med. 1998;24:336-342[Medline] [Order article via Infotrieve].

153. Inthorn D, Hoffmann JN, Hartl WH, Mühlbayer D, Jochum M. Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis. Shock. 1998;10:90-96[Medline] [Order article via Infotrieve].

154. Hack CE, Ogilvie AC, Eisele B, Eerenberg AJ, Wagstaff J, Thijs LG. C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2. Intensive Care Med. 1993;19(suppl 1):S19-S28[Medline] [Order article via Infotrieve].

155. Nuijens JH, Eerenberg-Belmer AJ, Huijbregts CC, et al. Proteolytic inactivation of plasma C1-inhibitor in sepsis. J Clin Invest. 1989;84:443-450[Medline] [Order article via Infotrieve].

156. Jansen PM, Eisele B, de Jong IW, et al. Effect of C1 inhibitor on inflammatory and physiologic response patterns in primates suffering from lethal septic shock. J Immunol. 1998;160:475-484[Abstract/Free Full Text].

157. Giebler R, Schmidt U, Koch S, Peters J, Scherer R. Combined antithrombin III and C1-esterase inhibitor treatment decreases intravascular fibrin deposition and attenuates cardiorespiratory impairment in rabbits exposed to Escherichia coli endotoxin. Crit Care Med. 1999;27:597-604[Medline] [Order article via Infotrieve].

158. Kirschfink M, Nürnberger W. C1 inhibitor in anti-inflammatory therapy: from animal experiment to clinical application. Mol Immunol. 1999;36:225-232[Medline] [Order article via Infotrieve].

159. Caliezi C, Wuillemin WA, Zeerleder S, Redondo M, Eisele B, Hack CE. C1-esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Pharmacol Rev. 2000;52:91-112[Abstract/Free Full Text].

160. Calnek DS, Grinnell BW. Thrombomodulin-dependent anticoagulant activity is regulated by vascular endothelial growth factor. Exp Cell Res. 1998;238:294-298[Medline] [Order article via Infotrieve].

161. Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost. 1999;82:718-721[Medline] [Order article via Infotrieve].

162. Dahlbäck B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thromb Haemost. 1991;66:49-61[Medline] [Order article via Infotrieve].

163. Hillarp A. Molecular analysis of the beta-chain of human C4b-binding protein. Scand J Clin Lab Invest Suppl. 1991;204:57-69[Medline] [Order article via Infotrieve].

164. Fijnvandraat K, Peters M, Derkx B, van Deventer S, ten Cate JW. Endotoxin induced coagulation activation and protein C reduction in meningococcal septic shock. Prog Clin Biol Res. 1994;388:247-254[Medline] [Order article via Infotrieve].

165. Fijnvandraat K, Derkx B, Peters M, et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost. 1995;73:15-20[Medline] [Order article via Infotrieve].

166. Roback MG, Stack AM, Thompson C, Brugnara C, Schwarz HP, Saladino RA. Activated protein C concentrate for the treatment of meningococcal endotoxin shock in rabbits. Shock. 1998;9:138-142[Medline] [Order article via Infotrieve].

167. Fourrier F, Jourdain M, Tournoys A, Gosset P, Mangalaboyi J, Chopin C. Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock. Shock. 1998;10:364-370[Medline] [Order article via Infotrieve].

168. Smith OP, White B. Infectious purpura fulminans: diagnosis and treatment. Br J Haematol. 1999;104:202-207[Medline] [Order article via Infotrieve].

169. Taylor FB, Stearns-Kurosawa DJ, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000;95:1680-1686[Abstract/Free Full Text].

170. Johnsson E, Thern A, Dahlbäck B, Hedén LO, Wikström M, Lindahl G. A highly variable region in members of the streptococcal M protein family binds the human complement regulator C4BP. J Immunol. 1996;157:3021-3029[Abstract].

171. Berggård K, Johnsson E, Mooi FR, Lindahl G. Bordetella pertussis binds the human complement regulator C4BP: role of filamentous hemagglutinin. Infect Immun. 1997;65:3638-3643[Abstract].

172. Heumann D, Glauser MP, Calandra T. Molecular basis of host-pathogen interaction in septic shock. Curr Opin Microbiol. 1998;1:49-55[Medline] [Order article via Infotrieve].

173. Bone RC. Gram-positive organisms and sepsis. Arch Intern Med. 1994;154:26-34[Abstract].

174. Opal SM, Cohen J. Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med. 1999;27:1608-1616[Medline] [Order article via Infotrieve].

175. Sriskandan S, Cohen J. Gram-positive sepsis: mechanisms and differences from gram-negative sepsis. Infect Dis Clin North Am. 1999;13:397-412[Medline] [Order article via Infotrieve].

176. Imamura T, Potempa J, Pike RN, Travis J. Dependence of vascular permeability enhancement on cysteine proteinases in vesicles of Porphyromonas gingivalis. Infect Immun. 1995;63:1999-2003[Abstract].

177. Sakata Y, Akaike T, Khan MM, et al. Activation of bradykinin generating cascade by Vibrio cholerae protease. Immunopharmacology. 1996;33:377-379[Medline] [Order article via Infotrieve].

178. Miyoshi N, Miyoshi S, Sugiyama K, Suzuki Y, Furuta H, Shinoda S. Activation of the plasma kallikrein-kinin system by Vibrio vulnificus protease. Infect Immun. 1987;55:1936-1939[Medline] [Order article via Infotrieve].

179. Kukkonen M, Saarela S, Lahteenmaki K, et al. Identification of two laminin-binding fimbriae, the type 1 fimbria of Salmonella enterica serovar typhimurium and the G fimbria of Escherichia coli, as plasminogen receptors. Infect Immun. 1998;66:4965-4970[Abstract/Free Full Text].

180. Darenfed H, Grenier D, Mayrand D. Acquisition of plasmin activity by Fusobacterium nucleatum subsp. nucleatum and potential contribution to tissue destruction during periodontitis. Infect Immun. 1999;67:6439-6444[Abstract/Free Full Text].

181. Pantzar M, Ljungh Å, Wadström T. Plasminogen binding and activation at the surface of Helicobacter pylori CCUG 17874. Infect Immun. 1998;66:4976-4980[Abstract/Free Full Text].

182. Tarshis M, Morag B, Mayer M. Mycoplasma cells stimulate in vitro activation of plasminogen by purified tissue-type plasminogen activator. FEMS Microbiol Lett. 1993;106:201-204[Medline] [Order article via Infotrieve].

183. Ullberg M, Kuusela P, Kristiansen BE, Kronvall G. Binding of plasminogen to Neisseria meningitidis and Neisseria gonorrhoeae and formation of surface-associated plasmin. J Infect Dis. 1992;166:1329-1334[Medline] [Order article via Infotrieve].

184. Engel LS, Hill JM, Caballero AR, Green LC, O'Callaghan RJ. Protease IV, a unique extracellular protease and virulence factor from Pseudomonas aeruginosa. J Biol Chem. 1998;273:16792-16797[Abstract/Free Full Text].

185. Ullberg M, Kronvall G, Karlsson I, Wiman B. Receptors for human plasminogen on gram-negative bacteria. Infect Immun. 1990;58:21-25[Medline] [Order article via Infotrieve].

186. Kuusela P, Saksela O. Binding and activation of plasminogen at the surface of Staphylococcus aureus: increase in affinity after conversion to the Lys form of the ligand. Eur J Biochem. 1990;193:759-765[Abstract].

187. Berge A, Sjöbring U. PAM, a novel plasminogen-binding protein from Streptococcus pyogenes. J Biol Chem. 1993;268:25417-25424[Abstract/Free Full Text].

188. Ben Nasr AB, Wistedt A, Ringdahl U, Sjöbring U. Streptokinase activates plasminogen bound to human group C and G streptococci through M-like proteins. Eur J Biochem. 1994;222:267-276[Abstract].

© 2000 by The American Society of Hematology.