Alteration of Hemostatic Coagulative Balance in Bacterial Meningitis: Activation of Coagulation & Inhibition of Fibrinolysis

Abstract

Bacterial Meningitis is an acute purulent infection of the leptomeninges in the subarachnoid space, most commonly caused by Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenzae. A variety of complications originate from a primary focus of bacterial meningitis, but none as severe as cerebrovascular complications. The basis for the development of post-infective cerebrovascular sequelae following an attack of bacterial meningitis remains largely speculative; however several studies suggest a derangement of the coagulative system in evoking such an outcome. A primary derangement of the coagulative status stems from an unbalance between the activation of coagulative processes and an inhibition of anticoagulant processes, resulting in a net heightened activation of coagulation. Multiple pieces of experimental evidence suggest a net overall procoagulant status is achieved by heightened activation of coagulation and inhibition of fibrinolysis. In our analysis of perturbations of coagulative status following acute bacterial meningitis, we begin our discussion by describing structural and functional properties of normal anticoagulant proteins in the circulation that normally function to limit excess coagulation, reducing the development of a procoagulant status in the blood. Next, we continue our discussion, by analyzing the various factors that contribute to a suppression/down regulation of normal anticoagulant pathways, thereby increasing procoagulative status of the blood. Subsequently, we analyze the initiators of activation of coagulation and their implications following an injury with an insight into molecular mechanisms capable of initiating such changes. Finally, we end the discussion by describing the initial short-lived acute fibrinolytic response to bacterial infection and inflammation followed by a late-rising sustained anti-fibrinolytic response capable of inhibiting fibrinolysis and enhancing procoagulant status. Our main objective in this study is to more closely understand possible perturbations in the coagulative profile of the blood that may contribute to the development of cerebrovascular sequelae following an post-infective meningitis infection.

Introduction

Acute bacterial meningitis is a life treating purulent infection of the leptomeninges, characterized by the influx of inflammatory cells into the subarachnoid space with the attendant development of a purulent exudate most commonly due to Streptococcus pneumonia, Haemophilus influenzae, and Neisseria meningitidis [1]. In spite of improvements in the antimicrobial treatment of bacterial meningitis over the last few decades, mortality and post-infective complications continue to present heavily to disease burden [2,3]. Intracerebral complications such as seizures, cerebral edema, cranial nerve palsies (CN 3, 4, 6, 7), hydrocephalus, and cerebrovascular events increase the clinical consequences of bacterial meningitis leading to an unfavorable clinical outcome [2,4]. A particularly disturbing complication of acute bacterial meningitis is the involvement of the cerebral vasculature with the attendant development of post-infective cerebrovascular sequelae [5-16]. Post-infective cerebrovascular sequelae are a predictable consequence of nearly one-fifth of adults with community acquired bacterial meningitis [3]. In most cases, cerebrovascular complications of bacterial meningitis are manifested by the development of arterial or venous thrombi, ischemic or hemorrhagic stroke, and cerebral venous sinus thrombosis.

Although numerous pathophysiological alterations are in play to evoke changes in the cerebral vasculature, a particularly important alteration is the alteration of coagulation [17]. The role of the coagulation system in bacterial meningitis plays an important role in understanding the cerebrovascular sequelae of bacterial meningitis. In bacterial meningitis, the normal hemostatic balance between a coagulative and an anticoagulative profile is perturbed, with a shifting towards a more procoagulant profile [18,19]. This is accomplished by derangements in several coagulation factors. For example, patients with bacterial meningitis have higher levels of tissue factor, an initiator of coagulation. Increased levels of tissue factor result in higher than normal activation of the extrinsic pathway of coagulation generating increased amounts of thrombin. A heightened coagulative profile is further enhanced by the attenuation of fibrinolysis due to increased levels of plasminogen-activator inhibitor 1. Increased levels of PAI-1 contributed to the hypercoagulability by blocking the conversion of inactive plasminogen into active plasmin, thereby reducing the breakdown of fibrin based blood clots.

With that being said, this review focuses on the alterations that take place in the cerebrospinal fluid following an attack of acute bacterial meningitis from heightened activation of coagulation to an attenuated fibrinolysis.

Normal Anticoagulant Pathways

Activation of coagulation following inflammation is kept balanced by 3 physiological anticoagulative hemostatic pathways. These coagulation pathway inhibitors function primarily to limit excessive coagulation and include heparin-antithrombin pathway, tissue factor pathway inhibitor, and the protein c and s pathways [20]. The first line of defense, Heparin-antithrombin pathway consists of individual anticoagulative contributions from heparin and antithrombin. Heparin, a sulfated mucopolysaccharide glycoprotein with a molecular weight of 6.5 kDA, binds to lysyl residues on antithrombin resulting in the formation of a heparin-antithrombin complex. The Heparin-Antithrombin complex limits coagulation by binding to and inactivating a number of different coagulation factors, including factors 2a, 9a, 10a, 11a, and 12a [21]. Amongst these, thrombin and factor 10a are most sensitive to inhibition with a tenfold greater inhibition of thrombin compared to factor 10a. Further, vascular heparin-like proteoglycans facilitate antithrombin mediated inhibition of factors 10a, 9a and thrombin [22]. Decreased activity of coagulation factors 10a and thrombin result in reduced conversion of inactive fibrinogen to active fibrin, Impairing development of fibrin-blood clots. Apart from directly modulating expression of coagulation factors, antithrombin inhibits endotoxin-induced interleukin 6-formation by inflammatory mononuclear cells and endothelium, preventing corresponding elevations in thrombin [23,24]. Moreover, antithrombin interaction with cell surfaces appears to block NFkb nuclear translocation with the subsequent release of cytokines and induction of adhesion molecules by the vascular endothelium [25,26] (Table 1).

Protein C and S pathways form the second line of defense. Protein C, a vitamin K dependent plasma protein, circulates in the plasma as an inactive zymogen. Under physiological conditions, the protein C pathway begins with the binding of thrombin to thrombomodulin present on the endothelial cell membrane [27]. Thrombomodulin, a cofactor constitutively expressed on endothelial cell surfaces, interacts with and modifies the activity of thrombin [28]. Thrombomodulin, following the binding of thrombin, results in a marked increase in the activation of protein C. Subsequent binding of protein C to the endothelial protein C receptor further increases the activation of protein C [20]. Ultimately, protein C exerts its anticoagulant effect by proteolytic inactivation of coagulation factors 5a and 7a and by promoting fibrinolysis by inhibiting plasminogen activator 1 [29].

Finally, the tissue factor pathway inhibitor forms the final line of defense. TFPI, the main inhibitor of tissue factor-factor 7 complex, similarly functions to limit thrombin generation [20] by binding to tissue factor-factor 7 complex, inhibiting activation of tissue factor-mediated coagulation.

Activation of Coagulation

In bacterial meningitis, coagulation begins with the activation of the tissue factor pathway. The procoagulant status noted in bacterial meningitis stems from increased thrombin generation, mediated by the tissue factor pathway [30-32]. In meningococcal sepsis, plasma from these patients demonstrates the presence of micro-particles consisting of CD14 and tissue factor. In the same study, an overabundance of thrombin was generated, noted by increased plasma levels of thrombin [33]. An attempt to elucidate the source of tissue factor during bacterial meningitis points towards monocytes and endothelial cells. The role of TF expression by monocytes is supported from infant models of bacterial meningitis, where more than 60% of circulating monocytes were shown to express tissue factor on the cell surface [34]. Indeed, increased levels of tissue factor were noted on the surface of circulating monocytes in meningococcal infections. Monocytes with very high tissue factor levels, in excess of nearly 60-3000x fold higher compared to normal quiescent cells, displayed a greater propensity for fatal outcomes of bacterial meningitis [35,36]. In a comparative study of tissue factor expression in circulating monocytes of patients with meningococcal sepsis were noted to have higher levels of tissue factor in non-survivors compared to survivors, providing a correlation between tissue factor levels and disease severity of bacterial meningitis. (Østerud)

Tissue Factor is a 4.5 kDA protein constitutively expressed in different sites within the arterial vasculature, usually not in contact with the circulating blood [37,38]. The hidden expression of tissue factor renders it inactive unless it comes in contact with blood following either disruption of the vascular endothelium or through overproduction of TF by cells in the circulation [39-41]. In the setting of infections, more commonly, the overproduction of proinflammatory cytokines by the vascular endothelium provides a source of tissue factor rather than vascular wall disruption [42-44]. Tissue factor expression by the endothelial cells is mediated by endothelial cell activation [45-48]. Endothelial activation is induced by a number of mediators such as proinflammatory cytokines [49]. Upon endothelial activation by proinflammatory cytokines TNF-alpha and IL-1, tissue factor interacts with factor 7 forming a tissue factor-factor 7 complex [49,50]. Subsequently, the Tissue Factor-Factor 7 complex activates factor 7. Following generation of tissue factor, the intrinsic pathway is activated, thereby carrying out the procoagulant behavior of the blood. First, tissue factor binds to and activates factor 7; the tissue factor-factor 7 complex subsequently catalyzes the cleavage of inactive factor 10 to activate factor 10. Now, Activated factor 10, along with factor 5a, prothrombin and calcium forms thrombin. Next, thrombin proteolytically acts of fibrinogen to convert it to fibrin, resulting in the development of a blood clot. Inhibition of the common pathway of coagulation, in animal models, is observed following the use of antibodies directed against tissue factor. The cerebrospinal fluid of patients with pneumococcal meningitis demonstrates higher levels of soluble tissue factor [30,50] compared to normal subjects. Further, children with meningococcal septic shock were shown to have activation of the intrinsic pathway of coagulation, which is mediated by tissue factor-factor 7.

Expression of tissue factor by vascular endothelial cells, monocytes, and macrophages is driven by the influence of endotoxin and TNF-alpha released in response to an infectious/inflammatory stimuli [51,52]. In bacterial meningitis, apart from tissue factor expression on circulating monocytes, the vascular endothelium also upregulates expression of tissue factor [40,53]. Activation of endothelial cell procoagulant activity by Neisseria meningitis may follow exposure of the endothelium to certain bacterial structural proteins [54-56]. One such structural wall component of gram negative bacteria is lipopolysaccharide. Pathogenic strains of neisseria meningitidis when grown together with human monocytes lead to the production of tissue factor. However, the production of tissue factor between N.meningitidis colonies capable of producing endotoxin and colonies unable to produce endotoxin differed. Specifically, a 10,000 fold increase in tissue factor levels were observed in N.meningitidis colonies capable of producing endotoxin compared to colonies unable to produce endotoxin. (Prins). Further, human endothelial cells challenged with colony forming units of N.meningitidis were found to induce tissue factor expression. Additionally, bacterial culture filtrate experiments suggest that tissue factor expression on endothelial cells following N.meningitidis infection appears to be a function of shed lipopolysaccharide from the cell surface [57]. Experiments involving use of limulus amoebocyte lysate, present in bacterial culture filtrates and capable of reacting with the LPS membrane component of gram negative bacteria such as Neisseria Meningitidis, and polymyxin B provide supportive evidence for the role of LPS in procuring a procoagulant status of the blood [57]. Bacterial culture filtrate experiments pretreated with limulus amoebocyte lysate and polymyxin B demonstrated an overall decrease in procoagulant activity. Moreover, the decrease in procoagulant activity was correlated with a similar reduction of lipopolysaccharide levels in the blood. In addition, meningococcal strains treated with penicillin, gentamicin and functional serum (with active complement and antibody-mediated killing) resulted in cellular lysis and destruction [58-60]. Here also, loss of active meningococcal strains reduced procoagulant effect with a similar decrease in plasma lipopolysaccharide levels [60].

In conclusion, coagulation in bacterial meningitis is initiated by several factors expressed in response to the infecting microorganism. Proinflammatory cytokines, TNF and IL-1, induced by the vascular endothelium in response to bacterial cell wall components and gram negative bacterial lipopolysaccharide endotoxin elicit tissue factor expression by the endothelium. The potent effect of proinflammatory cytokines & cell wall components on endothelial cells may be a contributory detrimental cause of cerebrovascular consequences in bacterial meningitis.

Suppression of Natural Anticoagulant Pathways

Several pieces of experimental evidence highlight perturbations in heparin-antithrombin pathway in bacterial meningitis. Decreased levels of antithrombin were noted in the serum of patients with acute meningococcal infections [59,60]. Upon exposure of meningococci and lipopolysaccharide endotoxin to the vascular endothelium, binding of antithrombin to the endothelium as well as functional activity of antithrombin is suppressed in vitro models [61]. Similarly, in a comparative study between patients with meningococcal septicemia and patients without localized meningococcal infections, patients with septicemia were observed to have lower serum concentrations of antithrombin 3. In the same study, within the meningococcal septicemic group, patients with the lowest antithrombin 3 levels were observed to have a higher incidence of fatal outcomes [62]. In response to severe inflammatory responses, antithrombin levels may be decreased due to a combination of factors: Excessive consumption (due to continued thrombin generation), decreased synthesis (secondary to negative acute phase responses), or increased degradation (due to elastase release by activated neutrophils [63-65]. First, proinflammatory cytokines reduce the synthesis and expression of glycosaminoglycans by the endothelial cells [60]. Second, reduced glycosaminoglycans impair the inhibitory potential of AT due to a decreased availability of the cofactor [66]. Building on this, infusion of a very high concentration of recombinant antithrombin, markedly reduced plasma levels of IL-6 and IL-8. Consequently, decreased levels of IL-6 had an overall net favorable effect on the outcome of DIC [67]. Given that IL-6 expression appears to be a primary prerequisite responsible for markedly increased tissue factor expression and increased fibrin formation, decreased levels of IL-6 result in reduced tissue factor expression, decreased fibrin formation, and increased fibrinogen levels, all of which ultimately reduce the procoagulant status of the blood.

In acute meningococcal acute infections, unopposed upregulation of procoagulant pathways leads to increased procoagulant status by suppressing the protein C pathway [59,68]. Plasma levels of anticoagulant proteins-antithrombin, protein C and protein C, are reduced in meningococcal sepsis. Further, reduced amounts of activated protein C are produced due to a loss of thrombomodulin and endothelial protein C receptors from the endothelial surface. As noted above, protein C activation is markedly imparied in severe meningococcal sepsis, similarly correlated with a suppression of endothelial thrombomodulin-endothelial protein C receptor activity [69,70]. Protein C-dependent antithrombotic mechanisms- thrombin binding to thrombomodulin on the endothelial surface, thrombin-thrombomodulin complex binding to protein C, and protein C/S mediated inactivation of coagulation factors 5a, 8a and downregulation of plasminogen activator inhibitor, are defective in meningococcal sepsis [71,72]. Skin biopsy samples in patients with meningococcal sepsis highlight a repression of both thrombomodulin and endothelial protein C receptor expression [73,74]. In a comparative study between severely ill and moderately ill patients with meningococcal septicemia, lower plasma levels of protein C in were observed in severely ill patients at the time of admission, providing a correlation between more severe outcomes of bacterial meningitis in protein C deficient states [59]. Following endotoxin challenge, several animal studies show an increased susceptibility to fatal outcomes with protein C deficiency, but demonstrated favorable outcomes and improved mortality with protein C administration [70]. Along the same lines, immunohistochemistry studies performed in septic patients highlighted reduced production of activated protein C [59,75,76]. Perturbation of the protein C anticoagulant pathway begins with endothelial dysfunction. Proinflammatory cytokines and endotoxin released by the dysfunctional endothelium influence expression of components of the protein C anticoagulant pathway [70]. TNF-alpha and IL-1 Beta, released by the vascular endothelium, mediate downregulation of thrombomodulin expression by the vascular endothelium [77]. Similarly, LPS endotoxin elaborated by gram negative meningococci induces regression of thrombomodulin from the endothelial cell surface. Additionally, proinflammatory cytokines (TNF-alpha and IL-1 Beta) and endotoxin inhibit thrombomodulin and endothelial cell protein c receptor gene transcription by the vascular endothelium [72,78]. Further, neutrophil elastase, derived from infiltrating inflammatory cells, degrades thrombomodulin and initiates suppression of endothelial thrombomodulin expression (Table 2).

Suppression of natural anticoagulant pathways during the course of bacterial meningitis occurs in response to proinflammatory cytokines and lipopolysaccharide endotoxin. Downregulation of these pathways abborates protective anticoagulative mechanisms tipping the balance towards procoagulation, increasing the likelihood of subsequent thrombotic/embolic manifestations of the cerebral vasculature.

Blunting of the Fibrinolytic Response

Fibrinolysis is a protective enzymatic response mediated by the circulating proteases, helping to break down fibrin-based clots and reduce the risk of microthrombosis and thrombotic complications. Vascular endothelial cells participate in fibrinolysis through the synthesis and elaboration of plasminogen activators-tissue type and urokinase-type plasminogen activators. Plasminogen activators aid in the proteolytic cleavage of inactive plasminogen to active plasmin, which subsequently binds to the fibrin polymer and enzymatically degrades into smaller non functional monomers. The initial response of the fibrinolytic system to inflammation rests upon the activation of endothelial cells in response to proinflammatory cytokines TNF and IL-1 [79]. A healthy balance between TPA and PAI-1 are necessary prerequisites for the occurrence of fibrinolysis. Elevated levels of plasminogen activator inhibitor-1 in the cerebrospinal fluid have been reported in various infectious/inflammatory neurological disorders [80-82].

Serum levels of tPA and PAI-1 are increased in patients with bacterial meningitis [70,83]. In response to acute meningococcal infections, proinflammatory stimuli induce release of tissue/urokinase plasminogen activator, to initiate coagulation, and plasminogen activator inhibitor 1, to inhibit coagulation [84]. Proinflammatory mediated activation of endothelial cells results in the release of tissue type and urokinase plasminogen activators from intercellular endothelial stores. However, the initial activation of plasminogen activators with subsequent generation of plasmin is short lived and replaced by the delayed but sustained release of plasminogen activator inhibitor 1. Indeed, in patients with bacterial meningitis, plasminogen activator inhibitor-1 levels show a deviation from the normal. Levels of plasminogen activator inhibitor-1, an inhibitor of the thrombotic pathway, are increased in acute meningococcal infections [85]. Likewise, a similar increase in the level of plasminogen activator 1 is observed in patients with meningococcal sepsis. In the same study, Kornelisse RF highlighted a direct correlation between the levels of PAI-1 and severity of the disease, suggesting a loss of fibrinolytic response is associated with a more severe disease state [86]. Further, Aiuto, et al., observed an improvement in hemodynamic profile and skin perfusion in patients with meningococcal purpura fulminans following the infusion of recombinant tPA [87]. As noted above, given the increase in PAI-1 levels in acute meningococcal infections/meningococcal sepsis, a heightened procoagulant activity is observed due to the depletion of plasminogen activators. Additionally, a genetic polymorphism in the plasminogen activator inhibitor type1 promoter site influences the expression of fibrinolysis in the human population. On exposure to Neisseria meningitidis inflection, patients with a functional polymorphism of the 4G/4G gene at the PAI-1 promoter site demonstrated significant increases in PAI-1 levels compared to patients without a functional polymorphism [88]. The same patients with the 4G/4G gene polymorphism were observed to develop meningococcal septicemia with a 2 fold greater increase in the mortality rate, thereby supporting the idea that a loss of fibrinolysis in bacterial meningitis correlated with a more adverse outcome [89]. Consequently, fibrinolysis is inhibited resulting in impaired clearance of fibrin from the plasma and a hypercoagulable state develops.

The heightened procoagulant state induced by increased levels of PAI-1 and decreased levels of plasminogen activators is highlighted by experimental data involving mice following the administration of endotoxin, a potent inducer of fibrin formation. Mice abborated of PAI-1 expression, when challenged with endotoxin, displayed decreased formation of thrombi, compared to mice with normal PAI-1 expression, where significant thrombi were present following endotoxin administration. Further, mice with a deficiency of plasminogen activators were found to have more extensive fibrin deposition with macro thrombosis following exposure to endotoxins [90]. Moreover, endothelial cells cultures when co cultured with endotoxins and proinflammatory mediators (TNF-alpha and IL-1) induce synthesis and promote release of plasminogen activator-1 and suppress tissue plasminogen activator production. Similarly, exogenous infusion of interleukin 1B into baboons elicited a transient and early activation of fibrinolysis, which was subsequently rapidly suppressed by increased production of PAI-1, effectively blunting the fibrinolytic response to IL-6 [91,92].

The potent role of TNF in shutting off the fibrinolytic response to infection is demonstrated in limited studies; however the role of anti-TNF agents in thwarting such a response may provide further supportive evidence. Anti-TNF agents when exogenously administered in humans and chimpanzees fail to display a rise in the levels of tPA and PAI-1. Given the key regulatory role of PAI-1 in the fibrinolytic system, decreased levels of PAI-1 supports the role of TNF in contributing to the development of a blunted fibrinolytic response to infection.

Conclusion

Bacterial meningitis is a severe purulent infection of the subarachnoid leptomeninges caused primarily by Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae that has a deleterious effect on cerebrovascular structures. The exact cause of post-infective cerebrovascular sequelae following bacterial meningitis is unknown; however, several studies suggest that a coagulative system derangement is to blame. An imbalance between activation of coagulative processes and the inhibition of anticoagulant processes lead to a net increase in coagulation activation. Multiple lines of evidence suggest that in bacterial meningitis increased activation of coagulation activation and heightened inhibition of fibrinolysis inhibition procure a net procoagulant state. Coagulation in infections begins with the activation of the tissue factor pathway. Procoagulant status in inflammation is caused by increased thrombin generation, which is mediated by the tissue factor pathway in response to either vessel endothelial disruption or overproduction of tissue factor by circulating inflammatory cells. Normally, anticoagulant proteins in the bloodstream are responsible for limiting excessive coagulation and preventing the development of a procoagulant state in the blood. In bacterial meningitis, Three physiological anticoagulative hemostatic pathways acting to balance coagulation activation are suppressed: the heparin-antithrombin pathway, the tissue factor pathway inhibitor, and the protein c and s pathways. Finally, fibrinolysis is abborated through a short lived acute fibrinolytic response to bacterial infection and inflammation followed by a sustained late occurring anti-fibrinolytic response, abolishing off fibrinolysis and increasing the likelihood of developing post-infective cerebrovascular prothrombotic sequalue. The observation of heightened procoagulant activity relative to anticoagulant activity in patients with bacterial meningitis who develop cerebrovascular consequences highlights a vital role of the coagulation-anticoagulation system in bacterial meningitis.

References

1. van de Beek D, de Gans J, Tunkel AR, et al. (2006) Community-acquired bacterial meningitis in adults. N Engl J Med 354: 44-53.
2. Swartz MN (1984) Bacterial meningitis: More involved than just the meninges. N Engl J Med 311: 912-914.
3. Bruyn GAW, Kremer HPH, deMarie S, et al. (1989) Clinical evaluation of pneumococcal meningitis in adults over a twelve-year period. Eur J Clin Microbiol Infect Dis 8: 695-700.
4. Pfister HW (1989) Complicated purulent meningitis of the adult: persisting high mortality caused by vasculitis and increased intracranial pressure. Nervenarzt 60: 249-254.
5. Cairns H, Russell DS (1946) Cerebral arteritis and phlebitis in pneumococcal meningitis. J Pathol Bacteriol 58: 649-665.
6. Adams RD, Kubik CS, Bonner FJ (1948) The clinical and pathological aspects of influenza1 meningitis. Arch Pediatr 65: 354-376.
7. Dodge PR, Swartz MN: Bacterial meningitis: a review of selected aspects - Special neurologic problems, postmeningitic complications and clinicopathological correlations N Engl J Med 272: 1003-1010.
8. Ferris EJ, Rudikoff JC, Shapiro JH (1968) Cerebral angiography of bacterial infection. Radiology 90: 727-734.
9. Davis DO, Dilenge D, Schlaepper W (1970) Arterial dilatation in purulent meningitis. Case report. J Neurosurg 32: 112-115.
10. Leeds NE, Goldberg HI (1971) Angiographic manifestations in cerebral inflammatory disease. Radiology 98: 595-604.
11. Thomas VH, Hopkins IJ (1972) Arteriographic demonstration of vascular lesions in the study of neurologic deficit in advanced Haemophilus influenzae meningitis. Dev Med Child Neurol 14: 783-787.
12. Rainiondi AJ, DiRocco C (1978) Cerebral angiography in meningocerebral inflammatory diseases in infancy and childhood: A study of thirty-five cases. Neurosurgery 3: 37-44.
13. Igarashi M, Gilmartin RC, Gerald B, et al. (1984) Cerebral arteritis and bacterial meningitis. Arch Neurol 41: 531-535.
14. Paulson OB, Brodersen P, Hansen EL, et al. (1974) Kristensen HS: Regional cerebral blood flow, cerebral metabolic rate of oxygen, and cerebrospinal fluid acid-base variables in patients with acute meningitis and with acute encephalitis. Acta Med Scand 196: 191-198.
15. Ashwal S, Stringer W, Tomasi L, et al. (1990) Cerebral blood flow and carbon dioxide reactivity in children with bacterial meningitis. J Pediatr 117: 523-530.
16. Gordon I, Orton M, Hughes T, et al. (1991) Evaluation of regional cerebral perfusion (rCBF) in acute neurological disorders in childhood. J Nucl Med.
17. Weisfelt M, Determann R (2007) Procoagulant and fibrinolytic activity in cerebrospinal fluid from adults with bacterial meningitis. J Infect 54: 545-550.
18. Vergouwen MD, Schut ES, Troost D, et al. (2010) Diffuse cerebral intravascular coagulation and cerebral infarction in pneumococcal meningitis. Neurocrit Care 13: 217-227.
19. Kowalik MM, Smiatacz T, Hlebowicz M, et al. (2007) Coagulation, coma, and outcome in bacterial meningitis-An observational study of 38 adult cases. J Infect 55: 141-148.
20. Levi M, van der Poll T, Büller Harry R (2004) Bidirectional relation between inflammation and coagulation. Circulation 109: 2698-2704.
21. Rosenberg RD, Jordan IR, Armand GL, et al. (1997) Antithrombin III and its interactions with heparin. Antithrombin IIVIth International Congress on Thromb Haemost 38: 119.
22. Marcum JA, Rosenberg RD (1984) Anticoagulantly active heparin-like molecules from vascular tissue. Biochemistry 23: 1730-1737.
23. Okajima K (2001) Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 184: 258-274.
24. Murakami K, Okajima K, Uchiba M, et al. (1996) Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87: 642-647.
25. White B, Schmidt M, Murphy C, et al. (2000) Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of NF-kappa and TNF-alpha production in the THP-1 monocytic cell line. Br J Haematol 110: 130-134.
26. Hancock WW, Grey ST, Hau L, et al. (1995) Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 60: 1525-1532.
27. Esmon CT, Colman RW, Hirsh J, et al. (2001) Hemostasis and Thrombosis: Basic Principles and Clinical Practicen. Philadelphia: Lippincott Williams & Wilkins.
28. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, et al. (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA 93: 10212-10216.
29. JF Dhainaut, SB Yan, A Cariou, et al. (2002) Soluble thrombomodulin, plasma-derived unactivated protein C, and recombinant human activated protein C in sepsis. Crit Care Med 30: S318-S324.
30. Nieuwland R, Berckmans RJ, McGregor S, et al. (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95: 930-935.
31. Hellum M, Øvstebø R, Brusletto BS, et al. (2014) Microparticle-associated tissue factor activity correlates with plasma levels of bacterial lipopolysaccharides in meningococcal septic shock. Thromb Res 133: 507-514.
32. Wang JG, Manly D, Kirchhofer D, et al. (2009) Levels of microparticle tissue factor activity correlate with coagulation activation in endotoxemic mice. J Thromb Haemost 7: 1092-1098.
33. Hopkin DA (1978) Frapper fort ou frapper doucement: A gram-negative dilemma. Lancet 2: 1193-1194.
34. Mertsola J, Ramilo O, Mustafa MM, et al. (1989) Release of endotoxin after treatment of gram-negative bacterial meningitis. Pediatr Infect Dis J 8: 904-906.
35. Rivers RPA, Hathaway WE (1975) Studies on tissue factor activity and production by leucocytes of human umbilical cord and adult origin. Pediatr Res 9: 167-171.
36. Heyderman RS, Klein NJ, Daramola OA, et al. (1995) Modulation of the endothelial procoagulant response to lipopolysaccharide and tumour necrosis factor-a in vitro: evaluation of new treatment strategies. Inflamm Res 44: 275-280.
37. Arditi M, Ables L, Yogev R (1989) Cerebrospinal fluid endotoxin levels in children with H. influenzae meningitis before and after administration of intravenous ceftriaxone. J Infect Dis 160: 1005-1011.
38. Bevilacqua MP, Pober JS, Majeau GR, et al. (1986) Recombinant tumour necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83: 4533-4537.
39. Drake TA, Pang M (1988) Staphylococcus aureus induces tissue factor expression in cultured human cardiac valve endothelium. J Infect Dis 157: 749-756.
40. Geelen S, Bhattacharyya C, Tuomanen E (1992) Induction of procoagulant activity on human endothelial cells by Streptococcus pneumoniae. Infect Immun 60: 4179-4183.
41. Sporn LA, Haidaris PJ, Shi RJ, et al. (1994) Rickettsia rickettsii infection of cultured human endothelial cells induces tissue factor expression. Blood 83: 1527-1534.
42. Mazure G, JE Grundy, G Nygard, et al. (1994) Measles virus induction of human endothelial cell tissue factor procoagulant activity in vitro. J Gen Virol 75: 2863-2871.
43. Contrino J, Hair G, Kreutzer DL, et al. (1996) In situ detection of tissue factor in vascular endothelial cells: Correlation with the malignant phenotype of human breast disease. Nat Med 2: 209-215.
44. Ryan J, Brett J, Tijburg P, et al. (1992) Tumor necrosis factor-induced endothelial tissue factor is associated with subendothelial matrix vesicles but is not expressed on the apical surface. Blood 80: 966-974.
45. Virji M, Makepeace K, Peak I, et al. (1995) Functional implications of the expression of PilC proteins in meningococci. Mol Microbiol 16: 1087-1097.
46. Virji M, Kayhty H, Ferguson DJ, et al. (1991) The role of pili in the interactions of pathogenic Neisseria with cultured human endothelial cells. Mol Microbiol 5: 1831-1841.
47. Burrows M, Cabellos C, Prasad S, et al. (1992) Bacterial components and the pathophysiology of injury to the blood-brain barrier: Does cell wall add to the effects of endotoxin in gram-negative meningitis? J Infect Dis 165: s82-s85.
48. Mandrell RE, Less AJ, Sugai JV, et al. (1990) In-vitro and in-vivo modification of neisseria-gonorrhoeae lipooligosaccharide epitope structure by sialylation. J Exp Med 171: 1649-1664.
49. Pawlinski R, Mackman N (2010) Cellular sources of tissue factor in endotoxemia and sepsis. Thrombosis Research.
50. Østerud B, Flægstad T (1983) Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: Related to an unfavourable prognosis. Thromb Haemostas 49: 5-7.
51. Thompson SA, Wang LL, West A, et al. (1993) Neisseria meningitidis produces iron-regulated proteins related to the RTX family of exoproteins. J Bacteriol 175: 811-818.
52. Mustafa MM, Mertsola J, Ramilo P, et al. (1989) Increased endotoxin and interleukin-1-beta concentrations in cerebrospinal fluid of infants with coliform meningitis and ventriculitis associated with intraventricular gentamicin therapy. J Infect Dis 160: 891-895.
53. Wilcox JN, Smith KM, Schwartz SM, et al. (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 86: 2839-2843.
54. Nieuwland R, Berckmans RJ, McGregor S (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood 95: 930-935.
55. Drake TA, Cheng J, Chang A, et al. (1993) Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 142: 1458-1470.
56. Drake TA, Morrissey JH, Edgington TS (1989) Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am J Pathol 134: 1087-1097.
57. Colucci M, Balconi G, Lorenzet R (1983) Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest 71: 1893-1896.
58. Rivers RP, Hathaway WE, Weston WL (1975) The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 30: 311-316.
59. Parry GCN, Mackman N (1998) NF- 6B mediated transcription in human monocytic cells and endothelial cells. Trends Cardiovasc Med 8: 138-142.
60. Lindmark E, Tenno T, Siegbahn A (2000) Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 20: 2322-2328.
61. Brandtzaeg P, Sandset PM, Abildgaard U, et al. (1989) The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. Thromb Res 55: 459-470.
62. Fourrier F, Lestavel P, Chopin C, et al. (1990) Meningococcemia and purpura fulminans in adults: Acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates. Intensive Care Med 16: 121-124.
63. Heyderman RS, Klein NJ, Shennan GI, et al. (1992) Reduction of the anticoagulant activity of glycosaminoglycans on the surface of the vascular endothelium by endotoxin and neutrophils: Evaluation by an amidolytic assay. Thromb Res 67: 677-685.
64. Stark JM (1996) Veno-venous haemodiafiltration in meningococcal septicaemia. Lancet 347: 613-615.
65. Vary TC, Kimball SR (1992) Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 262: C445-C452.
66. Seitz R, Wolf M, Egbring R, et al. (1989) The disturbance of hemostasis in septic shock: Role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution. Eur J Haematol 43: 22-28.
67. Kobayashi M, Shimada K, Ozawa T (1990) 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 144: 383-390.
68. Adachi T, Yamazaki N, Tasaki H, et al. (1998) Changes in the heparin affinity of extracellular-superoxide dismutase in patients with coronary artery atherosclerosis. Biol Pharm Bull 21: 1090-1093.
69. Mavrommatis AC, Theodoridis T, Orfanidou A, et al. (2000) Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 28: 451-457.
70. Kornelisse RF, Hazelzet JA, Savelkoul HF, et al. (1996) The relationship between plasminogen activator inhibitor-1 and proinflammatory and counter inflammatory mediators in children with meningococcal septic shock. J Infect Dis 173: 1148-1156.
71. Moore KL, Andreoli SP, Esmon NL, et al. (1987) Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 79: 124-130.
72. Taylor FB Jr, Chang A, Esmon CT, et al. (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79: 918-925.
73. Hazelzet JA, Risseeuw-Appel IM, Kornelisse RF, et al. (1996) Age-related differences in outcome and severity of DIC in children with septic shock and purpura. Thromb Haemost 76: 932-938.
74. Sheth SB, Carvalho AC (1991) Protein S and C alterations in acutely ill patients. Am J Hematol 36: 14-19.
75. Faust SN, Levin M, Harrison OB, et al. (2001) Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 345: 408-416.
76. Nawroth PP, Stern DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163: 740-745.
77. Biemond BJ, Marcel Levi, Hugo Ten Cate, et al. (1995) Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: Effect of interventions in the cytokine and coagulation cascades. Clin Sci 88: 587-594.
78. Sutton R, Keohane ME, VanderBerg SR, et al. (1994) Plasminogen activator inhibitor-1 in the cerebrospinal fluid as an index of neurological disease. Blood Coagul Fibrinolysis 5: 167-171.
79. Akenami FO, Koskiniemi M, Farkkila M, et al. (1997) Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease. J Clin Pathol 50: 157-160.
80. Akenami FO, Siren V, Koskiniemi M, et al. (1996) Cerebrospinal fluid activity of tissue plasminogen activator in patients with neurological diseases. J Clin Pathol 49: 577-580.
81. Winkler F, Kastenbauer S, Koedel U, et al. (2002) Role of the urokinase plasminogen activator system in patients with bacterial meningitis. Neurology 59: 1350-1355.
82. Winkler F, Kastenbauer S, Koedel U, et al. (2002) Increased serum concentrations of tissue plasminogen activator correlate with an adverse clinical outcome in patients with bacterial meningitis. J Neurol Neurosurg Psychiatry 73: 456.
83. Brandtzaeg P, Brusletto B, Kierulf P, et al. (1990) Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 57: 271-278.
84. Horne MDK (1997) Recombinant tissue plasminogen activator restores perfusion in Meningococcal Purpura fulminans. Critical Care Medicine 25: 909.
85. Dawson SJ, Wiman B, Hamsten A, et al. (1993) The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 268: 10739-10745.
86. Hermans PW, Hibberd ML, Booy R, et al. (1999) 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 354: 556-560.
87. Yamamoto K, Loskutoff DJ (1996) 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 97: 2440-2451.
88. De Boer JP, Creasy AA, Chang A, et al. (1993) Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. Circ Shock.
89. Van Deventer SJH, Buller HR, ten Cate JW, et al. (1990) Experimental endotoxinaemia in humans: Analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 76: 2520-2526.
90. Bauer KA, ten Cate H, Barzegar S, et al. (1989) Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans. Blood 74: 165-172.
91. van der Poll T, Buller HR, ten Cate H, et al. (1990) Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 322: 1622-1627.
92. Levi M, Biemond BJ, ten Cate H, et al. (1994) Endotoxin-induced activation and inhibition of febrinolysis: Effects of various interventions in the cytokine and coagulation cascades in experimental endotoxemia in chimpanzees. Fibrinolysis 8: 26.