Time Course of Hemostatic Abnormalities in Sepsis and its Relation to Outcome

Lorente, José A.; García-Frade, Luis Javier; Landín, Luis; Pablo, Raúl de; Torrado, C. Alegre; Renes, Emilio; García-Avello, Ángel

doi:10.1378/chest.103.5.1536

Cited by 304 publications

(214 citation statements)

References 42 publications

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“…Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death (Ref. 153). From a therapeutic perspective, treatment with recombinant human activated protein C significantly reduced mortality in patients with severe sepsis (Ref.…”

Section: Coagulation Modulatorsmentioning

confidence: 99%

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Geisbert

Hensley

2004

Expert Rev. Mol. Med.

112

106

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Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicised isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.

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Section: Coagulation Modulatorsmentioning

confidence: 99%

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Geisbert

Hensley

2004

Expert Rev. Mol. Med.

112

106

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“…2 This hypercoagulability may be related to an impaired fibrinolytic system, to the presence of lupuslike anticoagulant antibodies, [3][4][5][6][7] or to increased levels of proinflammatory procoagulant cytokines (interleukin 6, tumor necrosis factor-␣). 8 Thalidomide is an active agent in refractory MM 9 and is associated with a very low incidence of DVT (2%) when used as a single agent. 10 However, when thalidomide is part of a combination that includes other cytotoxic agents, the incidence of DVT increases substantially.…”

Section: Introductionmentioning

confidence: 99%

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Zangari

Siegel

Barlogie

et al. 2002

Blood

237

135

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Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphanide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P ‫؍‬ .02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing

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“…In sepsis patients, PAI-1 concentrations predict lethality in a very sensitive manner (3,4). Moreover, a (4G/ 5G) promoter deletion/insertion polymorphism in the PAI-1 gene has been found to influence the risk of the development of septic shock, and to be associated with a poor outcome in patients with meningococcal sepsis (5,6).…”

mentioning

confidence: 99%

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

Renckens

Pater

Poll

2006

The Journal of Immunology

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Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1−/−) mice demonstrated strongly elevated plasma IFN-γ concentrations after injection of either LPS or SEB. In addition, PAI-1−/− splenocytes released more IFN-γ after incubation with LPS or SEB than Wt splenocytes. Both PAI-1−/− CD4+ and CD8+ T cells produced more IFN-γ upon stimulation with SEB. LPS-induced IFN-γ release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN-γ release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN-γ release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.

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Time Course of Hemostatic Abnormalities in Sepsis and its Relation to Outcome

Cited by 304 publications

References 42 publications

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy

Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B

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