Tissue Factor Pathway Inhibitor and Thrombin Activatable Fibrinolytic Inhibitor Plasma Levels following Burnand Septic Injuries in Rats

Ravindranath, Thyyar; Gotō, Masakatsu; Demir, Muzaffer; Töbü, Mahmut; Kujawski, Maciej; Hoppensteadt, Debra; Samonte, V.; Iqbal, Omer; Sayeed, M. M.; Fareed, Jawed

doi:10.1177/107602960401000411

Cited by 9 publications

(14 citation statements)

References 19 publications

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“…Hepatic TAFI mRNA expression rapidly increased after endotoxin administration to rodents (19,20) and TAFI plasma levels were elevated during peritonitis induced by cecal ligation and puncture in rats (41). In line with these previous studies, we found that TAFI mRNA was expressed in the liver and became up-regulated during E. coli-induced peritonitis, which was accompanied by elevated TAFI protein levels in liver and plasma.…”

Section: Discussionsupporting

confidence: 78%

Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

Renckens¹,

Roelofs

Horst

et al. 2005

The Journal of Immunology

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Thrombin-activatable fibrinolysis inhibitor (TAFI), also known as carboxypeptidase R, has been implicated as an important negative regulator of the fibrinolytic system. In addition, TAFI is able to inactivate inflammatory peptides such as complement factors C3a and C5a. To determine the role of TAFI in the hemostatic and innate immune response to abdominal sepsis, TAFI gene-deficient (TAFI−/−) and normal wild-type mice received an i.p. injection with Escherichia coli. Liver TAFI mRNA and TAFI protein concentrations increased during sepsis. In contrast to the presumptive role of TAFI as a natural inhibitor of fibrinolysis, TAFI−/− mice did not show any difference in E. coli-induced activation of coagulation or fibrinolysis, as measured by plasma levels of thrombin-anti-thrombin complexes and D-dimer and the extent of fibrin depositions in lung and liver tissues. However, TAFI−/− mice were protected from liver necrosis as indicated by histopathology and clinical chemistry. Furthermore, TAFI−/− mice displayed an altered immune response to sepsis, as indicated by an increased neutrophil recruitment to the peritoneal cavity and a transiently increased bacterial outgrowth together with higher plasma TNF-α and IL-6 levels. These data argue against an important part for TAFI in the regulation of the procoagulant-fibrinolytic balance in sepsis and reveals a thus far unknown role of TAFI in the occurrence of hepatic necrosis.

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Section: Discussionsupporting

confidence: 78%

Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

Renckens¹,

Roelofs

Horst

et al. 2005

The Journal of Immunology

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“…21 Ravindranath et al examined the changes in plasma tissue factor pathway inhibitor (TFPI) and thrombin activatable fibrinolytic inhibitor (TAFI) levels in a rat model of burn and septic injuries by treating mice with 30% total body surface area cutaneous scald burn injury and caecal ligation and puncture (CLP). 29 The levels of TFPI decreased significantly at 24 hours in burn, CLP, and burn þ CLP groups, followed by incomplete rebound recovery at 72 hours in all three groups. Conversely, TAFI levels increased significantly at 24-and 72-hour time points in all three groups, suggesting that burn, sepsis, and their combined injuries might substantially perturb the coagulation cascade toward a procoagulant condition.…”

Section: Pathophysiology and Biochemistry Of Disseminated Intravasculmentioning

confidence: 87%

Disseminated Intravascular Coagulation in Burn Injury

Lippi¹,

Ippolito²,

Cervellin³

2010

Semin Thromb Hemost

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Disseminated intravascular coagulation (DIC) is a complex and multifaceted disorder characterized by the activation of coagulation and fibrinolytic pathways, consumption of coagulation factors, and depletion of coagulation regulatory proteins. The introduction into the circulation of cellular debris characterized by strong thromboplastic activity due to tissue factor exposition or release (in or from burned tissues), which can thereby activate extrinsic pathway of coagulation system and trigger massive thrombin generation when present in sufficient concentration, represents the most plausible biological explanation to support the development of intravascular coagulation in patients with burn injury. Severe burns left untreated might also lead to an immunological and inflammatory response (activation of the complement cascade), which can amplify fibrinolysis and blood clotting. Overall, the real prevalence of DIC in patients with burns is as yet unclear. Postmortem, retrospective, and even longitudinal investigations are in fact biased by several factors, such as the objective difficulty to establish whether DIC might have occurred as a primary complication of burns or rather as a consequence of other superimposed pathologies (e.g., sepsis, multiple organ failure), the different diagnostic criteria for assessing DIC, and the heterogeneity of the patient samples studied. Nevertheless, the current scientific evidence is consistent with the hypothesis that biochemical changes suggestive for DIC (hypercoagulability, hypo- and hyperfibrinolysis) are commonplace in patients with burn trauma, and their severity increases exponentially with the severity of injury. Overt DIC seems to occur especially in critically ill burn patients or in those with severe burns (up to third degree) and large involvement of body surface area, in whom an appropriate therapy might be effective to prevent the otherwise fulminant course. Although early prophylaxis with antithrombin concentrates holds promises, especially in the acute phase of thermal injury, larger clinical trials are needed to confirm the benefit of this therapeutic approach.

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“…In a septic rat model with Pseudomonas aeruginosa, the inhibition of TAFIa reduced the systemic inflammatory response, thus suggesting that TAFI plays an important role in the deterioration of organ dysfunction in sepsis [10]. In a rat model of a sepsis-complicating burn injury, TAFI was elevated after 24 and 72 h, confirming the close link between inflammation and coagulation [11]. Septic patients, as well as healthy study subjects with low-grade lipopolysaccharide (LPS)-induced endotoxemia, showed decreased levels of TAFI [12,13], and in polytraumatized patients, TAFI levels inversely correlated with the inflammation-associated development of complications [14].…”

Section: Introductionmentioning

confidence: 84%

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

Vollrath

Marzi

Herminghaus

et al. 2020

JCM

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Background: Sepsis frequently occurs after major trauma and is closely associated with dysregulations in the inflammatory/complement and coagulation system. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a dual role as an anti-fibrinolytic and anti-inflammatory factor by downregulating complement anaphylatoxin C5a. The purpose of this study was to investigate the association between TAFI and C5a levels and the development of post-traumatic sepsis. Furthermore, the predictive potential of both TAFI and C5a to indicate sepsis occurrence in polytraumatized patients was assessed. Methods: Upon admission to the emergency department (ED) and daily for the subsequent ten days, circulating levels of TAFI and C5a were determined in 48 severely injured trauma patients (injury severity score (ISS) ≥ 16). Frequency matching according to the ISS in septic vs. non-septic patients was performed. Trauma and physiologic characteristics, as well as outcomes, were assessed. Statistical correlation analyses and cut-off values for predicting sepsis were calculated. Results: Fourteen patients developed sepsis, while 34 patients did not show any signs of sepsis (no sepsis). Overall injury severity, as well as demographic parameters, were comparable between both groups (ISS: 25.78 ± 2.36 no sepsis vs. 23.46 ± 2.79 sepsis). Septic patients had significantly increased C5a levels (21.62 ± 3.14 vs. 13.40 ± 1.29 ng/mL; p < 0.05) and reduced TAFI levels upon admission to the ED (40,951 ± 5637 vs. 61,865 ± 4370 ng/mL; p < 0.05) compared to the no sepsis group. Negative correlations between TAFI and C5a (p = 0.0104) and TAFI and lactate (p = 0.0423) and positive correlations between C5a and lactate (p = 0.0173), as well as C5a and the respiratory rate (p = 0.0266), were found. In addition, correlation analyses of both TAFI and C5a with the sequential (sepsis-related) organ failure assessment (SOFA) score have confirmed their potential as early sepsis biomarkers. Cut-off values for predicting sepsis were 54,857 ng/mL for TAFI with an area under the curve (AUC) of 0.7550 (p = 0.032) and 17 ng/mL for C5a with an AUC of 0.7286 (p = 0.034). Conclusion: The development of sepsis is associated with early decreased TAFI and increased C5a levels after major trauma. Both elevated C5a and decreased TAFI may serve as promising predictive factors for the development of sepsis after polytrauma.

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Tissue Factor Pathway Inhibitor and Thrombin Activatable Fibrinolytic Inhibitor Plasma Levels following Burnand Septic Injuries in Rats

Cited by 9 publications

References 19 publications

Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

Disseminated Intravascular Coagulation in Burn Injury

Post-Traumatic Sepsis Is Associated with Increased C5a and Decreased TAFI Levels

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