Discrepant Fibrinolytic Response in Plasma and Whole Blood during Experimental Endotoxemia in Healthy Volunteers

Ostrowski, Sisse Rye; Berg, Ronan M. G.; Windeløv, Nis A.; Meyer, Mechthild; Plovsing, Ronni R.; Møller, Kirsten; Johansson, Pär I.

doi:10.1371/journal.pone.0059368

Cited by 34 publications

(33 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies of high-dose endotoxin infusion in healthy volunteers to model systemic inflammation have demonstrated an increase in core temperature and an acute hypercoagulability with indications of endothelial cell activation [34]. In a similar study of low-dose endotoxin infusion, we observed an induction of SIRS, hypercoagulability by TEG, and reduced platelet aggregation by Multiplate that was paralleled by increases in circulating tissue plasminogen activator [35]. Considering that hyperthermia is associated with hypercoagulability both in the present study, where no infection exists, and in the endotoxin study, it is tempting to consider hyperthermia as a contributor to the hypercoagulability that is seen in response to SIRS and sepsis [1].…”

Section: Discussionmentioning

confidence: 74%

Hypercoagulability in response to elevated body temperature and central hypovolemia

Meyer¹,

Ostrowski²,

Overgaard³

et al. 2013

Journal of Surgical Research

Self Cite

View full text Add to dashboard Cite

Background Coagulation abnormalities contribute to poor outcomes in critically ill patients. In trauma patients exposed to a hot environment, a systemic inflammatory response syndrome, elevated body temperature, and reduced central blood volume occur in parallel with changes in hemostasis and endothelial damage. The objective of this study was to evaluate whether experimentally elevated body temperature and reduced central blood volume (CBV) per se affects hemostasis and endothelial activation. Methods Eleven healthy volunteers were subjected to heat stress, sufficient to elevate core temperature, and progressive reductions in CBV by lower body negative pressure (LBNP). Changes in hemostasis were evaluated by whole blood haemostatic assays, standard hematologic tests and by plasma biomarkers of coagulation and endothelial activation/disruption. Results Elevated body temperature and decreased CBV resulted in coagulation activation evidenced by shortened activated partial tromboplastin time (−9% [IQR −7; −4]), thrombelastography: reduced reaction time (−15% [−24; −4]) and increased maximum amplitude (+4% (2; 6)), all P < 0.05. Increased fibrinolysis was documented by elevation of D-dimer (+53% (12; 59), P = 0.016). Plasma adrenaline and noradrenaline increased 198% (83; 346) and 234% (174; 363) respectively (P = 0.006 and P = 0.003). Conclusions This experiment revealed emerging hypercoagulability in response to elevated body temperature and decreased CBV, whereas no effect on the endothelium was observed. We hypothesize that elevated body temperature and reduced CBV contributes to hypercoagulability, possibly due to moderate sympathetic activation, in critically ill patients and speculate that normalization of body temperature and CBV may attenuate this hypercoagulable response.

show abstract

Section: Discussionmentioning

confidence: 74%

Hypercoagulability in response to elevated body temperature and central hypovolemia

Meyer¹,

Ostrowski²,

Overgaard³

et al. 2013

Journal of Surgical Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…However these effects were not appreciated until 3 hours after injection with evidence of inflammation of the pancreas and systemic levels of TUCA were not analyzed. This observation may have been an adaptive response to inflammation, which has previously been shown to shutdown fibrinolysis [24]. It would not be unexpected that TUCA has tissue dependent effects on fibrinolysis.…”

Section: Discussionmentioning

confidence: 78%

Shock releases bile acidinducing platelet inhibition and fibrinolysis

Wiener

Moore

et al. 2015

Journal of Surgical Research

View full text Add to dashboard Cite

Introduction Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis. Methods TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM to 750 μM was utilized due to biologic relevance. Whole blood mixtures were assayed using thrombelastography (TEG) for clot strength (MA) and fibrinolysis (LY30) quantification. Tranexamic acid (TXA) was used to block plasmin mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model. Results Fibrinolysis increased, when 750 μM TUCA was added to whole blood (median LY30 0.08 to 5.7, p=0.010), and clot strength decreased (median MA of 53.3 to 43.8, p=0.010). The addition of TXA, to a 750 μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 vs. with 2.7) and the decrease in clot strength (MA: without 48.2 vs. with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100 μM TUCA. Rats had a median 52-fold increase in TUCA, following a shock state that stayed elevated following resuscitation. Conclusion TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.

show abstract

“…26 Idell et al 27 in 1991 identified tissue factor as the perpetrator for excessive fibrin deposition that remained present for weeks because of decreased fibrinolysis activity. Ostrowski et al 28 recently used TEG to demonstrate fibrinolysis shutdown in healthy volunteers by administrations of endotoxin, suggesting the cross talk between inflammation and fibrinolysis. These observations are not new, as it was appreciated in the 1960s that “stress” impacts the fibrinolytic system and that there is a complex interaction with inflammation.…”

Section: Discussionmentioning

confidence: 99%

Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown

Moore

González³

et al. 2014

Journal of Trauma and Acute Care Surgery

388

254

View full text Add to dashboard Cite

BACKGROUND Fibrinolysis is a physiologic process maintaining patency of the microvasculature. Maladaptive overactivation of this essential function (hyperfibrinolysis) is proposed as a pathologic mechanism of trauma-induced coagulopathy. Conversely, the shutdown of fibrinolysis has also been observed as a pathologic phenomenon. We hypothesize that there is a level of fibrinolysis between these two extremes that have a survival benefit for the severely injured patients. METHODS Thrombelastography and clinical data were prospectively collected on trauma patients admitted to our Level I trauma center from 2010 to 2013. Patients with an Injury Severity Score (ISS) of 15 or greater were evaluated. The percentage of fibrinolysis at 30 minutes by thrombelastography was used to stratify three groups as follows: hyperfibrinolysis (Q3%), physiologic (0.081-2.9%), and shutdown (0-0.08%). The threshold for hyperfibrinolysis was based on existing literature. The remaining groups were established on a cutoff of 0.8%, determined by the highest point of specificity and sensitivity for mortality on a receiver operating characteristic curve. RESULTS One hundred eighty patients were included in the study. The median age was 42 years (interquartile range [IQR], 28Y55 years), 70% were male, and 21% had penetrating injuries. The median ISS was 29 (IQR, 22-36), and the median base deficit was 9 mEq/L (IQR, 6-13 mEq/L). Distribution of fibrinolysis was as follows: shutdown, 64% (115 of 180); physiologic, 18% (32 of 180); and hyperfibrinolysis, 18% (33 of 180). Mortality rates were lower for the physiologic group (3%) compared with the hyperfibrinolysis (44%) and shutdown (17%) groups (p = 0.001). CONCLUSION We have identified a U-shaped distribution of death related to the fibrinolysis system in response to major trauma, with a nadir in mortality, with level of fibrinolysis after 30 minutes between 0.81% and 2.9%. Exogenous inhibition of the fibrinolysis system in severely injured patients requires careful selection, as it may have an adverse affect on survival. LEVEL OF EVIDENCE Prognostic study, level III.

show abstract

Discrepant Fibrinolytic Response in Plasma and Whole Blood during Experimental Endotoxemia in Healthy Volunteers

Cited by 34 publications

References 93 publications

Hypercoagulability in response to elevated body temperature and central hypovolemia

Hypercoagulability in response to elevated body temperature and central hypovolemia

Shock releases bile acidinducing platelet inhibition and fibrinolysis

Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown

Contact Info

Product

Resources

About