Double-blinded, placebo-controlled study of early tranexamic acid treatment in swine uncontrolled hemorrhage model

Sondeen, Jill L.; Hanson, Margaret A.; Prince, M. Dale; Guzman, Rodolfo de; Polykratis, I. Amy; Aden, James K; Andrew, P.; Dubick, Michael A.

doi:10.1097/ta.0000000000000860

Cited by 7 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although PG has not been performed to understand species differences in fibrinolysis, it is still possible to compare our PG results with those previously published. Most fibrinolysis assays performed on blood samples from different animal species are based on clot lysis time measurements and demonstrate large intra-species variability 8,9,11 . Nonetheless, some of our results can be compared to and are consistent with previously published studies where fibrinolysis was induced by tPA.…”

Section: Discussionmentioning

confidence: 99%

“…There are limited studies that compare blood coagulation and fibrinolysis in various animals under the same conditions 10-17 . TG assays are sensitive for use in clinical and basic research studies; however, fibrinolysis testing primarily focused on clot lysis time, is often insufficiently sensitive and demonstrates high data variability 8,9,11 . Since 2011, several hemostasis assays have focused on simultaneous registration of thrombin and plasmin generation (PG) in plasma using tissue factor (TF) and tissue plasminogen activator (tPA), respectively 18-21 .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interspecies comparison of simultaneous thrombin and plasmin generation

Tarandovskiy

Shin

Baek

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Animal models of hemostasis are often extrapolated to humans; however, only a few studies have compared coagulation and fibrinolysis across species. Simultaneous thrombin (TG) and plasmin (PG) generation is useful to assessing coagulation and fibrinolysis within the same sample. In this study, we performed simultaneous TG and PG analysis in blood plasma samples from humans and 6 species commonly evaluated in pre-clinical research. TG and PG were investigated in male and female donor platelet-poor plasmas (PPP) obtained from 28 healthy humans, 10 baboons, 12 rhesus monkeys, 20 Yorkshire pigs, 20 Sprague-Dawley rats, 10 New Zealand White rabbits and 14 Hartley guinea pigs. The continuous generation of the 7-amino-4-methylcoumarin (AMC) from substrates specific to thrombin or plasmin was monitored. The thrombin and plasmin concentration peak heights (PH) and production rates (PR) were calculated. TG and PG parameters from baboon and rhesus macaque plasma approximated that of humans. The other species differed significantly from both human and nonhuman primates. For example, swine and rat plasmas demonstrated similar TG, but swine plasmas did not generate plasmin. TG and PG parameters from Guinea pig samples were extremely low, while rabbit plasmas showed variable PG curves demonstrating one or two peaks with low and high PR values, respectively. Correlations between PH and PR values were significant with the exceptions of human PG, baboon TG, rat TG and Guinea pig PG. These findings are informative to pre-clinical animal species selection and optimization of coagulation and fibrinolysis translational research.Animal models of hemostasis and thrombosis are widely used in basic and pharmaceutical research 1 . Results are frequently extrapolated to humans; however, data obtained from animal models often falls short of accurate predictions in human response 2 . Further, assays have limited relevant comparisons of hemostasis in human blood with that of differing animal species. The novel global assays of hemostasis such as thrombin generation (TG) and thromboelastography (TEG) or thromboelastometry (ROTEM) provide an opportunity to assess similarities in coagulation and fibrinolysis ex vivo on blood obtained from different species. Although TG and thromboelastographic assays are often used for analysis of hemostasis in different animals 1,3-9 , comparison among different species is rarely made. There are limited studies that compare blood coagulation and fibrinolysis in various animals under the same conditions 10-17 . TG assays are sensitive for use in clinical and basic research studies; however, fibrinolysis testing primarily focused on clot lysis time, is often insufficiently sensitive and demonstrates high data variability 8,9,11 . Since 2011, several hemostasis assays have focused on simultaneous registration of thrombin and plasmin generation (PG) in plasma using tissue factor (TF) and tissue plasminogen activator (tPA), respectively 18-21 . These approaches suggest high sensitivity to assessment of coagulation an...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Interspecies comparison of simultaneous thrombin and plasmin generation

Tarandovskiy

Shin

Baek

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Although IV TXA has some efficacy in hemorrhagic shock, 16 this has not been consistently reported. 22 Other protease inhibitors with differing effects on the coagulation system have also been found to be effective when given enterally to treat experimental shock, 23, 24 and the limited patient information on the subject appears to support the hypothesis that the protease inhibitors must be given enterally to display marked clinical improvement. 25 …”

Section: Discussionmentioning

confidence: 99%

Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock

Santamaria

Aletti

et al. 2017

Journal of Trauma and Acute Care Surgery

View full text Add to dashboard Cite

BACKGROUND Irreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically-mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically. Maintenance of blood pressure is achieved in part by α1 receptor modulation, which may be affected by vasoactive factors; we thus hypothesized that decreases in hemodynamic stability and vasopressor response in shock can be prevented by enteral protease inhibition. METHODS Rats were exposed to experimental hemorrhagic shock (35 mmHg mean arterial blood pressure for 2 hrs, followed by reperfusion for 2 hrs) and challenged with phenylephrine (2 μg/kg) at discrete intervals to measure vasopressor responsiveness. A second group of animals received enteral injections with the protease inhibitor tranexamic acid (TXA) (127 mM) along the small intestine and cecum one hour following induction of hemorrhagic shock. RESULTS Blood pressure response (duration and amplitude) to phenylephrine after reperfusion was significantly attenuated in animals subjected to hemorrhagic shock compared to baseline and control non-shocked animals, and was restored to near baseline by enteral TXA. Arteries from shocked animals also displayed decreased α1 receptor density with restoration to baseline following enteral TXA treatment. In vitro, rat shock plasma decreased α1 receptor density in smooth muscle cells, which was also abrogated by enteral TXA treatment. CONCLUSIONS Results from this study demonstrate that experimental hemorrhagic shock leads to decreased response to the α1-selective agonist phenylephrine and decreased α1 receptor density via circulating shock factors. These changes are mitigated by enteral TXA with correspondingly improved hemodynamics. Proteolytic inhibition in the lumen of the small intestine improves hemodynamics in hemorrhagic shock, possibly by restoring α1 adrenergic functionality necessary to maintain systemic blood pressure and perfusion.

show abstract

“…tranexamic acid proved useful in our experience, with the operator noting markedly less hemorrhage. Our dose of 50 mg kg À1 was about five times higher than the recommended dose for human subjects and also high compared with the few reports of its use in pigs (Sondeen et al 2016;Zentai et al 2016). However, we did not see any obvious adverse effects in this (nonsurvival) study; to our knowledge, little is known about whether the pharmacodynamic and pharmacokinetic parameters for tranexamic acid are similar between pigs and humans.…”

Section: Discussionmentioning

confidence: 51%

“…Our dose of 50 mg kg −1 was about five times higher than the recommended dose for human subjects and also high compared with the few reports of its use in pigs (Sondeen et al. ; Zentai et al. ).…”

Section: Discussionmentioning

confidence: 52%

Segmental innervation of the Göttingen minipig hind body. An electrophysiological study

et al. 2018

View full text Add to dashboard Cite

The Göttingen minipig is being used increasingly in biomedical research. The anatomical structure of the porcine peripheral nervous system has been extensively characterized, but no equivalent to the dermatome map, which is so valuable in human neurophysiological research, has been created. We characterized the medullar segmental skin and muscle innervations of the minipig hind body, using neurophysiological methodology. Six adult minipigs underwent unilateral laminectomy from L2 to S3, exposing the nerve roots. The skin of the hind part of the body was divided into 36 predefined fields, based on anatomical landmarks for consistent reproducibility. We recorded the evoked potential in each exposed nerve root L2-S3 for cutaneous stimulation of each skin field, mapping the sensory innervation of the entire hind body. We subsequently recorded the motor response in seven predefined muscles during sequential stimulation of the L2-S3 nerve roots. We obtained a clear sensory evoked potential in the nerve roots during stimulation of the skin fields, allowing us to map the sensory innervation of the minipig hind body. Neurophysiological data from skin stimulation and muscle recordings enabled us to map the sensory innervation of the Göttingen minipig hind body and provide information about muscular innervation. The skin fields were sensory innervated by more than one root. The muscles each had one dominant root with minor contribution from neighboring roots. This is consistent with experimental data from human studies.

show abstract

Double-blinded, placebo-controlled study of early tranexamic acid treatment in swine uncontrolled hemorrhage model

Abstract: TXA did not reduce BL, even though TXA was antifibrinolytic in the pigs. The possibility remains that the pig is highly resistant to fibrinolysis and not a good model to study the effects of antifibrinolytics or that fibrinolysis is not a major factor in bleeding from splenic injury.

Cited by 7 publications

References 21 publications

Interspecies comparison of simultaneous thrombin and plasmin generation

Interspecies comparison of simultaneous thrombin and plasmin generation

Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock

Segmental innervation of the Göttingen minipig hind body. An electrophysiological study

Contact Info

Product

Resources

About