Thrombelastography indicates limitations of animal models of trauma-induced coagulopathy

Abstract

Introduction Thrombelastography (TEG) has been used to characterize the coagulation changes associated with injury and shock. Animal models developed to investigate trauma-induced coagulopathy (TIC) have failed to produce excessive bleeding. We hypothesize that a native TEG will demonstrate marked differences in humans compared to these experimental models, which explains the difficulties in reproducing a clinically relevant coagulopathy in animal models. Methods Whole blood was collected from 138 healthy human volunteers, 25 swine and 66 Sprague Dawley rats prior to experimentation. Citrated native TEGs were conducted on each whole blood sample within 2 hours of collection. The clot initiation (R-time, min), angle (degrees), MA (mm), and LY30 (%) were analyzed and contrasted between species with data represented as the median and 25th to 75th quartile range. Difference between species was conducted with a Kruskall Wallis test with alpha adjusted with a Bonferroni correction for multiple comparisons (alpha = 0.016). Results Median R-Time (clot initiation) 14.65 min (IQR: 13.2–16.3 min) for humans, 5.7 (4.9–8.8) for pigs, and 5.2 (4.4–6) for rodents. Humans had longer R-Times than both pigs (p<0.0001) and rats (p<0.0001); pigs were not different from rats (p= 0.4439). Angle (fibrin cross-linking) was 42.3 degrees (IQR: 37.5–50.2) for humans, 71.7 (64.3–75.6) for pigs, and 61.8 (56.8–66.7) for rats. Humans had reduced Angle compared to both pigs (p<0.0001) and rats (p<0.0001); pigs were not different from rats (p=0.6052). MA (clot strength) was 55.5 mm (IQR: 52.0–59.5 for humans, 72.5 (70.4–75.5) for pigs, and 66.5 (56.5–68.6) for rats. Humans had reduced MA compared to both pigs (p<0.0001) and rats (p<0.0001); pigs were not different from rats (p=0.0161). LY30 (fibrinolysis) was 1.5 % (IQR: 0.975–2.5) for humans, 3.3 (1.9–4.3) for pigs, and 0.5 (0.1–1.2) for rats. Humans had a lesser LY30 than pigs (p=0.0062) and a greater LY30 than rats (p<0.0001), and pigs had a greater LY30 than rats (p<0.0001). Conclusion Humans, swine, and rodents have distinctly different coagulation systems, when evaluated by citrated native TEG. Animals are hypercoagulable with rapid clotting times and clots strengths nearly 50% stronger than humans. These coagulation differences indicate the limitations of previous models of TIC in producing coagulation abnormalities associated with increased bleeding. The inherent hypercoagulable baseline tendencies of these animals may result in subclinical biochemical changes that are not detected by conventional TEG and should be taken into consideration when extrapolated to clinical medicine.

Redefining postinjury fibrinolysis phenotypes using two viscoelastic assays

“…The addition of tissue factor to TEG or EXTEM has been thought to reduce the sensitivity of both tests by masking coagulation abnormalities. 32,33 For this reason, the use of native assays (without activators), for example, remains relevant for use in research owing to its ability to dampen false signals to determine fibrinolysis and therefore the cutoff points, which predict transfusion needs in TIC. 32 However, a recent comparison of native citrated kaolin, and rapid TEG suggested that transfusion thresholds can be used with confidence without concern for masking coagulation abnormalities by using an activated TEG, as there was significant overlap in the performance of the these three TEG assays.…”

Development of Optimized Tissue-Factor-Targeted Peptide Amphiphile Nanofibers to Slow Noncompressible Torso Hemorrhage

“…Taken together, these values provide insight into the activity of coagulation factors in the blood sample. Heparin was used as an anticoagulant because rats are more prone to coagulation at baseline and we were unable to determine treatment effect without anticoagulation of the sample, as clotting occurred too rapidly . Citrate was not used as an anticoagulant as studies looking at TF-dependent reactions are impaired by citrate chelation .…”

“…Heparin was used as an anticoagulant because rats are more prone to coagulation at baseline and we were unable to determine treatment effect without anticoagulation of the sample, as clotting occurred too rapidly. 28 Citrate was not used as an anticoagulant as studies looking at TF-dependent reactions are impaired by citrate chelation. 29 Furthermore, the high levels of calcium required to overcome citrate chelation can negatively affect nanofiber formation.…”

FFP maintains normal coagulation while Kcentra induces a hypercoagulable state in a porcine model of pulmonary contusion and hemorrhagic shock

“…It is a known phenomenon that swine are hypercoagulable at baseline. 18 This hypercoagulable state has been shown to be augmented through the act of instrumentation. 19 Thus, instrumentation alone may have induced the coagulopathy seen in the control animals.…”