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Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia.

Spronk HM, Braunschweig T, Rossaint R, Wüst DC, van Oerle R, Lauritzen B, Tolba R, Grottke O - PLoS ONE (2015)

Bottom Line: At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group.As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG.Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

ABSTRACT

Background: Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury.

Methods: A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6-33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes.

Results: Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138-1470] mL) relative to placebo (2677 [2337-3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.

Conclusion: Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.

No MeSH data available.


Related in: MedlinePlus

Haemoglobin (A), platelet count (B), fibrinogen (C) and thrombin-antithrombin (TAT; D) levels at baseline (Bl), after haemodilution (HD) and 10, 60 and 120 minutes after trauma.Data are presented as the median with inter-quartile ranges (IQR) for controls (solid black line, n = 7) and animals treated with 90 μg/kg rFVIIa (dotted black line, n = 7). For comparison, data from animals treated with either 180 or 360 μg/kg rFVIIa are presented as grey dotted lines. *P<0.05 control versus rFVIIa; #P<0.05 over time between baseline and haemodilution.
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pone.0113979.g001: Haemoglobin (A), platelet count (B), fibrinogen (C) and thrombin-antithrombin (TAT; D) levels at baseline (Bl), after haemodilution (HD) and 10, 60 and 120 minutes after trauma.Data are presented as the median with inter-quartile ranges (IQR) for controls (solid black line, n = 7) and animals treated with 90 μg/kg rFVIIa (dotted black line, n = 7). For comparison, data from animals treated with either 180 or 360 μg/kg rFVIIa are presented as grey dotted lines. *P<0.05 control versus rFVIIa; #P<0.05 over time between baseline and haemodilution.

Mentions: All baseline parameters were comparable among groups. As previously observed with this model [13,14], haemodilution produced a significant decrease in the concentration of erythrocytes, platelets, haemoglobin and fibrinogen (Fig 1A, 1B and 1C), whereas TAT levels remained unaltered (Fig 1D). Furthermore, haemodilution prolonged the PT and aPTT (Fig 2A and 2B). Whole-blood thromboelastometry parameters, determined by TEM analysis, indicated significantly decreased MCF and increased CFT (Fig 3C and 3B, respectively), whereas the dilution of coagulation factors resulted in a decrease in plasma thrombin generation (Fig 3E).


Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia.

Spronk HM, Braunschweig T, Rossaint R, Wüst DC, van Oerle R, Lauritzen B, Tolba R, Grottke O - PLoS ONE (2015)

Haemoglobin (A), platelet count (B), fibrinogen (C) and thrombin-antithrombin (TAT; D) levels at baseline (Bl), after haemodilution (HD) and 10, 60 and 120 minutes after trauma.Data are presented as the median with inter-quartile ranges (IQR) for controls (solid black line, n = 7) and animals treated with 90 μg/kg rFVIIa (dotted black line, n = 7). For comparison, data from animals treated with either 180 or 360 μg/kg rFVIIa are presented as grey dotted lines. *P<0.05 control versus rFVIIa; #P<0.05 over time between baseline and haemodilution.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476676&req=5

pone.0113979.g001: Haemoglobin (A), platelet count (B), fibrinogen (C) and thrombin-antithrombin (TAT; D) levels at baseline (Bl), after haemodilution (HD) and 10, 60 and 120 minutes after trauma.Data are presented as the median with inter-quartile ranges (IQR) for controls (solid black line, n = 7) and animals treated with 90 μg/kg rFVIIa (dotted black line, n = 7). For comparison, data from animals treated with either 180 or 360 μg/kg rFVIIa are presented as grey dotted lines. *P<0.05 control versus rFVIIa; #P<0.05 over time between baseline and haemodilution.
Mentions: All baseline parameters were comparable among groups. As previously observed with this model [13,14], haemodilution produced a significant decrease in the concentration of erythrocytes, platelets, haemoglobin and fibrinogen (Fig 1A, 1B and 1C), whereas TAT levels remained unaltered (Fig 1D). Furthermore, haemodilution prolonged the PT and aPTT (Fig 2A and 2B). Whole-blood thromboelastometry parameters, determined by TEM analysis, indicated significantly decreased MCF and increased CFT (Fig 3C and 3B, respectively), whereas the dilution of coagulation factors resulted in a decrease in plasma thrombin generation (Fig 3E).

Bottom Line: At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group.As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG.Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

ABSTRACT

Background: Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury.

Methods: A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6-33.4°C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 μg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes.

Results: Total blood loss was significantly lower following 90 μg/kg rFVIIa (1206 [1138-1470] mL) relative to placebo (2677 [2337-3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events.

Conclusion: Early administration of 90 μg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa.

No MeSH data available.


Related in: MedlinePlus