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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

Contribution of rFVIIa to plasma thrombin generation assessed by the calibrated automated thrombogram and triggered with 0.25 (squares) or 4 (circles) pM tissue factor (TF) and 4 μM phospholipids.Left panel: Maximum thrombin generation presented as the peak height (A). Right panel: endogenous thrombin potential (ETP; B).
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pone.0113979.g005: Contribution of rFVIIa to plasma thrombin generation assessed by the calibrated automated thrombogram and triggered with 0.25 (squares) or 4 (circles) pM tissue factor (TF) and 4 μM phospholipids.Left panel: Maximum thrombin generation presented as the peak height (A). Right panel: endogenous thrombin potential (ETP; B).

Mentions: To assess whether the effect of rFVIIa treatment can be monitored by thrombin generation, the CAT assay was optimised with regard to phospholipid, TF and rFVIIa concentrations. rFVIIa was added to plasma obtained from healthy volunteers in increasing concentrations from 0 to 80 nM. Phospholipid concentrations varied between 0 and 6.4 μM, and the optimal concentration was 4 μM (data not shown). Varying the TF concentration between 0.25 and 4 pM revealed more pronounced thrombin generation by rFVIIa at 0.25 pM TF than at 4 pM TF, as indicated by peak height and ETP (Fig 5A and 5B). Based on these observations, thrombin generation in pig plasma samples was assessed using 0.25 pM TF and 4 μM phospholipids. After haemodilution, thrombin generation triggered by 0.25 pM TF was characterised by a shortening of the lag time (from 4.64 minutes [4.24–5.21] to 3.36 minutes [3.19–3.65], P<0.05) and a decrease in peak height from 81 nM (76–90) to 66 nM (58–75) (P<0.05), whereas the endogenous thrombin potential (ETP) was comparable between the two time points (270 nM [260–298] versus 318 nM [301–365], P = 0.06) (Fig 3D, 3E and 3F). Thrombin generation remained low after trauma and was comparable to that after haemodilution. The lag time decreased upon rFVIIa administration at 30, 60, 90 and 120 minutes after trauma. For the combined time points, the lag time shortened on average from 2.90 minutes (2.43–310) to 1.87 minutes (1.66–2.01) (all time points P<0.05). Despite a small significant difference in peak height between 30 and 120 minutes, the overall potential for thrombin generation (ETP) was not influenced by treatment with rFVIIa in trauma.


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)

Contribution of rFVIIa to plasma thrombin generation assessed by the calibrated automated thrombogram and triggered with 0.25 (squares) or 4 (circles) pM tissue factor (TF) and 4 μM phospholipids.Left panel: Maximum thrombin generation presented as the peak height (A). Right panel: endogenous thrombin potential (ETP; B).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0113979.g005: Contribution of rFVIIa to plasma thrombin generation assessed by the calibrated automated thrombogram and triggered with 0.25 (squares) or 4 (circles) pM tissue factor (TF) and 4 μM phospholipids.Left panel: Maximum thrombin generation presented as the peak height (A). Right panel: endogenous thrombin potential (ETP; B).
Mentions: To assess whether the effect of rFVIIa treatment can be monitored by thrombin generation, the CAT assay was optimised with regard to phospholipid, TF and rFVIIa concentrations. rFVIIa was added to plasma obtained from healthy volunteers in increasing concentrations from 0 to 80 nM. Phospholipid concentrations varied between 0 and 6.4 μM, and the optimal concentration was 4 μM (data not shown). Varying the TF concentration between 0.25 and 4 pM revealed more pronounced thrombin generation by rFVIIa at 0.25 pM TF than at 4 pM TF, as indicated by peak height and ETP (Fig 5A and 5B). Based on these observations, thrombin generation in pig plasma samples was assessed using 0.25 pM TF and 4 μM phospholipids. After haemodilution, thrombin generation triggered by 0.25 pM TF was characterised by a shortening of the lag time (from 4.64 minutes [4.24–5.21] to 3.36 minutes [3.19–3.65], P<0.05) and a decrease in peak height from 81 nM (76–90) to 66 nM (58–75) (P<0.05), whereas the endogenous thrombin potential (ETP) was comparable between the two time points (270 nM [260–298] versus 318 nM [301–365], P = 0.06) (Fig 3D, 3E and 3F). Thrombin generation remained low after trauma and was comparable to that after haemodilution. The lag time decreased upon rFVIIa administration at 30, 60, 90 and 120 minutes after trauma. For the combined time points, the lag time shortened on average from 2.90 minutes (2.43–310) to 1.87 minutes (1.66–2.01) (all time points P<0.05). Despite a small significant difference in peak height between 30 and 120 minutes, the overall potential for thrombin generation (ETP) was not influenced by treatment with rFVIIa in trauma.

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