Effects of increasing doses of activated recombinant factor VII on haemostatic parameters in swine

Abstract

This study examined dose-response relationships between activated recombinant factor VII (rFVIIa) and (1) in vivo haemostasis and (2) in vitro measures of coagulation and platelet function. Anesthetized swine were used. Ear bleeding time (BT) was measured and blood was sampled following increasing doses of rFVIIa (0, 90, 180, 360 and 720 microg/kg; n=6) or saline (n=6). BT was not altered by rFVIIa. Prothrombin time (PT) using standard or pig-specific methods was decreased by rFVIIa. Activated clotting time (ACT) was decreased by rFVIIa. Thromboelastography using collagen (COLL) or pig thromboplastin (p-ThP) as agonist demonstrated shorter reaction times, shortened time to reach maximum velocity of clot formation, and increased alpha-angle in the presence of rFVIIa. rFVIIa dosing increased maximum velocity of clot formation when p-ThP was used to initiate the reaction but not when COLL was used. rFVIIa at the highest concentration increased maximum amplitude when COLL was used to initiate the reaction. Platelet aggregation was not altered by rFVIIa. Following completion of the dose escalation phase, a severe liver injury was produced. rFVIIa altered neither blood loss nor survival time following injury but improved mean arterial pressure. A small increase in systemic thrombin-antithrombin III complex occurred after administration of rFVIIa at doses of 180 microg/kg and above. However, there was no histological evidence of intravascular coagulation after rFVIIa administration. In summary, rFVIIa activity was detectable in vitro but did not change haemostasis in normal swine.

Prothrombin complex concentrate mitigates diffuse bleeding after cardiopulmonary bypass in a porcine model

“…For instance, PT measured with a porcine-specific assay is greater by over three-fold than with the standard assay designed for human specimens. 3739 The porcine-specific assay revealed a nearly 50% prolongation of PT during hypothermia, while no effect was detectable by the standard assay method. 39 It is possible that the use of the standard assay may account for the relatively small impact of CPB on PT in the present study, despite the substantial increase in blood loss observed after CPB and saline infusion.…”

“…Thus, despite an over three-fold absolute PT difference at baseline, the average relative shortening of PT by 90 µg kg −1 human rFVIIa was comparable when measured by standard assay (64%) vs the porcine-specific method (51%). 37 …”

Effect of Recombinant FVIIa in Hypothermic, Coagulopathic Pigs with Liver Injuries

“…All such studies, but one, have made use of liver injuries and associated hemorrhage. Four studies have involved normothermic pigs, an absence of hemodilution prior to injury, and did not supplement rFVIIa therapy with liver packing when liver injury was involved (Tables 8a,c; Lynn et al, 2002;Jeroukhimov et al, 2002;Schreiber et al, 2003;Pusateri et al, 2003). In one of these studies, resuscitation was used beginning 15 min postinjury (Schreiber et al, 2003), and at a rate lower than that used in the current study (100 mil/min).…”

“…Similarly, normothermic, non-coagulopathic pigs were administered rFVlla (0, 90, 180, 360, and 720 jig/kg) during an 80 min period, and at 20 minutes after the last dose (100 minutes after the initial dose), pigs were subjected to a Grade V liver injury. Survival time was monitored for up to 1 hour with no resuscitation (Pusateri et al, 2003). There was no effect of rFVIIa on blood loss, survival time or percent survival even though in vitro procedures to monitor coagulation (PT, activated clotting time, and TEGassociated R-time) were enhanced (Pusateri et al, 2003).…”

“…Survival time was monitored for up to 1 hour with no resuscitation (Pusateri et al, 2003). There was no effect of rFVIIa on blood loss, survival time or percent survival even though in vitro procedures to monitor coagulation (PT, activated clotting time, and TEGassociated R-time) were enhanced (Pusateri et al, 2003).…”