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

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.

Application of a granular mineral-based hemostatic agent (QuikClot) to reduce blood loss after grade V liver injury in swine.

BACKGROUND: Uncontrolled hemorrhage is a leading cause of death in cases of trauma. Many products currently are under development to control traumatic bleeding. One such Food and Drug Administration (FDA)-approved product is QuikClot. This study determined the efficacy of QuikClot, a hemostatic agent, in reducing blood loss and mortality in a standardized model of severe liver injury as well as the consequences of its use. METHODS: Swine received either QuikClot or gauze treatment after induction of grade V liver injuries. Hemostasis, blood loss, resuscitation volume, 60-minute survival, and peak tissue temperatures were measured. RESULTS: Hemostasis was improved with QuikClot (p < 0.05), and resuscitation volume was consequently reduced (p < 0.05). Posttreatment blood loss was reduced (p < 0.01) with QuikClot (1,397 mL), as compared with gauze (5,338 mL). The survival rate was seven of eight in the QuikClot group and one of eight in the gauze group (p < 0.01). Peak temperature at the tissue interface was increased (p < 0.01) with QuikClot (93.3 +/- 10.5 degrees C), as compared with gauze (37.5 +/- 6.5 degrees C). QuikClot use was associated with both macro- and microscopic tissue damage caused by the exothermic reaction. CONCLUSION: QuikClot provides hemostasis and decreased mortality in this model of severe liver injury. The beneficial aspects of QuikClot treatment must, however, be balanced against the tissue-damaging effects of the exothermic reaction.

Structural design of the dry fibrin sealant dressing and its impact on the hemostatic efficacy of the product.

We compared the hemostatic efficacy of a production version of a dry fibrin sealant dressing (DFSD) to a prototype that was previously successful in large animal studies. The results were used to improve manufacturing processes. Grade-V liver injuries were induced in swine and treated with gauze sponges (GAU), the prototype dressings (DFSD-1), or the scaled-up production version dressings (DFSD-2 in experiment 1 and DFSD-3 in experiment 2). Blood loss, hemostasis, resuscitation volume, and 60-min survival were quantified. In experiment 1, the DFSD-1 treatment reduced blood loss (p < 0.01), increased hemostasis at 4 min (p < 0.05), and improved survival (p < 0.05) compared with GAU. The DFSHD-2 decreased blood loss (p < 0.05) but did not increase hemostasis or survival significantly. Based on these results, manufacturing processes were altered, producing DFSD-3. In experiment 2, the DFSD-1 and DFSD-3 were equally effective in reducing blood loss (p < 0.01) and resuscitation volume (p < 0.05) compared with GAU. Hemostasis occurred more frequently in both the DFSD-1 and DFSD-3 groups (p < 0.01) compared with GAU. The structural design of DFSD-2 did not meet the efficacy requirement for release of the product. The subsequent change incorporated in DFSD-3 improved all hemostatic parameters of the dressings equal to those of the prototype product.

Advanced hemostatic dressing development program: animal model selection criteria and results of a study of nine hemostatic dressings in a model of severe large venous hemorrhage and hepatic injury in Swine.

BACKGROUND: An advanced hemostatic dressing is needed to augment current methods for the control of life-threatening hemorrhage. A systematic approach to the study of dressings is described. We studied the effects of nine hemostatic dressings on blood loss using a model of severe venous hemorrhage and hepatic injury in swine. METHODS: Swine were treated using one of nine hemostatic dressings. Dressings used the following primary active ingredients: microfibrillar collagen, oxidized cellulose, thrombin, fibrinogen, propyl gallate, aluminum sulfate, and fully acetylated poly-N-acetyl glucosamine. Standardized liver injuries were induced, dressings were applied, and resuscitation was initiated. Blood loss, hemostasis, and 60-minute survival were quantified. RESULTS: The American Red Cross hemostatic dressing (fibrinogen and thrombin) reduced (p < 0.01) posttreatment blood loss (366 mL; 95% confidence interval, 175-762 mL) and increased (p < 0.05) the percentage of animals in which hemostasis was attained (73%), compared with gauze controls (2,973 mL; 95% confidence interval, 1,414-6,102 mL and 0%, respectively). No other dressing was effective. The number of vessels lacerated was positively related to pretreatment blood loss and negatively related to hemostasis. CONCLUSION: The hemorrhage model allowed differentiation among topical hemostatic agents for severe hemorrhage. The American Red Cross hemostatic dressing was effective and warrants further development.