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

Anthony E. Pusateri; Kathy L. Ryan; Angel V. Delgado; Raul S. Martinez; John M. Uscilowicz; Douglas S. Cortez; Uri Martinowitz

doi:10.1160/TH04-03-0200

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(02): 275-283
DOI: 10.1160/TH04-03-0200

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

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

Authors

Anthony E. Pusateri

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
Kathy L. Ryan

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
Angel V. Delgado

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
Raul S. Martinez

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
John M. Uscilowicz

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
Douglas S. Cortez

¹U.S. Army Institute of Surgical Research, Fort Sam Houston, Texas, USA
Uri Martinowitz

²Israel National Haemophilia Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Abstract

Summary

This study examined dose-response relationships between activated recombinant factorVII (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 μg/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 α -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 μg/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.

Keywords

Pharmacological haemostasis - liver injury - trauma - thromboelastography

Volltext

Referenzen

References
1 Hedner U. Recombinant activated factor VII as a universal haemostatic agent.. Blood Coag Fibrinol 1998; 9: S147-S152.
2 Martinowitz U, Kenet G, Lubetski A. et al Possible role of recombinant activated factor VII (rFVIIa) in the control of hemorrhage associated with massive trauma.. Can J Anesth 2002; 49: S15-S20.
3 Martinowitz U, Kenet G, Segal G. et al Recombinant factor VII for adjunctive hemorrhage control in trauma.. J Trauma 2001; 51: 431-9.
4 Martinowitz U, Holcomb JB, Pusateri AE. et al Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries.. J Trauma 2001; 50: 721-9.
5 Schreiber MA, Holcomb JB, Hedner U. et al The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries.. J Trauma 2002; 53: 252-9.
6 Jeroukhimov I, Jewelewicz D, Zaias J. et al Early injection of high-dose recombinant factor VIIa decreases blood loss and prolongs time from injury to death in experimental liver injury.. J Trauma 2002; 53: 1053-7.
7 Lynn M, Jerokhimov I, Jewelewicz D. et al Early use of recombinant factor VIIa improves mean arterial pressure and may potentially decrease mortality in experimental hemorrhagic shock: a pilot study.. J Trauma 2002; 52: 703-7.
8 Schreiber MA, Holcomb JB, Hedner U. et al The effect of recombinant factor VIIa on non-coagulopathic pigs with grade V liver injuries.. J Am Coll Surg 2003; 196: 691-7.
9 Monroe DM, Hoffman M, Oliver JA. et al Platelet activity of high-dose factor VIIa is independent of tissue factor.. Br J Haemat 1997; 99: 542-7.
10 Butenas S, Brummel KE, Bouchard BA. et al How factor VIIa works in haemophilia.. J Thromb Haemost 2003; 1: 1158-60.
11 Janson TL, Stormorken H, Prydz H. Species specificity of tissue thromboplastin.. Haemostasis 1984; 14: 440-4.
12 Kase F. The effect of homo- and heterologous thromboplastins on plasmas of man, seven mammalian and two avian species: a comparative study.. Comp Bioch Physiol 1978; 61A: 65-8.
13 Girard P, Nony P, Erhardtsen E. et al Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acencoumarol.. Thromb Haemost 1998; 80: 109-13.
14 Holcomb JB, Pusateri AE, Harris RA. et al Effect of dry fibrin sealant dressings versus gauze packing on blood loss in grade V liver injuries in resuscitated swine.. J Trauma 1999; 46: 49-57.
15 Ravanat C, Freund M, Dol F. et al Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species.. Blood Coag Fibrinol 1995; 6: 446-55.
16 Chandler WL. The thromboelastograph and the thromboelastograph technique.. Sem Thromb Haemost 1995; 21 (Suppl. 04) 1-6.
17 Sorenson B, Johansen P, Christiansen K. et al Whole blood coagulation thromboelastographic profiles employing minimal tissue factor activation.. J Thromb Haemost 2003; 1: 551-8.
18 SAS/STAT User’s Guide. 4th ed Cary, NC: SAD Institute, Inc; 1990
19 Bernstein DE, Jeffers L, Erhardtsen E. et al Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a preliminary report.. Gastroenterology 1997; 113: 1930-7.
20 Erhardtsen E, Nony P, Dechavanne M. et al The effect of recombinant factor VIIa (NovoSeven ^TM) in healthy volunteers receiving acencoumarol to an international normalization ratio above 2.0.. Blood Coag Fibrinol 1998; 9: 741-8.
21 Friedrich PW, Henny CP, Messelink EJ. et al Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial.. Lancet 2003; 361: 201-5.
22 Hedner U, Ingerslev J. Clinical use of recombinant FVIIa (rFVIIa).. Transfus Sci 1998; 19: 163-76.
23 Hendriks HGD, Meijer K, deWolf JTM. et al Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation.. Blood Coag Fibrinol 2002; 13: 309-13.
24 Bajaj SP, Joist JH. New insights into how blood clots: implications for the use of aPTT and PT as coagulation screening tests and in monitoring of anticoagulant therapy.. Sem Thromb Haemost 1999; 25: 407-18.
25 Telgt DS, Macik BG, McCord DM. et al Mechanism by which recombinant factor VIIa shortens the aPTT: activation of factor X in the absence of tissue factor.. Thromb Res 1989; 56: 603-9.
26 Sutor AH. The bleeding time in pediatrics.. Sem Thromb Haemost 1998; 24: 531-4.
27 Sondeen JL, Pusateri AE, Hedner U. et al Recombinant factor VIIa increases the pressure at which rebleeding occurs in porcine uncontrolled aortic hemorrhage model.. Shock 2004; 22: 163-8.