Download PDF
Thromb Haemost 2014; 112(02): 304-310
DOI: 10.1160/TH13-09-0798
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Sustained pro-haemostatic activity of rFVIIa in plasma and platelets in non-bleeding pigs may explain the efficacy of a once-daily prophylaxis in humans

Anne Marieke Schut
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
,
Agon Hyseni
2   Department of Clinical Chemistry and Haematology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands
,
Jelle Adelmeijer
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
,
Joost C. M. Meijers
3   Departments of Experimental Vascular Medicine and Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Philip G. de Groot
2   Department of Clinical Chemistry and Haematology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands
,
Ton Lisman
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
› Author Affiliations Financial support: This study was supported in part by an unrestricted educational grant from Novo Nordisk.
Further Information

Publication History

Received: 26 September 2013

Accepted after major revision: 08 March 2014

Publication Date:
21 November 2017 (online)

    Permissions and Reprints

Summary

Recombinant factor VIIa (rFVIIa) is registered for treatment of inhibitor-complicated haemophilia, and a once-daily prophylactic administration of rFVIIa is successful in reducing the number of bleeding events. This suggests that a single rFVIIa dose has a pro-haemostatic effect up to 24 hours (h), which is difficult to explain given its half-life of 2 h. In this study, six pigs received a 90 µg/kg rFVIIa bolus. Plasma was collected and platelets were isolated at various time points up to 48 h, and analysed for FVIIa levels and associated haemostatic activity. Elevated plasma FVIIa levels were detected up to 24 h post-administration (36 (32–56) mU/ml [median (interquartile range [IQR]), 24 h] vs 2 (2–14) mU/ml [baseline]). Corresponding prothrombin time (PT) values remained shortened compared to baseline until 24 h post-administration (9.4 (9.3–9.9) seconds (s) [24 h] vs 10.5 (10.2–11.0) s [baseline], p ≤0.01). The lag time in thrombin generation testing as well as clotting times in plasma-based assays were shortened up to 12 or 24 h post-administration, respectively (lag times 1.8 (1.7–2.1) minutes (min) [12 h] vs 2.3 (2.3–2.6) min [baseline], p ≤0.01 and clotting times 3.8 (3.2–3.9) min [24 h] vs 5.2 (4.6–5.5) min [baseline], p ≤0.001). Platelet FVIIa levels were elevated up to 48 h (7.7 (3.4–9.0) ng VIIa/mg actin [48 h] vs 2.5 (0.7–4.8) ng VIIa/mg actin [baseline]). In conclusion, elevated and haemostatically active plasma and platelet FVIIa levels are detectable up to 24–48 h following rFVIIa administration in pigs. This prolonged pro-haemostatic effect of FVIIa may explain the prophylactic efficacy of a once-daily rFVIIa treatment.

Keywords

Factor VIIa - haemophilia - prophylaxis - platelet - thrombin generation
 

  • References

  • 1 Baudo F, Collins P, Huth-Kuhne A. et al. Management of bleeding in acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120: 39-46.
    CrossrefPubMedGoogle Scholar
  • 2 Lusher JM, Roberts HR, Davignon G. et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia 1998; 04: 790-798.
    CrossrefPubMedGoogle Scholar
  • 3 Salaj P, Brabec P, Penka M. et al. Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HaemoRec registry data from the Czech Republic. Haemophilia 2009; 15: 752-759.
    CrossrefPubMedGoogle Scholar
  • 4 Sørensen B, Dargaud Y, Kenet G. et al. On-demand treatment of bleeds in haemophilia patients with inhibitors: strategies for securing and maintaining predictable efficacy with recombinant activated factor VII. Haemophilia 2012; 18: 255-262.
    CrossrefPubMedGoogle Scholar
  • 5 Young G, Cooper DL, Gut RZ. et al. Dosing and effectiveness of recombinant activated factor VII (rFVIIA) in congenital haemophilia with inhibitors by bleed type and location: the experience of the Haemophilia and Thrombosis Research Society (HTRS) Registry (2004-2008). Haemophilia 2012; 18: 990-996.
    CrossrefPubMedGoogle Scholar
  • 6 Lisman T, De Groot PG. Mechanism of action of recombinant factor VIIa. J.Thromb.Haemost 2003; 01: 1138-1139.
    CrossrefPubMedGoogle Scholar
  • 7 Lisman T, Adelmeijer J, Cauwenberghs S. et al. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost 2005; 03: 742-751.
    CrossrefPubMedGoogle Scholar
  • 8 Lisman T, Mosnier LO, Lambert T. et al. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe haemophilia A. Blood 2002; 99: 175-179.
    CrossrefPubMedGoogle Scholar
  • 9 Young G, Auerswald G, Jimenez-Yuste V. et al. When should prophylaxis therapy in inhibitor patients be considered?. Haemophilia 2011; 17: e849-857.
    CrossrefPubMedGoogle Scholar
  • 10 Teitel JM, Sholzberg M. Current status and future prospects for the prophylactic management of haemophilia patients with inhibitor antibodies. Blood Rev 2013; 27: 103-109.
    CrossrefPubMedGoogle Scholar
  • 11 Konkle BA, Ebbesen LS, Erhardtsen E. et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in haemophilia patients with inhibitors. J Thromb Haemost 2007; 05: 1904-1913.
    CrossrefPubMedGoogle Scholar
  • 12 Young G, Auerswald G, Jimenez-Yuste V. et al. PRO-PACT: retrospective observational study on the prophylactic use of recombinant factor VIIa in haemophilia patients with inhibitors. Thromb Res 2012; 130: 864-870.
    CrossrefPubMedGoogle Scholar
  • 13 Mathijssen NC, Masereeuw R, Verbeek K. et al. Prophylactic effect of recombinant factor VIIa in factor VII deficient patients. Br J Haematol 2004; 125: 494-499.
    CrossrefPubMedGoogle Scholar
  • 14 Mariani G, Dolce A, Napolitano M. et al. Invasive procedures and minor surgery in factor VII deficiency. Haemophilia 2012; 18: e63-65.
    CrossrefPubMedGoogle Scholar
  • 15 Gopalakrishnan R, Hedner U, Clark C. et al. rFVIIa transported from the blood stream into tissues is functionally active. J Thromb Haemost 2010; 08: 2318-2321.
    CrossrefPubMedGoogle Scholar
  • 16 Gopalakrishnan R, Hedner U, Ghosh S. et al. Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa). J Thromb Haemost 2010; 08: 301-310.
    CrossrefPubMedGoogle Scholar
  • 17 Lopez-Vilchez I, Tusell J, Hedner U. et al. Traffic of rFVIIa through endothelial cells and redistribution into subendothelium: implications for a prolonged haemostatic effect. J Coag Disorders 2009; 01: 1-6.
    PubMedGoogle Scholar
  • 18 Beeby TL, Chasseaud LF, Taylor T. et al. Distribution of the recombinant coagulation factor 125I–rFVIIa in rats. Thromb Haemost 1993; 70: 465-468.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Lopez-Vilchez I, Hedner U, Altisent C. et al. Redistribution and haemostatic action of recombinant activated factor VII associated with platelets. Am J Pathol 2011; 178: 2938-2948.
    CrossrefPubMedGoogle Scholar
  • 20 Peterson JE, Zurakowski D, Italiano Jr. JE. et al. Normal ranges of angiogenesis regulatory proteins in human platelets. Am J Hematol 2010; 85: 487-493.
    CrossrefPubMedGoogle Scholar
  • 21 Bijsterveld NR, Moons AH, Boekholdt SM. et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-2554.
    CrossrefPubMedGoogle Scholar
  • 22 Friederich PW, Levi M, Bauer KA. et al. Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects. Circulation 2001; 103: 2555-2559.
    CrossrefPubMedGoogle Scholar
  • 23 Villar A, Aronis S, Morfini M. et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A. Haemophilia 2004; 10: 352-359.
    CrossrefPubMedGoogle Scholar
  • 24 Lindley CM, Sawyer WT, Macik BG. et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 1994; 55: 638-648.
    CrossrefPubMedGoogle Scholar
  • 25 Levi M, Peters M, Büller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review. Crit Care Med 2005; 33: 883-890.
    CrossrefPubMedGoogle Scholar
  • 26 Tiede A, Friedrich U, Stenmo C. et al. Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa). J Thromb Haemost 2011; 09: 1191-1199.
    CrossrefPubMedGoogle Scholar