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; Agon Hyseni; Jelle Adelmeijer; Joost C. M. Meijers; Philip G. de Groot; Ton Lisman

doi:10.1160/TH13-09-0798

Thrombosis and Haemostasis, Table of Contents

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

Authors

Anne Marieke Schut

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Agon Hyseni

²Department of Clinical Chemistry and Haematology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands
Jelle Adelmeijer

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
Joost C. M. Meijers

³Departments of Experimental Vascular Medicine and Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
Philip G. de Groot

²Department of Clinical Chemistry and Haematology, Utrecht University, University Medical Center Utrecht, Utrecht, the Netherlands
Ton Lisman

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

Abstract

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

Full Text

References

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