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.
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.
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AM
Schut
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A
Hyseni
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Adelmeijer
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JC
Meijers
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PG
De Groot
Ton Lisman, Surgical Research Laboratory, BA 44, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Tel.: +31 50 3619028, Fax: +31 50 363 2796, E-mail: j.a.lisman@umcg.nl.
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Lisman
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003029:Coagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D015942:Factor VIIa / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007267:Injections; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013552:Swine; D013917:Thrombin / Q000378:metabolism
D003029:Coagulants; D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa; D013917:Thrombin
Factor VIIa; haemophilia; platelet; prophylaxis; thrombin generation