Hemophilia Research Today is a free monthly online journal that collates and summarizes the latest research about Hemophilia, including details on genetics, causes, symptoms, blood transfusion. | ||||||||
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Enhanced efficacy of recombinant FVIII in noncovalent complex with PEGylated liposome in hemophilia A mice.Pan J, Liu T, Kim JY, Zhu D, Patel C, Cui ZH, Zhang X, Newgren JO, Reames A, Canivel D, Jesmok G, Pierce GF, Sommer JM, Jiang H Bayer HealthCare LLC, Richmond, CA 94806, USA. Recombinant FVIII formulated in PEG-ylated liposomes (rFVIII-PEG-Lip) was reported to increase the bleed-free days from 7 to 13 days (at 35 IU/kg rFVIII) in severe hemophilia A patients. To understand the underlying mechanism, we sought to recapitulate its efficacy in hemophilia A mice. Animals treated with rFVIII-PEG-Lip achieved approximately 30% higher survival relative to rFVIII after tail vein transection inflicted 24 hours after dosing. The efficacy of rFVIII-PEG-Lip represents an approximately 2.5-fold higher "apparent" FVIII activity, which is not accounted for by its modestly increased (13%) half-life. The enhanced efficacy requires complex formation between rFVIII and PEG-Lip before the administration. Furthermore, PEG-Lip associates with the majority of platelets and monocytes in vivo, and results in increased P-selectin surface expression on platelets in response to collagen. Rotational thromboelastometry (ROTEM) analysis of whole blood from rFVIII-PEG-Lip-treated animals at 5 minutes up to 72 hours after dosing recapitulated the 2- to 3-fold higher apparent FVIII activity. The enhanced procoagulant activity is fully retained in plasma unless microparticles are removed by ultracentrifugation. Taken together, the efficacy of rFVIII-PEG-Lip is mediated mainly by its sensitization of platelets and the generation of procoagulant microparticles that may express sustained high-affinity receptors for FVIII. Published 25 September 2009 in Blood, 114(13): 2802-11.
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