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 Blood, 24 September 2009, Vol. 114, No. 13, pp. 2802-2811.
Prepublished online as a Blood First Edition Paper on August 4, 2009; DOI 10.1182/blood-2009-03-212423.

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THROMBOSIS AND HEMOSTASIS

Enhanced efficacy of recombinant FVIII in noncovalent complex with PEGylated liposome in hemophilia A mice

Junliang Pan1, Tongyao Liu1, Ji-Yun Kim1, Daguang Zhu1, Chandra Patel1, Zhi-Hua Cui1, Xin Zhang1, James O. Newgren1, Aaron Reames1, Dodie Canivel1, Gary Jesmok1, Glenn F. Pierce1, Jurg M. Sommer1, and Haiyan Jiang1

1 Bayer HealthCare LLC, Richmond, CA

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.


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