ASH 2016 PREVIEW
Using platelet microcapsules to deliver factor VIII, a process that is expected to increase factor VIII efficacy and avoid the development of neutralizing antibodies, is being examined via in vitro testing, according to an abstract to be featured during a press conference at the annual meeting of the American Society of Hematology.
Caroline E. Hansen of the Georgia Institute of Technology, Atlanta, and her colleagues performed in vitro experiments that show this technology has the potential to increase factor VIII efficacy for hemophilia A patients with inhibitors.
“Current work evaluating localized thrombin generation due to the factor VIII–loaded microcapsules and the effect of platelet contraction force via pharmacologic agents, such as blebbistatin, ROCK, and myosin inhibitors, [is] ongoing,” the researchers wrote in their abstract.
They fabricated polyelectrolyte layers onto calcium carbonate cores and incorporated fibrinogen into the final layer to facilitate binding with platelets. The microcapsule’s inner core contains factor VIII separated from the polyelectrolyte layers by a dextran core.
In the in vitro model, platelets adhered to the microcapsules, which were incorporated into fibrin networks upon platelet activation. During clot contraction, the microcapsules ruptured only in the vicinity of contracting platelets, ensuring drug delivery was targeted at sites of active clot formation.
The researchers perfused recalcified whole blood and platelet poor plasma into in vitro microfluidic models of vascular injury, which consisted of a collagen/tissue factor patch. The efficacy of systemic and microcapsular factor VIII was quantitatively evaluated by comparing fibrin fluorescence intensity on the patch, which was normalized to platelet number.
Fibrin formation was comparable using microcapsules without dextran, fibrinogen, and loaded factor VIII. Compared with standard systemic infusion of 0.05 U/mL factor VIII, however, microcapsules loaded with 0.01 U/mL factor VIII produced four times as much fibrin.
To mimic hemophilia A blood with inhibitors, a factor VIII inhibitory antibody was introduced into healthy blood samples. Again, significantly more fibrin was produced in samples with microcapsules loaded with 0.01 U/mL factor VIII than with systemic factor VIII infusions at clinically relevant high and low dosages of 0.05 and 0.5 U/mL (P less than .05).
This increased efficacy is likely due to the microcapsule shielding effect on factor VIII, preventing exposure to inhibitory antibodies, the researchers reported.
Ms. Hansen had no relevant financial disclosures. One of her colleagues, Shannon L. Meeks, MD, disclosed adviser relationships with Biogen, Genentech, Bayer Healthcare, Grifols, CSL Behring, and Shire. Another, Wilbur A Lam, MD, PhD, disclosed equity ownership in Sanguina.
Abstract 81: Leveraging the Contractile Force of Platelets for Targeted Factor VIII Delivery in Hemophilia With Inhibitors.
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