Abstract
Hemophilia A is the most common inherited bleeding diathesis and is due to a deficiency of functional coagulation factor (F) VIII. Most patients have a severe deficiency and require a program of prophylactic plus acute infusions of recombinant FVIII to prevent significant joint and other target organ damage. One of the greatest challenges remaining in the care of these patients is that one fifth to third of the patients develop inhibitors to the infused proteins. While a significant portion of such inhibitors can be either overcome or the inhibitors eliminated, some patients with persistent and significant titers of inhibitors need to rely on second tier therapies that are not as effective at preventing significant bleeding morbidity or mortality. A number of groups have been developing therapeutic strategies for FVIII gene therapy for this disorder. Virtually all of these therapies have in common a rise in the plasma level of FVIII, and interpretation of their efficacy is straightforward related to levels achieved. However, several groups have also shown that FVIII can be ectopically expressed in developing megakaryocytes, where although plasma FVIII levels remain undetectable, this FVIII can be released and be effective at sites of platelet activation. Moreover, it is clear that this platelet (p) FVIII is protected to a degree from inhibitors, making pFVIII a particularly attractive strategy for gene therapy for hemophilia A. Yet at the same time, we have shown that pFVIII has a different availability and distribution in a growing thrombus than plasma FVIII. The clinical implications and challenges of these findings as murine and canine hemophilia A preclinical studies go forward with pFVIII are discussed.