Approximately 1:5000 males have the most common inherited form of severe bleeding, hemophilia A, a deficiency of functional coagulation factor VIII. Patients with severe hemophilia A suffer from recurrent bleeding with significant morbidity and mortality with 20-30% of these patients developing antibodies to infused Factor (F) VIII therapy. One area of on-going research for treatments for these patients is ectopically expressing FVIII in megakaryocytes and platelets. This FVIII, termed pFVIII, is stored in alpha granules of platelets and is capable of restoring hemostasis in FVIIInull mice, even in the presence of circulating inhibitors. pFVIII has been proposed to be used for gene therapy for patients with hemophilia A, intractable inhibitors, and life-threatening bleeds. However, prior studies by us have shown that high levels of pFVIII can injure developing megakaryocytes. Combined with the known risk of prolonged thrombocytopenia following bone marrow transplantation, this may limit its utility of this strategy. Because of these limitations, we now propose an alternative therapeutic pFVIII strategy of infusing pFVIII-expressing megakaryocytes or platelets. We envision that such a product would be generated beginning with induced-pluripotent stem cells (iPSCs). iPSC-derived megakaryocytes, termed iMks, that are modified to express pFVIII may then be used to improved hemostasis in problematic inhibitor patients with hemophilia A. As proof-of-principle, we demonstrate that improved hemostasis can be achieved in vitro and in vivo with human pFVIII-expressing murine platelet. Infusion of such platelets can provide several days of improved hemostasis in FVIIInull mice. They were effective in the presence of inhibitors, and the efficacy of pFVIII was enhanced by recombinant factor VIIa. Human pFVIII-expressing iMks also improved hemostasis in vitro and derived platelets from infused human pFVIII-iMks improved hemostasis in FVIIInull mice. These studies indicate the potential therapeutic use of recurrent pFVIII-expressing megakaryocyte or platelet infusions with prolonged hemostatic coverage that may be additive with present-day bypassing agents in hemophilia A patients with clinically relevant neutralizing inhibitors.