Ectopic platelet-delivered factor (F) VIII for the treatment of Hemophilia A: Plasma and platelet FVIII, is it all the same?

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.

In vivo efficacy of platelet-delivered, high specific activity factor VIII variants.

Ectopically expressed, human B-domainless (hB) factor 8 (F8) in platelets improves hemostasis in hemophilia A mice in several injury models. However, in both a cuticular bleeding model and a cremaster laser arteriole/venule injury model, there were limitations to platelet-derived (p) hBF8 efficacy, including increased clot embolization. We now address whether variants of F8 with enhanced activity, inactivation resistant F8 (IR8) and canine (c) BF8, would improve clotting efficacy.

Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia.