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 Blood, 15 August 2008, Vol. 112, No. 4, pp. 1101-1108.
Prepublished online as a Blood First Edition Paper on June 16, 2008; DOI 10.1182/blood-2008-04-152959.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Analysis of the spatial and temporal characteristics of platelet-delivered factor VIII–based clots

Michael Neyman1, Jamie Gewirtz1, and Mortimer Poncz1,2

1 Division of Hematology, Children's Hospital of Philadelphia, PA; and 2 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia

Normally factor (F) VIII is not expressed in megakaryocytes, but when human FVIII was transgenically expressed in murine megakaryocytes, it was stored in platelet {alpha}-granules and released at sites of injury. This platelet FVIII (pFVIII) is effective in correcting hemostasis, even in the presence of circulating inhibitors, so it offers a potential gene therapy strategy for hemophilia A. To understand clot development by pFVIII, we have examined clot response to laser injury in both cremaster arterioles and venules in FVIIInull mice either infused with FVIII or transgenic for pFVIII. In both sets of vessels, pFVIII is at least as effective as infused FVIII. However, there are temporal and spatial differences in fibrin and platelet accumulation within clots depending on how FVIII is delivered. These differences may be related to the temporal and spatial distribution of the {alpha}-granular–released FVIII within the developing clot, and may explain the increased frequency and size of embolic events seen with pFVIII. These observations may not only have implications for the use of pFVIII in gene therapy for hemophilia A, but may also have physiologic consequences, explaining why many procoagulant factors are delivered both in the plasma and in platelet {alpha}-granules.


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