Faculty Collaboration Database

The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies. J Thromb Haemost 2015 Jul;13(7):1301-9

Date

05/09/2015

Pubmed ID

25955153

Pubmed Central ID

PMC4496307

DOI

10.1111/jth.13001

Scopus ID

2-s2.0-84935446637 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

BACKGROUND: Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors).

OBJECTIVE: To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors.

METHODS: 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test.

RESULTS: Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group.

CONCLUSION: VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors.

Author List

Shi Q, Schroeder JA, Kuether EL, Montgomery RR

Authors

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Autoantibodies
Blood Coagulation
Blood Platelets
Bone Marrow Transplantation
Disease Models, Animal
Factor VIII
Genetic Predisposition to Disease
Genetic Therapy
Hemophilia A
Humans
Immunization
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phenotype
von Willebrand Factor