Document Type

Master's thesis

Date of Degree

2013

Degree Name

MS (Master of Science)

Department

Anatomy and Cell Biology

First Advisor

David G. Motto

Abstract

Von Willebrand factor (VWF) is a plasma glycoprotein that can bind collagen at a wound site as well as circulating platelets. VWF forms high molecular weight multimers (>20,000 kDa). VWF can also form VWF strings that appear to be attached to the endothelial surface and are capable of binding platelets. These strings are only observed in vitro and in vivo in the absence of the VWF-cleaving protease ADAMTS13. Deficiency in ADAMTS13 results in thrombotic thrombocytopenic purpura (TTP), a clotting disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, renal dysfunction, neurological dysfunction and fever. Patients suffering from TTP demonstrate VWF-and platelet-rich thrombi in the microvasculature of numerous organ systems, but most notably in the kidneys, heart, and brain. While VWF strings have not been directly connected to TTP, their presence in vivo was only identified with the ADAMTS13 knockout mouse (a model of TTP), suggesting a possible relationship.

Recently we identified glycerol as an agent, similar to histamine, that triggers the formation of VWF strings in vitro. We found that glycerol and histamine trigger TTP in an ADAMTS13-deficient mouse model. In addition, we determined conditions in vitro that promote the formation of dense VWF networks. These networks of VWF can be greater than 70 μm thick and appear to be able to form fibers as long as several millimeters in length. These networks have not been previously identified and may underlie a possible mechanism by which VWF-rich thrombi form in TTP. These networks were formed solely from cultured endothelial cells, leading us to believe that endothelial cells alone are capable of producing more VWF than perhaps previously appreciated. These data suggest that secretion of VWF from the endothelium may play an important role in the pathophysiology of TTP.

Pages

iv, 26

Bibliography

23-26

Copyright

Copyright 2013 Gilbert Van Schaeffer