Friday, May 9, 2025
5/9/2025
von Willebrand Factor in Sickle Cell Disease Pathophysiology - PROJECT SUMMARY This application is to continue our studies examining the role of von Willebrand factor (VWF) in the pathophysiology of sickle cell disease (SCD). During the current funding period we have shown that in SCD a) the plasma concentration of VWF is very high and the molecule is hyperadhesive; b) transplantation of mouse SCD bone marrow into ADAMTS13‐/‐ mice results in spontaneous vaso‐occlusive crisis; c) SCD patient plasma is able to activate endothelial cells to release VWF; d) plasma ADAMTS13 is defective in cleaving multimeric VWF and VWF strings, but not a small peptide substrate such as that currently used in the clinical ADAMTS13 activity assay; e) VWF from SCD plasma shows less ADAMTS13‐mediated proteolysis and more methionine oxidation than control VWF; f) high‐dose intravenous infusion of N‐acetylcysteine (NAC) decreases VWF multimer size, reduces dense cell formation and erythrocyte fragmentation, and increases the concentration of plasma small molecule thiols. We also have strong evidence that the self‐association of VWF is a very important factor in determining its functions, that VWF self‐association is enhanced in SCD, and that the process is decreased by plasma high‐density lipoprotein (HDL) and accelerated by thrombospondin‐1 (TSP‐1). We plan to continue our studies of the role of the VWF–ADAMTS13 axis with the following specific aims. Specific Aim 1: To identify the molecular lesion(s) responsible for defective ADAMTS13 cleavage of multimeric VWF in sickle cell disease. We have found that ADAMTS13 proteolysis of multimeric VWF is defective in SCD and will investigate several possibilities for this defect. Specific Aim 2: To evaluate the effects of TSP‐1 or ApoA‐I deficiency, or ApoA‐I overexpression, on the course of disease in sickle mice. Here, we will test whether genetic conditions that either diminish or worsen VWF adhesive activity alter the course of SCD in mice. Specific Aim 3: To evaluate the effect on the course of SCD in mice of treatment with ADAMTS13, ApoA‐I, or VWF, or with both ADAMTS13 and ApoA‐I. These studies will complement those of Specific Aim 2 to explore whether treatments that alter VWF adhesive activity will affect the acute or chronic manifestations of SCD. We expect these studies to provide further biological insights into the roles in SCD pathophysiology played by the VWF–ADAMTS13 axis and oxidative stress. We also anticipate that we will discover new targets for SCD therapy.
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