Announcement
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| The role of von Willebrand factor in sickle cell disease chronic organ damage Marta Wolosowicz1, Tomasz Kaminski1, Ayyanar Sivanantham1, Nicholas Swendrowski1, Nandhine Rajasekhar1, Tirthadipa Pradhan-Sundd1, 2. 1Versiti Blood Research Institute, Milwaukee, WI, USA.2Medical College of Wisconsin, Wauwatosa, WI, USA |
Abstract
Introduction: Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ~100,000 African Americans and over 8 million people worldwide. Sickling of red blood cells (RBCs) promotes hemolysis, leading to the release of cell-free hemoglobin (Hb), which acts as a damage-associated molecular pattern molecule (DAMP) and promotes tissue damage. Research over the last decade has documented a cascade of events associated with cell-free Hb accumulation in SCD, including increased adhesion of leukocytes and RBCs to the endothelium, nitric oxide scavenging, Hb-heme-induced TLR4 pathway activation, elevated oxidative stress, and sterile inflammation, all of which correlate with disrupted blood flow, ischemia reperfusion injury (also known as vaso-occlusion), end-organ damage, and increased mortality. In the absence of a functional spleen, the liver plays a predominant role in cell-free Hb clearance in SCD. Recently, we have shown that cell-free Hb accumulation leads to liver sinusoidal endothelial cell (LSEC) senescence and liver dysfunction. However, the exact role of Hb in LSEC senescence and dysfunction is not well understood. Thus, to further characterize the role of cell-free Hb in promoting LSEC senescence and liver dysfunction, we analysed the expression of LSEC-specific proteins at baseline and post-Hb challenge in SCD mice. Remarkably, our data showed a strong upregulation of hemostatic protein von-Willebrand factor (VWF) in SCD mice post oxyHb challenge, which positively correlated with exacerbated hepatic ischemia reperfusion injury and liver dysfunction. As VWF was not previously associated with liver dysfunction, we sought to characterize its role in SCD liver disease pathophysiology by using the humanized Townes SCD mouse model. Results: As LSECs promote VWF synthesis, secretion, and clearance, we first examined each of these processes in SCD mice liver at baseline and post- Hb challenge. Remarkably, whereas VWF synthesis, multimerization, and secretion appeared unaffected in SCD mice post- Hb challenge, we found a delay in VWF clearance and increased VWF accumulation in hepatic Kupffer cells and LSECs. Coimmunoprecipitation and proximity ligation assays confirmed a direct binding of Hb with VWF in LSECs of SCD mice, suggesting that binding to Hb can negatively impact their clearance of VWF. Moreover, we found that Hb binding caused a conformational change in VWF, resulting in its exacerbated cleavage. Mechanistically, we found that Hb accumulation significantly reduced the expression of the LSEC-specific scavenger receptor stabilin 2, which is involved in liver endothelial VWF clearance. Finally, blocking senescence using senolytics in the SCD mice liver led to reduced expression of VWF, which positively correlated with amelioration of hepatic ischemia reperfusion damage. In conclusion, our study identifies a positive association of VWF with ischemia reperfusion, LSEC senescence, and liver dysfunction. These data also confirms the role of cell-free Hb in the regulation of VWF homeostasis in SCD mice liver.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.