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. 2023 Oct 4;7(22):6974–6989. doi: 10.1182/bloodadvances.2023010824

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© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

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Figure 7. — Representation of proposed multifactorial mechanisms through which HC or BT disease-modifying therapies affect endothelial cell activation VWF–ADAMTS13 axis dysfunction in children with SCD. Key steps highlighted in red. (1) Significantly higher free heme levels were seen in children treated with HC compared with those treated with BT. (2) Plasma concentrations of free heme present in children treated with HC were sufficient to drive Weibel-Palade body exocytosis from human umbilical vein endothelial cells in vitro. (3) LDH and free heme were both independently associated with plasma VWF levels, suggesting that rate of hemolysis and amount of free heme can affect endothelial cell activation. (4) High-molecular-weight VWF multimers were significantly reduced in children treated with HC, consistent with ongoing high-molecular-weight VWF multimers consumption. (5) Although modified by ABO blood group, increased VWF levels were predominantly attributable to increased endothelial cell secretion. (6) FVIII:C levels were significantly higher in children treated with HC, driving enhanced thrombin generation. (7) Plasma levels of VWFpp, angiopoetin-2, and osteoprotegerin were all significantly elevated in children treated with HC. Downstream consequences are currently unknown. (8) Mediation analysis highlighted feedback mechanism through which increased plasma VWF levels may directly promote hemolysis.