Extracellular Hemoglobin Regulation of von Willebrand Factor Activity in Plasma of Patients with Sickle Cell Disease

Abstract

Elevated levels of ultralarge (UL) von Willebrand factor (VWF) multimers in plasma play an important role in cell adhesion and vascular occlusion in sickle cell disease (SCD). Recently, we have shown that the binding of extracellular hemoglobin (ECHb) to the A2 domain of VWF significantly blocks VWF cleavage by the metalloprotease ADAMTS13in vitro. We speculated that on release from the inflamed endothelium, the VWF multimers maintain the UL structure in plasma if ECHb prevents their cleavage. We observed that a subpopulation of VWF multimers that are bound to ECHb (HbVWF), which accounted for about 14 % of the total VWF in the plasma of SCD patients. The plasma HbVWF level is parallely correlated with the ECHb and VWF-antigen levels. The HbVWF multimers are resistant to the metalloprotease ADAMTS13in vitroand are more adhesive to platelets and collagen compared with their Hb-free counterpart. Therefore, we speculate that the HbVWF, which are probably UL multimers, play an important role in tethering and stably adhering blood cells to the vascular endothelium and culminate in vascular occlusion/thrombosis/strokes in SCD patients. Thus, this article provides a new insight into the molecular pathophysiology of SCD.