Intravascular hemolysis is a major component of anemia in sickle cell disease (SCD). Plasma extracellular hemoglobin
(ECHb) liberated by intravascular hemolysis has deleterious effects on the vasculature. ECHb scavenges nitric
oxide (NO) and promotes the pathogenesis of several clinical events including pulmonary hypertension, priapism and
non-hemorrhagic strokes. ECHb reduces the bioavailability of NO which down-regulates platelet activation, leading to
platelet aggregation and vascular clot formation. Recently we have identified an additional mechanism whereby increased
hemolysis can lead to a prothrombotic state in SCD by increasing the activity of von Willebrand factor (VWF), a multimeric
plasma glycoprotein secreted by the endothelium. Our studies show that ECHb binds to the A2-domain on VWF at
the proteolytic site of the metalloprotease, ADAMTS13, and blocks VWF cleavage in vitro. Elevated ECHb is associated
with high levels of ultralarge and hyperactive VWF multimers in SCD patients’ plasma. A sub-population of VWF multimers,
bound to ECHb is hyperactive, and exists in greater quantity in SCD patients’ plasma compared to normal controls.
These results suggest a possible role for plasma ECHb in the accumulation of hyperactive VWF multimers in vivo
that may mediate thrombotic and vasoocclusive complications in SCD patients.