Current Vascular Pharmacology

Dimitri P. Mikhailidis  
Academic Head, Deptartment of Clinical Biochemistry
Royal Free Hospital Campus
University College London Medical School
University College London (UCL)
Pond Street
London, NW3 2QG
UK

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Molecular Link between Intravascular Hemolysis and Vascular Occlusion in Sickle Cell Disease

Author(s): Zhou Zhou, Donald L. Yee and Prasenjit Guchhait

Affiliation: Baylor College of Medicine, One Baylor Plaza, N1319, Houston, TX 77030, USA.

Abstract:

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.

Keywords: Extracellular hemoglobin, von Willebrand factor multimers, sickle cell disease

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Article Details

VOLUME: 10
ISSUE: 6
Page: [756 - 761]
Pages: 6
DOI: 10.2174/157016112803520738
Price: $58