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Sickle erythrocyte-endothelial interactions in microcirculation: the role
of von Willebrand factor and implications for vasoocclusion
DK Kaul, RL Nagel, D Chen and HM Tsai
Division of Hematology, Albert Einstein College of Medicine, Bronx, NY
10461.
To determine the role of von Willebrand factor (vWF) in adhesion of sickle
(SS) erythrocytes in microvascular flow conditions, we have perfused the ex
vivo mesocecum vasculature of the rat with desmopressin, an analogue of
vasopressin that causes the release of endothelial vWF. Analysis of vWF in
the venous effluent of the isolated vasculature showed mainly the presence
of extra-large molecular weight forms characteristic of endothelial vWF,
which in the presence of desmopressin showed an average increase of 54%.
Also, desmopressin induced a significant increase in adhesion of washed
oxygenated (oxy) unseparated SS erythrocytes, accompanied by a persistent
microvascular obstruction and a pronounced increase in the peripheral
resistance (PRU). In contrast, infusion of SS deformable discocytes (SS2)
in desmopressin-perfused vasculature resulted in a significant adhesion but
not in persistent vasoocclusion, showing that SS2 discocytes alone are not
sufficient for microvascular obstruction. Furthermore, SS4 erythrocytes
(dense discocytes and irreversibly sickled erythrocytes) caused a
persistent microvascular blockage and a significantly higher PRU than SS2
discocytes. However, the increase in PRU for SS4 erythrocytes following
desmopressin treatment was 50% less compared with a corresponding increase
for SS2 discocytes over the control values, which showed a smaller effect
of desmopressin on the hemodynamic behavior of SS4 dense erythrocytes.
Incubation of desmopressin-treated vasculature with anti-vWF antibodies
resulted in a pronounced decrease in adhesion and significantly improved
hemodynamic behavior of SS cells. Also, in untreated vasculature, similarly
incubated with anti-vWF antibodies, there was almost complete inhibition of
adhesion. Under the described perfusion conditions, antibodies to
fibronectin and thrombospondin, as well as incubation of SS erythrocytes
with anti-vWF antibodies did not affect adhesion. These results are
compatible with a model for SS vasoocclusion in which extra- large
vWF-mediated adhesion of deformable SS erythrocytes is the first step
followed by an accelerated entrapment of dense SS erythrocytes.
Volume 81,
Issue 9,
pp. 2429-2438,
05/01/1993
Copyright © 1993 by The American Society of Hematology
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