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Complement-induced vesiculation and exposure of membrane prothrombinase
sites in platelets of paroxysmal nocturnal hemoglobinuria
T Wiedmer, SE Hall, TL Ortel, WH Kane, WF Rosse and PJ Sims
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee
53233.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem-cell disorder
in which the glycolipid-anchored membrane proteins, including the
cell-surface complement inhibitors, CD55 and CD59, are partially or
completely deleted from the plasma membranes of mature blood cells. To gain
insight into the pathogenesis of thrombosis that is frequently observed in
this disorder, the procoagulant responses of PNH platelets exposed to the
human terminal complement proteins C5b-9 were investigated. C5b-9 complexes
were assembled on gel-filtered platelets by incubation with purified C5b6,
C7, C9, and limiting amounts of C8. Platelet microparticle formation and
exposure of plasma membrane- binding sites for coagulation factor Va were
then analyzed by flow cytometry. PNH platelets exhibiting undetectable
levels of surface CD59 antigen showed an approximately 10-fold increase in
sensitivity to C5b- 9-stimulated expression of membrane-binding sites for
factor Va when compared with platelets from normal controls. Expression of
catalytic surface for the prothrombinase complex (VaXa) paralleled the
exposure of factor Va-binding sites; the rate of prothrombin conversion by
C5b-9- treated PNH platelets exceeded that of C5b-9-treated normal controls
by approximately 10-fold at the maximal input of C8 tested (500 ng/mL).
These data indicate that PNH platelets deficient in plasma membrane CD59
antigen are exquisitely sensitive to C5b-9-induced expression of
prothrombinase activity, and suggest that the tendency toward thrombosis in
these patients may be due, at least in part, to the deletion of this
complement inhibitor from the platelet plasma membrane.
Volume 82,
Issue 4,
pp. 1192-1196,
08/15/1993
Copyright © 1993 by The American Society of Hematology
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