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Functional and binding studies of the roles of prothrombin and beta 2-
glycoprotein I in the expression of lupus anticoagulant activity
P Permpikul, LV Rao and SI Rapaport
Department of Medicine, University of California, San Diego, La Jolla, CA.
We present functional and binding data relevant to the reported roles for
prothrombin and beta 2-glycoprotein I (beta 2GPI) in the expression of
lupus anticoagulant activity. In a purified system containing human
prothrombin, Xa, Va, and a rate-limiting concentration of
phosphatidylserine (PS)/phosphatidylcholine (PC) vesicles, the preliminary
incubation of vesicles with protein A separated IgG preparations from 10
lupus anticoagulant plasmas, calcium, and prothrombin enhanced the
inhibitory effect of all IgG preparations upon thrombin generation.
Experiments in a purified factor X activation system provided supporting
data that a similar preliminary incubation with prothrombin enhanced the
inhibitory effect of many of the IgG preparations upon factor X activation.
However, we could not obtain unequivocal evidence that prothrombin was an
obligatory cofactor for lupus anticoagulant IgG to inhibit procoagulant
phospholipid function, because lupus anticoagulant IgG separated by protein
A chromatography contained traces of prothrombin. The binding of many IgG
preparations to immobilized PS was enhanced by prothrombin when calcium
ions were present. beta 2GPI enhanced binding of many of the IgG
preparations to immobilized PS both in the presence and absence of calcium,
yet beta 2GPI failed to enhance the ability of the IgG preparations to
inhibit phospholipid function in purified prothrombin and factor X assays.
Moreover, the IgG preparations prolonged the dilute Russell's viper venom
time (dRVVT) of beta 2GPI-depleted normal plasma. Nine of 10 IgG
preparations bound to prothrombin on Western blots in the absence of
calcium and phospholipid, whereas no preparation bound to beta 2GPI.
Passage of five citrated lupus anticoagulant plasmas through a prothrombin
affinity column in the absence of added calcium and phospholipid removed
most of the activity prolonging the dRVVT of normal plasma, and IgG in the
pass-through plasma no longer bound to PS in the presence of prothrombin
and calcium ions. IgG in prothrombin column eluates had strikingly enhanced
specific lupus anticoagulant activity and also specific PS binding activity
in the presence of prothrombin and calcium ions. Thus, lupus anticoagulant
plasmas were shown to contain IgG binding to prothrombin, in the absence of
calcium ions and phospholipid, which could also, in the presence of calcium
ions and prothrombin, bind to PS and express lupus anticoagulant activity.
Volume 83,
Issue 10,
pp. 2878-2892,
05/15/1994
Copyright © 1994 by The American Society of Hematology
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