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Differential Effects of Anti- 2-Glycoprotein I and Antiprothrombin
Antibodies on the Anticoagulant Activity of Activated Protein C
Monica Galli,
Luisa Ruggeri, and
Tiziano Barbui
From the Department of Haematology, Ospedali Riuniti, Bergamo, Italy.
Antiprothrombin and anti- 2-glycoprotein I (2-GPI) antibodies
belong to the family of antiphospholipid (APL) antibodies and represent
the phospholipid-dependent inhibitors of coagulation. They may be
distinguished by analyzing the coagulation profiles generated by the
comparison of the ratios of two coagulation tests, the Kaolin Clotting
Time (KCT) and the dilute Russell's Viper Venom Time (dRVVT), commonly
adopted for their diagnosis. The KCT profile is caused by
antiprothrombin antibodies, whereas anti-2-GPI antibodies are
responsible for the dRVVT coagulation profile. The presence of aPL
antibodies is frequently associated with acquired resistance to
activated Protein C (APC-R), but limited information is
available regarding the role of the different antibodies in its
development. We studied the time-course of activated Factor V (FVa)
generation and inactivation in the plasma of 42 patients with
well-defined phospholipid-dependent inhibitors of coagulation: 24 displayed the dRVVT coagulation profile, whereas the other 18 cases
showed the KCT profile. In normal pooled plasma, the peak
values of FVa (mean ± standard deviation, [SD]: 16.307 ± 4.372 U/mL) were reached in 4 to 5 minutes and an almost complete inactivation (0.088 ± 0.123 U/mL) was obtained within 20 minutes. At
this time point, values of residual FVa exceeding 2 SD the mean of
controls (0.344 U/mL) were considered abnormal. Patients belonging to
the KCT coagulation profile group reached the maximal amount of FVa in
plasma (22.740 ± 7.693 U/mL, P = not
significant v controls) within 4 to 5 minutes; at
20 minutes, the residual amount of FVa in plasma ranged from 0 to 1.09 U/mL (0.293 ± 0.298; P = .027), but it was found
abnormal in only six of the 18 cases. The time-course of FVa in plasma
of patients belonging to the dRVVT coagulation profile group differed
from that of normal controls in that the peak values (10.955 ± 5.092 U/mL) were reached at 10 minutes and the amount of residual FVa at 20 minutes ranged from 0.320 to 14.450 U/ml (2.544 ± 3.580 U/mL;
P = .0191 v normal controls and P = .0114 v KCT group patients). Twenty of the 24 patients belonging to
the dRVVT profile group had an abnormal inactivation of FVa
( 2 = 0.001 v KCT group patients).
History of venous thrombosis was experienced by 15 patients: an
abnormal rate of FVa inactivation was found in 11 of them (73%) versus
15 of the 27 cases without thrombosis (56%) (x2
= 0.2556). The effect of affinity-purified IgG
phospholipid-dependent inhibitors of coagulation on the time-course of
FVa generation and inactivation in normal plasma was also investigated.
Anti-2-GPI, but not antiprothrombin antibodies, hampered the
inactivation of FVa by endogenous APC, thus reproducing the behavior of
the original plasmas. This effect was strictly 2-GPI-dependent. In conclusion, our findings confirm that anti-2-GPI antibodies
identify patients with phospholipid-dependent inhibitors of coagulation at increased risk of thrombosis and suggest acquired APC-R as a
possible explanation of the pathogenesis of the thromboembolic events.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1999-2004
© 1998 by The American Society of Hematology.
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