Blood, 15 February 2003, Vol. 101, No. 4, pp. 1655-1655
CORRESPONDENCE
To the editor:
Thrombocytopenia following treatment with platelet glycoprotein
IIb/IIIa inhibitors
In their recent report, Bougie et al1 demonstrate
the presence of drug-dependent antibodies to platelet glycoprotein
IIb/IIIa (GPIIb/IIIa) in patients who developed thrombocytopenia
following treatment with the GPIIb/IIIa inhibitors tirofiban and
eptifibatide. In an effort to locate the epitope(s) recognized by those
antibodies, the authors performed blocking experiments with abciximab.
The latter is the Fab fragment of a chimeric IgG construct (human IgG
with murine antigen-binding region) derived from the murine monoclonal
antibody 7E3, which binds with high affinity to an epitope close to the
fibrinogen binding site on GPIIb/IIIa. The degree of blocking of
antibody binding was assessed by measuring the effect of incubation
with abciximab on the amount of test serum immunoglobulin (Ig) bindable
to control platelets pretreated with fiban (tirofiban or eptifibatide).
In their description of the blocking experiments, the investigators do
not provide data on antibody binding to abciximab-treated platelets not
previously exposed to fiban, and therefore, in this setting,
recruitment of Ig onto the platelet surface could have been caused by
the presence of either antifiban or antiabciximab antibodies. Although elsewhere in the paper it is stated that "[n]one of the antibodies reacted with abciximab-treated platelets," 1(p2073)
no data or methods descriptions are given to support this. As a matter of fact, this statement appears to be at variance with previously published work showing that a statistically significant elevation of platelet-bound IgG occurred in patients with coronary heart disease (CHD) receiving infusions of Fab fragments of chimeric 7E3, and that 14 of 21 control sera from CHD patients contained varying
amounts of IgG bindable in vitro to 7E3-Fab-coated
platelets.2 These phenomena might be related to the
existence of "naturally occurring" antibodies to the Fab fragments
derived by enzymatic cleavage of the IgG molecule, which are commonly
found in sera from healthy individuals.3,4 More evidence
will be therefore required before the great differences in the extent
of blocking of antibody binding by abciximab observed by Bougie et al
are ascribed to the existence of multiple antifiban epitopes, as it is
possible that they were merely a reflection of differences in the
titers of "naturally occurring" anti-Fab (ie, antiabciximab) in the
test sera.
Constantinos G. Christopoulos
Correspondence: "A. Fleming" General Hospital,
1st Department of Internal Medicine, 25 Martiou 14, Melissia, Athens
15127, Greece; e-mail: chrada{at}ath.forthnet.gr
References
1.
Bougie DW, Wilker PR, Wuitschick ED, et al.
Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa.
Blood.
2002;100:2071-2076[Abstract/Free Full Text].
2.
Christopoulos C.
Platelet surface IgG in patients receiving infusions of Fab fragments of a chimaeric monoclonal antibody to glycoprotein IIb-IIIa.
Clin Exp Immunol.
1994;98:6-11[Medline]
[Order article via Infotrieve].
3.
Kormeier LC, Ing JT, Mandy WJ.
Specificity of antiglobulin factors in normal human serum reacting with enzyme digested 
G globulin.
J Immunol.
1968;100:612-621[Abstract/Free Full Text].
4.
Persselin JE, Stevens RH.
Anti-Fab antibodies in humans. Predominance of minor immunoglobulin G subclasses in rheumatoid arthritis.
J Clin Invest.
1985;76:723-730[Medline]
[Order article via Infotrieve].
Response:
Immune thrombocytopenia associated with fiban therapy
Dr Christopoulos refers to our finding1 that
eptifibitide and tirofiban-dependent antibodies differ in the extent to
which their binding is blocked by abciximab, providing evidence that they recognize different epitopes on GPIIb/IIIa. He points out that
naturally occurring antibodies specific for the papain cleavage site on
Fab fragments such as abciximab are commonly found in patients and
normal sera and correctly notes that, if such antibodies were present
in any of the patient samples used in our study, it might have been
impossible to know whether abciximab blocked drug-dependent antibody
binding or not.
The naturally occurring antibodies to which Dr Christopoulos
refers are usually weak2 and would be undectable at
the dilutions used in our studies (generally 1:20 or more). But we
specifically stated that "[n]one of the antibodies reacted with
abciximab-treated platelets." 1(p2073) Probably, we
should have reiterated this in paragraph 5 of "Discussion" where
the abciximab blocking studies are specifically described.
We thank Dr Christopoulos for the opportunity to clarify
this issue.
Daniel Bougie and Richard H. Aster
Correspondence: Daniel Bougie, Blood Center of
Southeastern Wisconsin, Blood Research Institute, P O Box 2178, Milwaukee, WI 53201-2178; e-mail:
dwbougie{at}bcsew.edu
References
1.
Bougie DW, Wilker PR, Wuitschick ED, et al.
Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa.
Blood.
2002;100:2071-2076[Abstract/Free Full Text].
2.
Curtis BR, Swyers J, Divgi A, McFarland JG, Aster RH.
Thrombocytopenia after second exposure to abciximab is caused by antibodies that recognize abciximab-coated platelets.
Blood.
2002;99:2054-2059[Abstract/Free Full Text].
