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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1988-1992
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Rifampicin-dependent antibodies bind a similar or identical
epitope to glycoprotein IX-specific quinine-dependent
antibodies
Janette K. Burgess,
Jose A. Lopez,
Leonie E. Gaudry, and
Beng H. Chong
From the Centre for Thrombosis and Vascular Research, University of
New South Wales, and Department of Hematology, Prince of Wales
Hospital, Sydney, Australia; and Baylor College of Medicine, Houston,
TX.
 |
Abstract |
The drug-dependent antibody of a patient with rifampicin-induced
thrombocytopenia was characterized using the antigen-capture enzyme-linked immunosorbent assay (MAIPA assay), flow cytometry, and
immunoprecipitation. The antibody was found to bind glycoprotein (GP)
Ib-IX but not GPIIb-IIIa because (1) it immunoprecipitated drug-dependently the former but not the latter glycoprotein complex and (2) the MAIPA assay showed strong rifampicin-dependent
antibody binding when anti-GPIb-IX monoclonal antibodies (mAbs) (AK2
and FMC25) but not anti-GPIIb-IIIa mAbs (AP2, SZ21, and SZ22) were used
to capture the antigen. The antibody binding site was further localized
to the GPIX subunit of the GPIb-IX complex because flow cytometric
analysis revealed drug-dependent antibody binding to L cells
transfected with human GPIb and GPIX complementary DNA (L IX
cells) but not with human GPIb and GPIb complementary DNA (L
cells). Finally, in the MAIPA assay, the rifampicin-dependent antibody almost completely cross-blocked the binding of the anti-GPIX mAb (SZ1) to platelets. Similar cross-blocking of SZ1binding to platelets by the quinine-dependent antibodies was also observed. This
finding not only confirms that the epitope of the rifampicin-dependent antibody is on GPIX but it is also identical to or located in close
proximity to that of the quinine-dependent antibody and SZ1. Further
characterization of the epitopes of these antibodies may have important
implications for a general understanding of the mechanism of
drug-induced thrombocytopenia.
(Blood. 2000;95:1988-1992)
© 2000 by The American Society of Hematology.
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Introduction |
Rifampicin is a widely used agent for the treatment of
tuberculosis. Adverse effects from the administration of rifampicin can
include interstitial nephritis, thrombocytopenia, and hemolytic anaemia. The first incidence of rifampicin-induced thrombocytopenia was
reported in 1970 by Blajchman et al.1 Since then, many other cases have been reported.2,3 Several investigators have demonstrated rifampicin-dependent antiplatelet antibodies2,3 but have not characterized the platelet antigen of these
antibodies. Kakaiya et al2 demonstrated that rifampicin did
not bind platelets directly. They suggested that the antibody first
reacts with the drug to form a drug-antibody complex that then binds to
platelets, resulting in their clearance through an "innocent
bystander" mechanism. Martinez et al4 suggested that the
interaction of the offending drug with blood cell membrane proteins
leads to the formation of an antigenic complex to which the
drug-dependent antibodies bind. Our observations favor the second mechanism.
In this study, we have characterized the antibody from a patient who
developed rifampicin-induced thrombocytopenia. Using flow cytometry,
monoclonal antibody-specific immobilization of platelet antigens
(MAIPA) assay, and immunoprecipitation, we demonstrated that the
antibody reacted with the glycoprotein (GP) Ib-IX complex on the
platelet surface. The antibody epitope was further mapped to the GPIX
subunit of the complex. More specifically, the antibody binding site
was located at a site where the epitopes of 3 other drug-induced
antibodies (quinine-, quinidine-, and ranitidine-induced) have been
previously located. These data imply that this site on GPIX is strongly
immunogenic when it combines with drugs. A careful analysis of this
GPIX region may provide useful information about the pathophysiology of
drug-induced thrombocytopenia in general.
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Materials and methods |
Materials
Bovine serum albumin (BSA), phenylmethylsulfonyl fluoride (PMSF),
ethylenediaminetetraacetic acid, disodium salt (EDTA), bacitracin, benzamidine, dithiothreitol (DTT), dimethylsulfoxide, iodoacetamide, propidium iodide, and 2,2'-azinobis 3-ethylbenzthiazolinesulfonic acid (ABTS) were purchased from Sigma (St Louis, MO);
3,3',5,5'-tetramethylbenzidine dihydrochloride from
Kirkegaard & Perry (Gaithersburg, MD); sulfosuccinimidobiotin from
Pierce (Rockford, IL); Western blot chemiluminescence reagents from
DuPont (Boston, MA); and the sheep anti-mouse-coated Dynabeads and the
sheep anti-rabbit immunoglobulin G (IgG)-coated Dynabeads from Dynal
(Oslo, Norway). Rifampicin was purchased from Marion Merrell Dow
(Sydney, Australia). All chemicals were of analytical reagent grade.
Antibodies
The goat anti-mouse immunoglobulin and the horseradish peroxidase
(HRP)-conjugated goat anti-human immunoglobulin (Jackson, West Grove,
PA), rabbit anti-mouse HRP-conjugated antibody (Dako, Carpentaria, CA),
and the streptavidin-HRP conjugate (Amersham, Bucks, United Kingdom)
were purchased as indicated.
All monoclonal antibodies (mAb) were of the IgG class. MOPC21 (Becton & Dickinson, San Jose, CA), a murine IgG1 myeloma protein, was used as a control immunoglobulin, and SZ1, SZ21, and SZ22 were
purchased from Immunotech (Marseille, France). The sheep anti-mouse
fluorescein isothiocyanate (FITC)-conjugated secondary antibody was
purchased from Silenius (Hawthorn, Australia), and the rabbit
anti-human FITC-conjugated secondary antibody from Dako.
AK2 and FMC25 mAbs, which are directed against epitopes on various
parts of the human GPIb-IX complex, were obtained from Dr M. Berndt
(Melbourne, Australia).5 AP2, a mAb that is directed against an epitope on GPIIb-IIIa, was a kind gift from Dr T. J. Kunicki
(La Jolla, CA).
Patient
Mrs N.P., a 66-year-old woman, was diagnosed with pulmonary
tuberculosis and was begun on rifampicin and isoniazid. Four months later, she noted spontaneous bruising. Physical examination revealed petechiae on her legs but no other bleeding. Blood counts showed a
severe thrombocytopenia: platelets 9 × 109/L,
hemoglobin 165 g/L, and white blood cells
5.0 × 109/L. A diagnosis of drug-induced
thrombocytopenia was made, and all drugs she was taking were stopped.
She was begun on 50 mg of prednisone daily. A test for drug-dependent
antibodies using an antigen-capture assay MAIPAdemonstrated a
rifampicin-dependent antiplatelet antibody with specificity against
GPIb-IX complex, but no isoniazid-dependent antibody was detected. A
bone marrow aspirate revealed normal numbers of megakaryocytes and
erythroid and myeloid precursors, consistent with a thrombocytopenia
due to increased peripheral platelet destruction. Her platelet count rose to 124 × 109/L,
189 × 109/L, and 214 × 109/L on
days 4, 6, and 7, respectively, after withdrawal of
antituberculosis drugs. Prednisone was then stopped.
Cell lines
Chinese hamster ovary (CHO) DUK- (dihydrofolate
reductase-negative [DHFR-]) cells and mouse L
(tk-) cells stably transfected with complementary DNA
(cDNA) encoding the GPIb-IX subunits in various combinations were
produced in one of our laboratories (J.A.L.) as previously
described.6 The cloning of the cDNAs for GPIb , GPIb,
and GPIX has been reported previously.7-9 The 3 cDNAs (each
containing the entire coding sequence and the 3'-untranslated
region) were cloned separately into the eukaryotic expression vector
pDX (a kind gift from Dr K. Berkner, Seattle, WA), in which
transcription is driven by the adenovirus major late promoter and the
SV40 enhancer.
Methods
Transfection of CHO and L cells with GPIb-IX genes.
The CHO cells were transfected with the following combinations of
GPIb-IX subunit cDNAs: (a) GPIb, GPIb, and GPIX,
(b) GPIb and GPIb, (c) GPIb and GPIX, and
(d) GPIb and GPIX. The L cells were transfected with
(a) GPIb and GPIb and (b) GPIb and GPIX. Expression of the GPIb-IX subunits in the cell lines was substantiated by Northern blot analysis to detect messenger RNA (mRNA) and by flow
cytometry and enzyme-linked immunosorbent assay (ELISA) to ensure
protein expression of the subunits on the cell surface. In all cell
lines, the appropriate GPIb-IX subunits were expressed on the cell
surface except in the CHO cells transfected with GPIb and GPIX cDNA.
In this cell line, GPIb was expressed on the cell surface, but GPIX
was located in the cytoplasm when detected by flow cytometry.
Enzyme-linked immunosorbent assay.
The ELISA was performed as previously described.10
MAIPA assay.
The MAIPA assay was performed as previously described with minor
modifications.11 Group O platelets
(2 × 107 per tube) were washed once in
phosphate-buffered saline (PBS)/1% EDTA buffer, resuspended in 100 µL PBS/2% (w/v) BSA, and added to 50 µL of patient serum with or
without 5 µL of rifampicin (final concentration, 70 µg/mL). The
positive control for the assay was normal pooled platelets at a
concentration of 2 × 107/100 µL plus 50 µL of
patient serum known to contain an anti-PLA1 antibody.
Flow cytometry.
Flow cytometry was performed on a FACStar Plus flow cytometer (Becton & Dickinson) fitted with a 100-mW air-cooled argon ion laser using the
488-nm green line for fluorescence excitation. The cell emission
spectra were collected on FL1 (green) using a band pass filter 530 DF
30. Dead cells were excluded using propidium iodide on FL3 using a 700 LP filter. Cells or group O platelets for flow cytometry were prepared
as described previously.10 Primary antibody incubation, mAb
(10 µg/mL) or patient serum (1:20 dilution), was performed for 10 minutes at room temperature in the presence or absence of rifampicin
(700 µg/mL). In experiments carried out in the presence of
rifampicin, the working or wash buffer contained the drug beyond this
stage at a concentration of 700 or 600 µg/mL, respectively.
Biotin labeling of glycoprotein Ib-IX subunits.
The platelets (2 × 1010) were incubated with 168 µmol of sulfosuccinimidobiotin, and the free biotin was quenched with
excess glycine. The platelets were then incubated with one of the
following: a mouse IgG1 control (MOPC21; 10 µg/mL), the
GPIX-specific mAb (GRP; 10 µg/mL), or AB or patient serum (40 µL of
each with or without the drug at 700 µg/mL) for 30 minutes. In
experiments performed in the presence of rifampicin, the working or
wash buffer contained the drug beyond this stage at a concentration of
700 or 600 µg/mL, respectively. After 3 washes, the platelets were lysed by resuspension in 500 µL of 0.01 mol/L
triethanolamine-buffered saline containing 0.5% Triton
X-100, 0.05% Tween-20, and protease inhibitors (PMSF 2 mmol/L,
leupeptin 10 µM/L, aprotinin 10 µM/L, EDTA 5 mM/L) and incubated
for 1 hour. Following centrifugation at 12 000g for 30 minutes, the supernatant (450 µL) was collected; 1 × 107 sheep anti-mouse-coated Dynabeads, or
2.25 × 107 Dynabeads coated with goat anti-rabbit
IgG linked to rabbit anti-human IgG, were added to the mAb or the human
serum immunoprecipitates, respectively. After incubation for 2 hours,
the Dynabeads were washed 5 times using the MPC-E-1 magnet before
resuspension in 10 µL 2 × Laemmli buffer12 and
storage at  80°C until analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
SDS-PAGE and detection of proteins.
The 20-µL samples for SDS-PAGE analysis were treated with 2 µL of
0.5-mol/L DTT and boiled for 5 minutes. Free DTT was
quenched by 4 µL of 0.5-mol/L iodoacetamide. SDS-PAGE
was performed according to the method of Laemmli12 using
12% Tris-glycine gels (Bio-Rad, Hercules, CA). After electrophoresis,
the proteins were transferred to polyvinylidine difluoride
(PVDF) membrane. Membranes were blocked overnight in 5% (w/v) skim
milk (Diploma) and the following morning washed 5 times in PBS/0.05%
Tween-20. Streptavidin HRP diluted 1:2000 in 2% BSA/PBS/0.05%
Tween-20 was incubated with the membrane for 60 minutes. After 5 washes, the presence of a signal was detected using the Western blot
chemiluminescence reagents according to the manufacturer's instructions.
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Results |
Rifampicin-dependent antibody binds to GPIb-IX and not to GPIIb-IIIa
The patient serum was analyzed using the MAIPA assay. Antibody
binding was only seen in the presence of rifampicin. The serum showed
rifampicin-dependent antibody binding to platelets when the
GPIb-specific mAb, AK2, was used to capture the antigen (GPIb-IX complex). Similarly, strong rifampicin-dependent antibody binding occurred when the non cross-blocking GPIX-specific mAb, FMC25, captured
the antigen (Figure 1). When a
GPIIb-IIIa-specific mAb, AP2, SZ21, or SZ22, was used as the capture
antibody, a negative result was obtained. These data indicate that the
rifampicin-dependent serum contains an antibody that reacts with the
GPIb-IX but not GPIIb-IIIa complex.
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| Fig 1.
Binding of rifampicin-dependent antibody to platelet
surface glycoproteins.
MAIPA assay, an antigen-capture ELISA, was performed using SZ21, SZ22,
and AP2, anti-GPIIb-IIIa mAbs, to capture the GPIIb-IIa complex or AK2
(an anti-GPIb mAb) or FMC25 (a non-cross-blocking anti-GPIX mAb) to
capture the GPIb-IX complex. The studies were performed in the presence
and absence of rifampicin with patient serum (Pt) or the control (AB
serum). Samples were assayed in the presence or absence of rifampicin.
Binding was not observed with the AB serum in the presence or absence
of rifampicin with any of the mAbs. The patient serum did not bind in
the absence of rifampicin. In the presence of rifampicin, the patient
serum gave a positive result in the presence of GPIb-specific mAb
AK2 and GPIX-specific mAb FMC25. A negative result was observed with
GPIIb-IIIa mAbs SZ 1, SZ22 (data not shown), and AP2. These data
suggest that the antibody(ies) in the patient serum reacted with
GPIb-IX complex but not with the GPIIb-IIIa complex.
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When immunoprecipitation experiments were performed using human AB or
patient serum with and without rifampicin, the GPIb-IX complex
components were isolated only in the presence of the patient serum and rifampicin (Figure 2). When the
experiment was repeated in the presence of a nonimmune mouse
IgG1 (MOPC21) and the GPIX-specific mAb, GRP,
immunoprecipitation of the GPIb-IX complex components was observed with
GRP in both the presence and absence of the drug, but no specific band
was observed with MOPC21. The immunoprecipitation of the GPIb-IX
subunits by the patient serum in the presence of rifampicin indicates
that the drug-dependent antibody has specificity for the GPIb-IX
complex.
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| Fig 2.
Immunoprecipitation of the GPIb-IX complex using the
rifampicin-dependent antibodies.
After labeling the surface proteins of the platelets with biotin, the
GPIb-IX complex was immunoprecipitated using AB serum, patient serum, a
nonspecific murine IgG1 (MOPC21), and the GPIX-specific mAb
(GRP), all in the presence or absence of the drug as indicated. The
platelets were lysed, and the immunoprecipitated proteins were
collected using Dynabeads coated with the appropriate capture
antibodies. The proteins were analyzed by SDS-PAGE, transferred to PVDF
membrane, and detected by streptavidin HRP and chemiluminescence
reagents. The GPIb-IX complex (GPIb, 143-kd band; GPIb, 24-kd
band; and GPIX, 20-kd band) was only detected with the patient serum in
the presence of the drug (lane 4) and with the anti-GPIX mAb (GRP) in
both the absence (lane 7) and presence (lane 8) of the drug.
Nonspecific bands (165 kd and 65 kd) were seen both with the test, and
control antibodies in the presence or absence of the drug and were
present in no particular pattern.
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Further localization of rifampicin-dependent antibody binding to
GPIX
Flow cytometry was used to test the binding of the patient antibody
to platelets and CHO cells stably transfected with GPIb, GPIb,
and the GPIX cDNAs. A negative control of AB serum detected no specific
antibody binding in the presence of the drug on platelets (Figure 3) or CHO cells (not shown).
Rifampicin-dependent antibody binding was observed on both the
platelets and the CHO IX cells. These results confirm that the
rifampicin-dependent antibody binds to the GPIb-IX complex.
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| Fig 3.
Binding of rifampicin-dependent antibodies to platelets
and CHO IX cells.
The platelets or CHO IX cells were labeled with primary antibody
(patient serum or AB serum) in the presence or absence of rifampicin,
followed by an FITC-conjugated secondary antibody (rabbit anti-human
IgG), and examined by flow cytometry. The AB serum did not bind to the
platelets in the presence or absence of the drug (A). A similar result
was observed when the CHO IX cells were labeled with AB serum in
the presence or absence of rifampicin (not shown). The patient serum
bound to the platelets (B) and the CHO IX cells (C) in the
presence of the drug. The shaded peak in each graph represents the
binding of the serum in the absence of the drug. Pt indicates
patient.
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Flow cytometry was also used to test the binding of the patient
antibody to mouse L cells that had been stably transfected with either
the human GPIb and GPIX cDNA (L IX cells) or the human GPIb
and GPIb cDNA (L cells). Binding was not observed in the
absence of rifampicin. In the presence of rifampicin, the drug-dependent antibody bound only to L IX cells and not to the L
cells (Figure 4). These data
indicate that the rifampicin-dependent antibody binds specifically to
the GPIX subunit of the GPIb-IX complexGPIX is the only component not
present on the L cells.
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| Fig 4.
Binding of the rifampicin-dependent antibodies to L IX
and L cells.
The L IX and L cells were incubated with patient serum in the
presence or absence of rifampicin, followed by an FITC-conjugated
secondary antibody, and examined by flow cytometry. The patient serum
did not bind in the absence of the drug (shaded peak). The patient
serum bound to the L IX cells (A) but not to the L cells (B)
in the presence of the drug. The shaded peak in each graph represents
the binding of the serum in the absence of the drug. The figure
illustrates the results from 1 experiment that is representative of the
results observed on the 3 occasions the experiment was performed.
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Rifampicin- and quinine-induced antibodies bind a similar or
identical epitope on GPIX
The MAIPA assay is an antigen-capture ELISA that uses an mAb to
capture GPIb-IX after the human drug-dependent antibody has attached to
the GP complex at a site distant from the mAb-binding site
(Figure 5A). If the human antibody and the
murine mAb-binding sites coincide or are in close proximity, the human
antibody will cross-block the binding of the mAb, the antigen is not
captured, and a negative result is obtained (Figure 5B).
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| Fig 5.
Schematic representation of the MAIPA assay.
The MAIPA assay is an antigen-capture ELISA that uses a mAb to capture
GPIb-IX complex to which the human drug-dependent antibody has already
bound at a site distant from the mAb-binding site (A). If the human
antibody and the murine mAb-binding sites coincide or are in close
proximity to each other, the human antibody cross-blocks the mAb, the
antigen/drug-dependent antibody complex is not captured by the
anti-mouse IgG antibody, and a negative result is obtained (B).
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When the experiment was repeated using the anti-GPIX mAb, SZ1, a
negative result was obtained because the rifampicin-dependent antibody
bound to platelet GPIb-IX blocked the antigen capture by SZ21
(Figure 6A). As we have shown previously
(Figure 1), antigen capture was not inhibited when other
non-cross-blocking mAbs (GPIb-specific, AK2, and GPIX-specific,
FMC25) were used, and a positive result was obtained with each of these
mAbs. These data confirm that the specificity of the antibody in the
patient's serum is GPIX rather than GPIb or GPIb. The same
antibody panel was used to assay the binding to platelets of the
GPIX-specific quinine-dependent antibody, and a comparable result was
obtained (Figure 6B). These results indicated that the epitopes of the
rifampicin- and quinine-dependent antibodies were identical or located
in close proximity to each other (and also to that of mAb SZ1).
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| Fig 6.
Inhibition of rifampicin- and quinine-dependent antibody
binding by anti-GPIX mAbs.
MAIPA studies were performed in the presence and absence of rifampicin
(A) or quinine (B) with patient serum and a mAb as indicated in the
figure. (A) The results of the rifampicin-induced serum binding to
platelets in the presence or absence of rifampicin and a cross-blocking
anti-GPIX mAb (SZ1) or a non-cross-blocking anti-GPIX mAb (FMC25).
Binding was not observed in the absence of rifampicin. The
rifampicin-dependent antibody did not inhibit the binding of FMC25,
giving a positive result. Conversely, the drug-dependent antibody
almost completely inhibited SZ1 binding, giving a negative result. (B)
The results of 1 representative quinine-induced thrombocytopenia
patient's serum binding to platelets in the presence or absence of
quinine and an anti-GPIX mAb (FMC25 or SZ1). No binding was observed in
the absence of quinine. The quinine-dependent antibody did not inhibit
the binding of FMC 25, again giving a positive result. Conversely, the
quinine-dependent antibody inhibited SZ1 binding, giving a negative
result. The striped box indicates binding in the presence of the drug;
the filled box indicates binding in the absence of the drug; Qn,
quinine; Rif, rifampicin; Pt, patient.
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Discussion |
In this study, we have shown that the antibody of a patient with
rifampicin-induced thrombocytopenia interacts drug-dependently with the
platelet GPIb-IX complex, and not the GPIIb-IIIa complex, using flow
cytometry, the MAIPA assay, and immunoprecipitation.
GPIb is a major sialoglycoprotein on the platelet cell surface, with
approximately 25 000 copies per platelet.13 GPIb is composed of 2 subunits, the subunit of approximately 143 kd that is
disulphide-bonded to a smaller subunit of about 24 kd. GPIb is
noncovalently linked to GPIX that has a molecular mass of 20 kd. The 3 glycoproteins have leucine-rich motifs, and they exist as a
heterodimeric complex in the platelet
membrane.5,6,14 The subunits of GPIb-IX are
encoded by separate genes.7-9,15
To determine which component of the GPIb-IX complex, the
rifampicin-dependent antibody, was binding to, we used CHO and mouse L
cells stably transfected with various components of this complex as
described in "Methods." Drug-dependent binding of the patient antibody was observed on the CHO IX cells that contained all 3 components of the complex. When the mouse L cells were transfected with
2 of the 3 components of the complex, binding was only observed on the
L IX cells in the presence of the drug. Binding was not observed on
the L cells, indicating that neither of these components contained the epitope recognized by the drug-induced antibodies. These
results indicate that the rifampicin-dependent antibodies bind an
epitope on GPIX on the platelet surface. The CHO cell line transfected
with GP Ib and GPIX cDNA was not tested because it expressed only
GPIb on the cell surface, but GPIX was present in the cytoplasm
(see "Methods").
The rifampicin-dependent antibody was able to inhibit the binding of
the mAb SZ1, specific for GPIX,16 in the competitive MAIPA
assay. The binding of this mAb was also inhibited by binding of the
quinine-dependent antibody in the same assay, shown in this study and
previously reported by our group.17 It is interesting that
2 other drug-induced antibodies could also block the binding of the mAb
SZ1 to platelets. Gentilini et al18 recently reported that
the ranitidine-induced antibody blocked the binding of SZ1 to
platelets, and we have observed the same inhibitory effect previously
on the binding by quinidine-induced antibodies.17 These
observations suggest that these 4 drug-induced antibodies and the mAb
SZ1 bind to either the same site or sites very close to each other.
Because the binding sites of 4 drug-induced antibodies have been mapped
to this region of GPIX, it is possible that the epitopes of many other
drug-induced antibodies may also be localized to this site. The reason
for the colocalization of the binding sites of these 4 antibodies is at
present unclear because the drugs involved are chemically or
structurally dissimilar, except for quinine and its optic isomer, quinidine.
In summary, this is the first study to map the epitope of the
rifampicin-dependent antibody to the GPIX subunit of the GPIb-IX complexmore specifically, to a domain that is also the common binding
site of 3 other drug-induced antibodies. This region of GPIX
obviously plays an important role in epitope formation for drug-induced antibodies. Further elucidation of the characteristics of
this region on GPIX is clearly required, and it will provide useful
insights into the mechanisms of drug-induced thrombocytopenias.
| |
Acknowledgment |
We wish to thank Ms Sue Evans for assistance with the MAIPA assay.
| |
Footnotes |
Submitted February 8, 1999; accepted November 15, 1999.
Supported by a grant from the National Health and Medical Research
Council of Australia.
Reprints: Beng H. Chong, Department of Hematology, Prince of
Wales Hospital High and Avoca Sts, Randwick, NSW 2031, Australia;
e-mail: b.h.chong{at}unsw.edu.au.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction