Blood, 1 April 2001, Vol. 97, No. 7, pp. 2186-2187
CORRESPONDENCE
To the editor:
Drug-dependent antibodies against the prodrug carbimazole do
not react with the active metabolite thiamazole
Drug-induced immune thrombocytopenia (DITP) is a sometimes
severe complication of drug treatment. Recently, we described 5 patients who presented with relatively mild thrombocytopenia after treatment with the antithyroid drug carbimazole
(1-carbethoxy-3-methyl-2-thioimidazole).1 Serologic and
immunochemical analysis revealed drug-dependent antibodies (DDAbs)
against the platelet endothelial cell adhesion molecule-1 (PECAM-1,
CD31). Because the chemical analog of carbimazole, thiamazole
(3-methyl-2-thioimidazole), is widely used for the treatment of
hyperthyroidism in the US, we asked the question whether carbimazole
DDAbs cross-reacted with thiamazole. Sera from 4 patients of our
initial study (patients 2-5; patient 1 died and no further serum was
available) were analyzed by enzyme immunoassay with intact platelets in
the presence and in the absence of 1 mg/mL carbimazole or thiamazole,
as previously described.1 As shown in Figure
1, all carbimazole DDAbs failed to react
with platelets in the presence of thiamazole. Analysis of DDAbs in the
glycoprotein-specific immunoassay (MAIPA) revealed positive reactions
with PECAM-1 in the presence of carbimazole but not with
thiamazole (data not shown). Specific interaction between carbimazole
and the platelet membrane has to be assumed because only a minor
chemical modification of carbimazole led to destruction of the
carbimazole DDAb reactivity. This has already been suggested by our
finding that the second extracellular loop of PECAM-1 was crucial for
epitope formation.1 In addition, the carbethoxy group
of carbimazole at position C-1 seems to be important for the immune
response and subsequent thrombocytopenia in the patient after drug
treatment. Carbimazole is a prodrug that is rapidly and totally
converted to thiamazole in the body by cleavage of the carbethoxy
group.2 This phenomenon could contribute to the clinical
presentation of mild thrombocytopenia in our patients. Due to the high
specificity of DDAbs, binding and platelet destruction could only occur
during the phase immediately after carbimazole administration. After
metabolism to thiamazole, no further platelet destruction takes place.
This phenomenon might represent an interesting counterpart of the
situation observed in patients in whom metabolite-specific DDAbs induce
a prolonged effect in relation to drug excretion.3 We
conclude that both the chemical structure and the metabolism of the
drug may have a major influence on the clinical presentation of DITP,
particularly on the degree of thrombocytopenia. Further observations
will be required to define whether thiamazole itself is able to raise a
drug-dependent immune response against platelets.
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| Figure 1.
Carbimazole-dependent antibodies in enzyme immunoassay.
Binding of carbimazole-dependent antibodies in sera from 4 patients in
the presence of carbimazole (1 mg/mL), thiamazole (1 mg/mL), and
without either drug. O.D., optical density.
|
|
Hartmut Kroll, Astrid Giptner, and Sentot Santoso
Institute for Clinical Immunology and Transfusion
Medicine, Justus Liebig University Giessen Giessen, Germany
References
1.
Kroll H, Sun Q-H, Santoso S.
The platelet endothelial cell adhesion molecule-1 (PECAM-1) is a target glycoprotein in drug-induced thrombocytopenia.
Blood.
2000;96:1409-1414[Abstract/Free Full Text].
2.
Jansson R, Dahlberg PA, Lindstrom B.
Comparative bioavailability of carbimazole and methimazole.
Int J Clin Pharmacol Ther Toxicol.
1983;21:505-510[Medline]
[Order article via Infotrieve].
3.
Kiefel V, Santoso S, Schmidt S, Salama A, Mueller-Eckhardt C.
Metabolite-specific (IgG) and drug-specific antibodies (IgG, IgM) in two cases of trimethoprime-sulfamethoxazole-induced immune thrombocytopenia.
Transfusion.
1987;27:262-265[CrossRef][Medline]
[Order article via Infotrieve].
