Discussion
Anti-TNFα induced thrombocytopenia has been reported previously in
patients with rheumatoid arthritis (2), psoriasis (3,4) and CD (5-7).
Patients were treated with both etanercept and infliximab (2),
infliximab monotherapy (5) or adalimumab monotherapy (3,4, 6,7). Of
note, most of these reports have not reported on the presence of
specific autoantibodies against platelets. Furthermore, only two of the
aforementioned reports involved patients with CD who developed
thrombocytopenia associated with exposure to adalimumab (6,7). Salar et
al. (7) describe a patient with CD who received both infliximab and
adalimumab. A thrombocytopenia of 44×109/L occurred
with platelet-associated IgG detected with a (undefined) platelet
antibody test. More recently, Casanova et al. (6) reported a patient
with CD who developed severe thrombocytopenia of
25×109/L after rechallenge treatment with adalimumab.
Tests for the presence of antibodies were not performed. In accordance
with the two patients with CD (6,7) our patient showed an increased
number of megakaryocytes in the bone marrow supporting an ITP-related
mechanism. Although an ITP-related mechanism has been speculated on in
other reports, our report with confirmed GPIIb/IIIa and GV platelet
autoantibodies provides conclusive evidence for this notion.
Our patient developed thrombocytopenia after three weeks of treatment.
In other reports, the time between the first exposure of the anti-TNFα
agent varied and extended up to >2 years. Some reports
(3,6,7) showed an asymptomatic thrombocytopenia detected by routine
blood samples, while other cases presented with bleeding symptoms (1).
Drug-induced thrombocytopenia can be classified into nonimmune and
immune-mediated thrombocytopenia. Drug-induced immune-thrombocytopenia
(ITP) can be categorized into several mechanisms including the formation
of drug-specific antibodies or drug-dependent antibodies (e.g. quinine)
and production of autoantibodies specific to platelets (e.g. gold) (8).
The exact pathophysiological mechanism of adalimumab-induced ITP is not
known. A possible explanation, analogous to Aster et al. (8), is that
adalimumab interacts with the platelets membrane GPIIb/IIIa and GPV
through bridging interactions resulting in removal from the immune
system. Another possible mechanism is that binding of adalimumab to the
platelets membrane can cause a conformational change of the GPIIb/IIIa
and GPV resulting in a neo-epitope which stimulates the formation of
antibodies against platelets. Finally, previous reports hypothesized
that anti-TNFα agents could induce apoptosis of Th1 lymphocytes leading
to a relative excess of Th2 lymphocytes that could in turn lead to the
production of antibodies (6,7).
This report adds to a general understanding of drug-induced
thrombocytopenia induced by adalimumab, which could lead to a better
recognition of this potential fatal phenomenon. Adalimumab-induced
immune-thrombocytopenia is a rare cause of thrombocytopenia reversible
upon adalimumab discontinuation. We report antibodies against multiple
epitopes including GPIIb/IIIa and GPV without bone marrow suppression.
MAIPA assay testing, if available, can be used to determine the platelet
glycoprotein target(s). In order to prevent serious adverse events we
recommend to monitor thrombocyte levels closely after initiation of
anti-TNFα therapy. Although specific studies are lacking for
drug-induced ITP, standard ITP treatment with intravenous
immunoglobulins and/or steroids may be considered if interventions are
clinically warranted.
Acknowledgement : not applicable.
Conflict of interest: all authors state that they have no
conflict of interest
Funding: none.
Data availability statement: the data that support the findings
of this study are available from the corresponding author upon
reasonable request.