Metabolite‐specific (IgG) and drug‐specific antibodies (IgG, IgM) in two cases of trimethoprim‐sulfamethoxazole‐induced immune thrombocytopenia

Abstract

Two cases of trimethoprim-sulfamethoxazole (TMP-SMX)-induced immune thrombocytopenia are reported in which unusual drug-dependent platelet antibodies were demonstrated by immunofluorescence and enzyme-linked immunosorbent assay. Whereas two distinct sulfamethoxazole-dependent antibodies of the IgG and IgM class were detectable in the serum of one patient, the serum of the other patient contained a platelet antibody exclusively reactive with N-4-acetyl-sulfamethoxazole, a metabolite of sulfamethoxazole. Urine from a healthy volunteer collected after administration of therapeutic doses of TMP-SMX proved to be an appropriate source of ex vivo metabolites for antibody testing. The results of this study stress the role of metabolite-specific antibodies in drug-dependent immune thrombocytopenia and underscore the necessity of including metabolite preparations of drugs in serologic analyses.

Considerations when prescribing trimethoprim-sulfamethoxazole

“…Generation of antibodies to the glycoprotein IIb/IIIa complex on platelets can cause immune thrombocytopenia, which is typically observed within the first week of treatment and is generally reversible on discontinuation of the drug. [47][48][49] Although uncommon at therapeutic doses, the inhibition of folate metabolism by trimethoprim can cause dose-related leukopenia and megaloblastosis, both of which are responsive to folinic acid. 41,42 Periodic monitoring of the complete blood count may be advisable in patients receiving a high dose of trimethoprimsulfamethoxazole for extended periods.…”

“…Immune-mediated idiosyncratic reactions are often associated with a reactive metabolite, lead- [44][45][46] Hemolytic anemia Glucose-6-phosphate dehydrogenase deficiency [44][45][46] Drug-induced thrombocytopenia Antibody-mediated destruction of platelets with specificity for the glycoprotein IIb/IIIa complex [47][48][49] Cyanosis, "chocolate-coloured" blood, and falsely low oxygen saturation on pulse oximetry but a normal oxygen saturation on arterial blood gas measurement ("saturation gap")…”

Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen

“…Another explanation for failure to obtain laboratory confirmation in patients with apparent drug-induced immune cytopenia is that the sensitizing agent can be a structurally modified form of the sensitizing drug resulting from in vivo metabolism, [6][7][8] but the frequency of this complication and the range of metabolites that can cause it are poorly defined. We recently encountered 5 patients who experienced thrombocytopenia while taking the nonsteroidal anti-inflammatory drug (NSAID) naproxen or the antipyretic acetaminophen.…”

Drug-dependent antibodies against the prodrug carbimazole do not react with the active metabolite thiamazole

“…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.…”

“…The G-CSF-R became abnormal when he developed leukemia. 3 4. In our Seattle studies of patients with severe congenital neutropenia evolving to leukemia, 6 of 7 patients have had ELA2 mutations.…”