Chlorpropamide-induced pure white cell aplasia

Abstract

We investigated the mechanism for isolated agranulocytosis and marrow pure white cell aplasia in an elderly man receiving 0.5 to 1.0 g per day of chlorpropamide (Chl) without other toxic drug exposure or overt systemic illness. Patient marrow revealed an absence of recognizable granulocytic precursors; megakaryocytes and erythroid precursors were normal. The WBC count was 1800/mm3 on admission with only 2% neutrophils; the absolute neutrophil count first exceeded 500/mm3 on the 17th day following cessation of Chl. A serum Chl level on admission was 100 micrograms/mL (acute phase, AP); no Chl was detected in serum (convalescent phase, CP) assessed on the 22nd hospital day. Antineutrophil antibodies were not detected, and T cell depletion failed to augment patient in vitro granulopoiesis. Patient AP serum produced potent complement-mediated inhibition (87% +/- 7%) of autologous granulocyte progenitors (CFU-GM) with minimal inhibition of erythroid (11% +/- 5%) or multipotent (5% +/- 4%) progenitor cells. Selective inhibition by patient AP serum of CFU-GM (74% +/- 11%) was also seen against two allogeneic marrows. Patient CP serum no longer inhibited (6% +/- 4%) autologous CFU-GM. Addition of Chl (5 to 120 micrograms/mL) to CP serum but not to control serum resulted in potent drug concentration-dependent complement-mediated inhibition of autologous and allogeneic CFU-GM. Inhibition of CFU-GM in the presence of Chl was no longer demonstrable following immunoabsorbent removal of IgG from patient serum. Patient serum in the presence of Chl had limited activity against morphologically recognizable marrow granulocytic precursors in a microimmunofluorescence assay. These results are most consistent with the development of Chl-dependent, selective antibody-mediated immune inhibition of granulopoiesis.

Complete remission of pure white cell aplasia associated with thymoma, autoimmune thyroiditis and type 1 diabetes

“…There are only four descriptions of primary PWCA (3–6). Secondary PWCA has been described with ibuprofen (7) and chlorpropamide (8), with complement activation by a specific antibody exclusively in the presence of the drug. We report a case of PWCA associated with thymoma and unusual findings including simultaneous presence of autoimmune thyroiditis, type 1 diabetes, and anti‐striated muscle antibodies.…”

Pure White Cell Aplasia Complicated by Systemic Sclerosis with Accompanying Scleroderma Renal Crisis

“…However, drug-induced neutropenia was able to be ruled out in this case, as the neutrophil count eventually recovered even after continued medication. While the possibility of drug-induced PWCA could not be completely ruled out, a PubMed search revealed that the drugs commonly reported for drug-induced PWCA are chlorpropamide ( 8 ), ibuprofen ( 9 ), imipenem-cilastatin ( 10 ), mesalazine ( 11 ), and amodiaquine ( 12 ). No PWCA-inducing drugs or drugs of the same type were used in the present case.…”

“…Clinically, patients with PWCA suffer from recurrent infections. Previously, thymoma and thymic carcinoma (5)(6)(7) as well as drug-induced (8)(9)(10)(11)(12) and autoimmune diseases (13)(14)(15) were reported in PWCA patients. The immunologic mechanisms have been demonstrated in some PWCA cases where an inhibiting antibody was found (15).…”

Nonchemotherapy drug-induced agranulocytosis: experience of the Strasbourg teaching hospital (1985-2000) and review of the literature

“…The failure to reproduce such a mechanism experimentally may be due to either antibody specificity for a drug's intermediate metabolite or a low antibody titre (Claas, 1996). In some cases, antibody binding to a myeloid progenitor cell has been inferred from the inhibition of colony‐forming unit–granulocyte/macrophage‐derived colony formation by the patient's serum (Lewitt, 1987).…”