Cephalosporin‐induced immune cytopenia in the dog: Demonstration of erythrocyte‐, neutrophil‐, and platelet‐associated igg following treatment with cefazedone

Abstract

Cephalosporin treatment in man has been associated with a low incidence of hemolytic anemia, thrombocytopenia, and neutropenia; some cases have been shown to be immune-mediated. This triad of blood dyscrasias was also demonstrated in our laboratory in a series of toxicity studies in dogs of two cephalosporin compounds, cefonicid and cefazedone; these studies provided evidence for drug-associated immune hemolytic anemia, based on conventional laboratory tests. To further investigate possible immune mechanisms of the cephalosporin-induced cytopenias, we measured erythrocyte-associated, platelet-associated (PAIgG), and serum antineutrophil IgG over the course of cephalosporin treatment, using highly sensitive 125I-staphylococcal protein A (SPA) assays, as well as the direct antiglobulin test; we compared these findings with the hematologic changes. Intravenous treatment with high doses of cefazedone (540 mg/kg/day, increased to a maximum of 840 mg/kg/day for 4 months or until hematologic effects were evident) resulted in a high incidence of anemia (7/14), thrombocytopenia (11/14), and neutropenia (7/14). Of the affected dogs examined, 6/7 with anemia, 9/9 with thrombocytopenia, and 7/7 with neutropenia showed increased levels of the respective cell-associated antibody, compared with untreated controls. Unaffected dosed animals generally did not show these changes. In 3/3 dogs examined following remission of thrombocytopenia, PAIgG returned to levels comparable with controls; as one of these dogs suffered a relapse, increased PAIgG was again observed. Animals sacrificed during cytopenic episodes showed cytologic and histologic evidence of increased hemophagocytosis. We conclude that antibody-mediated blood cell destruction contributes to all three cephalosporin-induced cytopenias in the dog.

Canine idiopathic immune-mediated haemolytic anaemia: a review with recommendations for future research

“…Most of these risk factors have been taken from the human literature (Sokol et al 1992(Sokol et al , 1994, and relatively few have been confirmed in dogs. Sulphonamides, cephalosporin, and carprofen have been linked with IMHA (Bloom et al 1988;Trepanier et al 2003;Trepanier 2004;Mellor et al 2005;Lavergne et al 2006). The association of vaccination in one study was not confirmed in two other studies (Duval and Giger 1996;Astrup et al 1998;Carr et al 2002).…”

Treatment of canine idiopathic immune‐mediated haemolytic anaemia with mycophenolate mofetil and glucocorticoids: 30 cases (2007 to 2011)

“…IMHA occurs secondarily to infections, toxins, drugs, parasites and neoplasia although vaccines have also been implicated (Bloom et al . , Reimer et al . , Mellor et al .…”

“…Mortality rates for idiopathic IMHA range from 22 to 80%, with significantly increased mortality early in the disease course (Bloom et al . , Reimer et al . , McCullough , Piek et al .…”

“…IMHA may result from intravascular haemolysis of erythrocytes following activation of complement and/or extravascular haemolysis subsequent to immunoglobulin opsonization and phagocytosis by the reticulo-endothelial system (McCullough 2003, Mitchell & Kruth 2010. IMHA occurs secondarily to infections, toxins, drugs, parasites and neoplasia although vaccines have also been implicated (Bloom et al 1988, Reimer et al 1999, Mellor et al 2005, Mitchell & Kruth 2010, Swann & Skelly 2011, Whitley & Day 2011. Idiopathic or primary IMHA, reported in 60 to 75% of canine IMHA cases, is a diagnosis of exclusion (Reimer et al 1999, Mitchell & Kruth 2010.…”

Review of Continuing Education Course on Hemostasis

“…The Improved Fit model has been proposed for those drugs that only weakly interact with platelet proteins, such as quinidine, quinine, nonsteroidal anti-inflammatory drugs (NSAIDs), various antibiotics, sedatives, and anticonvulsants (Bougie, Wilker, and Aster 2006). DDAbs have been identified in a dog with cephalosporin-induced ITP (Bloom et al 1988) and in companion dogs with sulfonamide-induced ITP (LaVergne and Trepanier 2007). LaVergne and Trepanier (2007) were not able to identify the platelet target of the sulfonamideinduced antiplatelet antibodies in dogs but were able to determine that GPIIbIIIa and GPIb were not targeted as occurs in humans.…”