Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production <i>via</i> Phosphorylation of Myosin Light Chain 2

Abstract

Linezolid (LZD) is an antimicrobial that is commonly used for treatment of vancomycin-resistantEnterococci and methicillin-resistant Staphylococcus aureus infections. However, the development of thrombocytopenia, one of the most frequent adverse side effects of this antimicrobial, can lead to discontinuation of LZD treatment. While clinical studies indicate that risk factors for the development of LZD-induced thrombocytopenia include treatment for >14 consecutive days, renal dysfunction, and chronic liver disease, the fundamental mechanism governing the pathogenesis of this disorder remains unclear. In this study, we aimed to elucidate the mechanism of LZD-induced thrombocytopenia by investigating the impact of LZD treatment on platelet destruction and production using rat platelet-rich plasma (PRP) and human immortalized cell lines, respectively. Compared to the control population, an increase in lactate dehydrogenase release was not detected upon exposure of rat PRP to varying concentrations of LZD, indicating that this compound is not cytotoxic towards platelets. Meanwhile, LZD treatment resulted in a significant dose-dependent increase in the proliferation of HEL human erythroleukemia and MEG-01 human megakaryoblast cells in vitro, but did not influence the differentiation of these cell lines. Lastly, LZD treatment yielded elevated levels of phosphorylation of myosin light chain 2 (MLC2), which regulates platelet release, in MEG-01 cells. Based on these results, we speculate that LZD induces thrombocytopenia by promoting MLC2 phosphorylation and thereby suppressing the release of platelets from mature megakaryocytes. These findings provide the first insight into the mechanism of LZD-mediated thrombocytopenia and may facilitate the development of strategies to treat and/or prevent this disease.

A retrospective cohort study to screen linezolid-induced thrombocytopenia in adult patients hospitalized in the Midwestern Region of Brazil

“…For example, Tajima et al suggested that LDZ use for more than 14 days, renal dysfunction and chronic liver disease were risk factors linked to linezolid-induced thrombocytopenia. 9 In addition, a low baseline platelet count and body weight were associated with a decrease in the peripheral platelet count. 13 , 14 However, the main mechanism that regulates the pathogenesis of this adverse effect is still obscure.…”

“…Although linezolid use has advantages, it has been associated with adverse effects such as gastrointestinal disorders, hematological toxicity and cutaneous reactions. 8 , 9 The hematological reactions include anemia, eosinophilia, myelosuppression, neutropenia, cell aplasia and thrombocytopenia. 10 The normal peripheral platelet count is between 150 and 450 × 10 3 /mm 3 .…”

Reversible recurrent profound thrombocytopenia due to linezolid in a patient with multi-drug resistant tuberculosis

“…A previous study has shown that LZD could cause the inhibition of the release of platelets from mature megakaryocytes, thus resulting in the development of thrombocytopenia. [ 17 ] Similarly, other studies suggested that thrombocytopenia was caused by the inhibition of platelet formation. [ 18 ] In contrast, a case report found an immune-mediated mechanism of platelet destruction may be the mechanism.…”

Antibiotic Treatment Protocols and Germ-Free Mouse Models in Vascular Research

“…The underlying mechanisms for thrombocytopenia (i.e., a circulating platelet count inferior to 150,000/mm 3 ) are increased platelet consumption/destruction or reduced platelet production. Linezolid, an antibiotic commonly used to treat vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus infections, is known to induce myelosuppression, but is more frequently associated with thrombo- than pancytopenia (62). It was described that linezolid has no direct toxic effects on platelets and it does not affect the differentiation of hematopoietic stem cells, but via phosphorylation of an enzyme relevant for platelet release, it induces thrombocytopenia (62).…”

“…Linezolid, an antibiotic commonly used to treat vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus infections, is known to induce myelosuppression, but is more frequently associated with thrombo- than pancytopenia (62). It was described that linezolid has no direct toxic effects on platelets and it does not affect the differentiation of hematopoietic stem cells, but via phosphorylation of an enzyme relevant for platelet release, it induces thrombocytopenia (62). Although some influences of antibiotics on platelet functions were identified, the information on effects of antibiotic treatment on the coagulation system remains sparse.…”