Immune Thrombocytopenic Purpura following Administration of mRNA-Based SARS-CoV-2 and MMR Vaccinations: A Cautionary Tale.

We report a case of immune thrombocytopenic purpura (ITP) in an otherwise healthy 31-year-old man following coadministration of the live measles, mumps, and rubella (MMR) vaccine with the Pfizer-BioNTech mRNA SARS-CoV-2 vaccine. The patient was hospitalized briefly and treated for ITP with glucocorticoids, IVIG, and platelet transfusion. Although our patient's clinical presentation and subsequent course are similar to those of other cases of ITP in association with SARS-CoV-2 vaccination, to our knowledge, this is the first reported case of ITP following MMR and mRNA SARS-CoV-2 vaccine coadministration. It would be impossible to conclusively prove that the patient's thrombocytopenia was secondary to the SARS-CoV-2 vaccine alone, the MMR vaccine, or an additive effect of both vaccines. However, with the CDC guidelines recommending the coadministration of the mRNA SARS-CoV-2 vaccine without regards to timing with other vaccines, we urge further caution as there is limited evidence to inform practice. This case highlights the need for further safety data regarding the coadministration and timing of the mRNA SARS-CoV-2 vaccine with other vaccines.

Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling.

The transactivation of growth factor receptors is an early event in H(2)O(2)-induced signaling, although proximal targets in this process remain unclear. We found that inhibition of flavin- or heme-containing proteins eliminated H(2)O(2)-induced transactivation of the epidermal growth factor receptor and stimulation of its downstream targets, JNK and Akt. Inhibition of mitochondrial function with rotenone, antimycin A, KCN, carbonylcyanide-m-chlorophenylhydrazone, or oligomycin reproduced this effect, as did generation of mitochondrial DNA-deficient (pseudo-rho(0)) cells. Mitochondrial function had no role in JNK activation in response to UV irradiation or tumor necrosis factor-alpha. The impact of mitochondrial function on H(2)O(2)-induced growth factor transactivation was ubiquitous and applied to both the vascular endothelial growth factor (VEGF)-2 receptor and the platelet-derived growth factor-beta receptor in endothelium and fibroblasts, respectively. In contrast, ligand-induced growth factor activation was unrelated to mitochondrial function. Growth factor receptor transactivation and its downstream signaling in response to H(2)O(2) appeared to involve redox-sensitive mitochondrial events as they were abrogated by a mitochondrial-targeted antioxidants but not their nontargeted counterparts. Functionally, we found that mitochondrial-targeted antioxidants inhibited H(2)O(2)-induced apoptosis and cell death but had no effect with UV irradiation. These data establish a novel role for the mitochondrion as a proximal target specific to H(2)O(2)-induced signaling and growth factor transactivation.

Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation.

Phosphorylation of the p53 tumor suppressor protein is a critical event in the up-regulation and activation of p53 during cellular stress. In this study, we characterized the signaling pathway linking oxidative stress to p53 through the platelet-derived growth factor beta (PDGF beta) receptor and the ataxia telangiectasia mutated (ATM) kinase. In response to H2O2, we observed phosphorylation of p53 specifically at serine 15, but not serine 9, 20, or 392. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the p53 target p21CIP/WAF. We found that H2O2 induced phosphorylation of the PDGF beta receptor and increased ATM kinase activity, two events integral to p53 activation as either AG1433 (a PDGF beta receptor inhibitor) or caffeine (an ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Similarly, p53 activation by H2O2 was inhibited by kinase-inactive forms of the PDGF beta receptor or ATM. Inhibition of ATM kinase had no effect on H2O2-induced PDGF beta receptor tyrosine phosphorylation, whereas PDGF beta receptor suppression with RNA interference impaired H2O2-induced ATM activation, indicating that ATM lies downstream to the PDGF beta receptor in this signaling cascade. Functionally, inhibition of the PDGF beta receptor abrogated the inhibition of cell proliferation, and promotion of apoptosis due to H2O2 treatment. Thus, these data link PDGF beta receptor transactivation to H2O2-induced p53 phosphorylation and suggest a functional role for growth factor receptors in modulation of p53 function.