Hopefully, not too late to answer :-)
The question about TM is basically not an issue of OmegaT, but an issue of your habits as to workflow. I prefer to have separate TMs at least for different topics of translation (say, technical and legal apart, within technical, mechanics and electronics apart etc.). The largest combination of TM I use in a single project is about 80000 TUs in 3 files. I don't know, if it matches your criteria of “very large TM files”.
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