When we travel with a larger cat (that a few FT'ers have met at a few Dos) we try if at all possible to get a pair of seats in F and not stow any other luggage underseat. He's right near the 15 pound weight limit so we want to make sure he has all the possible room. We won't do a RJ at all, even if it means doing a connecting flight instead of a non-stop.
Rather than doing transcons, we also try to break up the flights with stopovers that prevent him from doing more than 3 hours per flight. For us in RDU, that usually means a stopover in the DFW/MSP area before continuing on the next flight.