With as far back as it is, there would be a real chance to do something different with the tribes at least.
We have seen the tribes used mechanically differently nearly each visit though, while they all have similar wider tribal themes they have had different tribal decks each time. Like spirit decks have always had control elements but first time was more flying and tapping, second trip was more blink and now we got the disturb and aura stuff.
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Additionally, I wouldn't see it ending with Avacyn's creation since I'm talking so far back wed be witnessing the genesis of the vampires.
Point remains, the conflict would still be humans being hunted by monster only vampires are the new kids on the block, only we know Sorin at some point later will make Avacyn and have balance.
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That far back, there are theoretically different things you could do, lean more heavily into the sea monsters, make the spirits in different colors, have alchemists be prominent instead of stitchers (since that was Edgar's thing in the first place), hell, there was even that old joke about elves once being on Innistrad but they were eaten into oblivion for being too delicious.
I mean we seen stuff like this in this "block", the alchemists and necromancers are more well liked after Emrakul and we see them prominent in the spell slinger theme in UR cards, vampires and werewolves got colors outside of their default, all the different horror sub genres they added in and at it base a lot of Innistrad is now changed due to Emrakul.
And a big thing is returns sets are meant to give more of what people liked. While they should be evolving and expanding on them, it does need to have some core identity that otherwise you could just make a new plane.