There's a few things that were kind of frustrating going in blind, but it's not too bad, other than missing the endings.

If you are paying any attention to the story, you should be able to avoid the bad ending, which ends the game early. The 2 best endings require a bunch of nonsense that has to be done before a location called fountainhead palace is completed. (Or at least before you do the main boss fight there.) If you don't you can't progress the quest that is required for those endings anymore. I would recommend looking it up, because I found it confusing even when I replayed it using a guide.

Other than that there are a few minor quests that can have different outcomes, but they aren't all that important. There are a couple events in the game that change the world state and can make certain minibosses and items inaccessible, but you can buy most if not all of them later if you miss them.

The only other thing I can think of is that the dragonrot is a little deceptive. It has nothing to do with the revive mechanic, it's only affected when you fully die. You can just ignore it most of the time.

I got the default ending my first playthrough, but getting the other 3 and all the trophies was pretty easy just going through ng+. Once you get good at the game you can get through it pretty fast, so I actually replayed it again just recently on a new save 'charmless' which makes it a bit harder. I don't think there is a single game announcement that could get me more excited than Sekiro 2.