The biggest was that they nuked their main product lines. Their Big Three (Vampire, Werewolf, and Mage) always had a vibe going of imminent ending, and they eventually published a set of three books (plus IIRC one for all the other lines) where that actually happened. This was then followed by the New World of Darkness which, while it certainly had some things going for it, never had the same appeal as the original WoD.
This was a bizarre self-own, caused -- IMO -- but White Wolf leaning into an audience that bought the books to read and were excited about the metaplot, rather than the people who actually used them to play.
So you give the readers an end point to stop reading the oWoD books by ending all of the lines. (Yes, there was always a strong fin de siècle element to the oWoD, but as we see in the real world, you can just keep nudging the apocalypse off into the future indefinitely, if you do it right.) And the readers got to the end of the oWoD and decided this was an opportunity to spend their dollars on something else going forward.
The remaining gamers who had gotten pretty vocal about the quality of the books going way downhill were being asked to finance the whole operation starting over again. Some of the lines, like VtR, were definitely better, while others, like Mage: The Awakening, had a harder time articulating what was cooler and more exciting about the new lines, which didn't exactly send the oWoD players rushing to switch over to nWoD.
And, of course, this is all around the same time that WotC was coincidentally pushing a return to a less-dusty, modernized 3E D&D, which almost certainly bled off at least a certain amount of oWoD gamer dollars.
They were also producing a huge number of product lines, with varying levels of relation to one another as well as various levels of using the same rules. You had the World of Darkness with its original Big Five (Vampire, Werewolf, Mage, Wraith, and Changeling), followed by assorted other product lines (Hunter, Mummy, Demon, Kindred of the East, probably something I'm forgetting), some of which required another core book. You also had the three games in the Trinity Continuum: AeonTrinity, Aberrant, and Adventure!. There was Exalted, which tried to challenge D&D for the fantasy space (I remember they were doing a promotion where you could send them your PHB and they'd send you the Exalted core book). I'm guessing they were learning some of the same lessons as TSR did about splitting the customer base too many ways.
They also had a hard time deciding whether these other lines were connected to the oWoD, which could in theory draw in some customers (especially the readers, who loved the hints of lore connections between Exalted and the oWoD), but which also likely made the customers who already felt overwhelmed by the amount of content roll their eyes and decide they didn't want to pick up another 20 books so that their White Wolf games would be "complete."
And eventually, the owners sold out to CCCP (the Icelandic company making Eve Online), who were flush with cash but pretty soon had to contract, and the RPG side were the ones suffering for it.
And, of course, in the 21st century, the ownership and management made a lot of bizarre and very public mistakes with the line, which kept lots of people away, making the lines less profitable for the ownership and making FLGSes less likely to shell out their money for books that could just gather dust on store shelves or, at worst, get the owners into some uncomfortable questions about what they were selling in their stores.