Mikuni's backstory. Let's just say it involves a sick little sister and we'll leave it at that.
When Jennifer Sato ended up being bankrupt by her deal with Mikuni. While she was sliced in half and bleeding out black bills, she passed on her Asset, Georges, to Kimimaro. Even though we know that she's alive, she looked like she was dying and now has no future.
The ending. Kimimaro's in a world where he shouldn't exist...
And before that, Mikuni opting to stay behind in the world of "today" (the one which had lost its future), plus Q and Msyu disappearing along with the FD. It gets sadder when Kimimaro pulls out a photo of himself with Mikuni, Q and Msyu at the end, considering that their chances of meeting again may well be zero.
Kimimaro: I should have been smiling.
And even before that, the dreamlike sequence where Mikuni talks to Takako, only to realize he's become a lot like his father, who stopped Takako's transfer to another hospital for financial reasons. And then he sees that she's gone. You can hear that he's on the verge of tears.
Hanabi from her third apperance or so on becomes more and more miserable, first with a flu, then depression and finally an obvious case of Sanity Slippage along with never having met Yoga to begin with. Considering that it's absolutely not her fault, it's really heart breaking to see. And of course, she also stands for all the other people we never see but get clued in to have increasingly more horrible lives as the FD battles continue on.