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Tear Jerker: Blood+
George's death is particularly saddening, considering before he dies he tells Kai to take care of Saya and Riku and tells Saya never to forget to smile. Later on Riku is killed by Diva, causing Saya to become a emotionally distant Death Seeker hellbent on revenge and estranged from her allies.
Everything about Mui. The last we see of her, she has been irreversably turned into a seemingly-mindless chiropteran mutant. She taps the bottom of her cage as if playing the piano, a lost, sad look in her eyes...
The deaths of all the Schiff except Lulu.
When Saya realizes that Riku has been raped and crystallized by Diva—it only gets worse when he starts to crumble away and a fallen shipping container smashes his body to bits.
The only thing more heartwrenching than Karl's death is his life.
Solomon getting poisoned by Saya's blood when he helps her kill James. He tells her to call for him when she needs him, then takes his leave with a smile. As he's dying in an alleyway, Amshel confronts him. Solomon fails to kill him and instead dies in his arms.
Saya and Diva's attempts at convincing each other of their point-of-view before their fight to the death. They're both obviously regretting that they have to kill one another, but they still feel that they have to, for their own reasons.
Diva crying out to Saya as she is crystallizing and her last thoughts of the time she'll never get to spend with her babies. Saya breaking down and screaming in anguish really didn't help matters, nor her holding Diva's crystallized hand, or Nathan's monologue. Meanwhile, in the manga the sisters are on the verge of reconciliation and Diva's last actions are to stop Saya from killing herself to join her and to tell her beloved sister to live. Tragic in both cases is that Saya wants to die together with Diva, having planned on it for centuries. It is only once Diva is dying that Saya reveals how much she still cares about her twin, who is visibly suprised.
As a chiropteran, Saya has a much longer lifespan, meaning that she will still be alive long after all the human characters, including her adoptive elder brother Kai, are dead.
George spent years looking after a hibernating Saya, always waiting for her to wake up. Eventually he was in so much despair over everything that had happened to him that he planned to go to the Miyagusuku tomb and kill himself. And just when he was going to, Saya woke up. He tries to walk away...but Saya grabs his ankle with a adorably helpless look on her face. It was that moment he decided that he will live, and raise this girl as his own.