After the events of the Mark of Cain, releasing the darkness and heaven being restored; Sam and Dean have been desperately looking for their friend/lover Melanie, who has been captured by her sire bond's nest and is being held in an abandoned bank vault with a few other vampires for three months, who are being deprived of human blood making them and her bloodthirsty. After attempting to save Melanie, they start to realize something is off with her behavior as she begins to go on a killing spree and they try their best to put the pieces back together to help her.

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