"You've got your warrior, your leader in the locker room, your leader of the team and that presence alone," Pagano said, via the team's official website. "It was missed last night and now it will be missed.
"Really a devastating blow for Robert, his family, our team and our organization. This one stings."
A finalist for Defensive Player of the Year last season, Mathis was the lone difference-maker on a defense that has allowed an average of 39 points and 431 yards in the last three games, going back to last year's playoffs.
Pagano was brought to Indianapolis for a defensive expertise that has yet to materialize as an organizational strength. If he can't generate a pass rush in Mathis' absence, Colts fans might begin to wonder if he's the right man for the job.