Saracens say that England lock Maro Itoje will be sidelined "for a number of weeks" after suffering a knee injury.
The Gallagher Premiership leaders revealed that the 26 times-capped forward was injured on England duty.
And it is potentially a colossal blow for England boss Eddie Jones if Itoje's Six Nations participation is under threat.
England's opening game is against Ireland in Dublin on February 2, while Saracens face a number of key Heineken Champions Cup games and Premiership matches throughout December and January.
"Maro Itoje will be sidelined for a number of weeks after suffering a knee injury," Saracens said in a statement.
"The 24-year-old took a knock whilst on international duty with England, and scans have revealed a chip in his patella."
While Itoje is out of Sunday's Champions Cup clash against Cardiff Blues at Allianz Park, his England and British and Irish Lions Test colleague Mako Vunipola returns to action.
Vunipola has not played since October because of a calf strain, missing England's autumn internationals, but he will start against the Welsh side.
Rob Baxter, meanwhile, is under no illusions at the size of Exeter's task as they pursue making progress in this season's Champions Cup.
Exeter, beaten only once in the Premiership this term and two points behind leaders Saracens, currently prop up Pool Two.
They host Gloucester on Saturday, then face a return fixture at Kingsholm next Friday, with Munster and Castres to be tackled in January.
"On paper, even if we were to lose this weekend, there would still be 15 points up for grabs - and we've seen sides in the past qualify with 18 points," Exeter rugby director Baxter said.