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.
— Saracens Rugby Club (@Saracens) December 7, 2018
"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.
"On anything other than paper, this really is a must-win game, and this is how we have to look at this game.
"Even then, we still have three very tough games in this competition, two of which are away to Gloucester and Munster, so it's going to be a tough challenge, but one that we are very much looking forward to."
Baxter welcomes back some of his international players for Gloucester's visit to Sandy Park after they sat out a Premiership defeat against Harlequins last Friday.
Gloucester, one point above Exeter in the scrap for European quarter-final places, hand a first start to hooker Jaco Visagie as they look to turn the tables following a league loss against the Chiefs last month.
"It's a new challenge and a new competition," Gloucester head coach Johan Ackermann said.
"We know that they are a leading side domestically and in Europe. They are going to test us on all fronts."
Bath hand James Wilson the number 10 shirt against Recreation Ground visitors Leinster in Pool One on Saturday, with Rhys Priestland and Freddie Burns both out injured.
Bath must win to keep the pressure on Leinster and Toulouse, but the Irish heavyweights arrive with star players like Johnny Sexton, Rob Kearney, Garry Ringrose and Jordan Larmour all starting.
Wasps tackle Toulouse at the Ricoh Arena on Saturday boosted by returning trio Josh Bassett, Tom Cruse and Thomas Young, who partners England pair Brad Shields and Nathan Hughes in the back row.
"Toulouse are a quality team," Wasps rugby director Dai Young said.
"Their off-loading game is second to none, and they have big physical players who can get over the gain-line. We are going to have to be at our best."