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England head coach Eddie Jones has been dealt two more injury blows ahead of this season's RBS 6 Nations Championship.
Leicester forward Ed Slater and Bath lock Dave Attwood both face lengthy spells on the sidelines.
Tigers skipper Slater, who can play in the second-row and back-row, will be out for up to two months because of a knee injury, while Attwood has undergone neck surgery and is unlikely to play again before late March.
England kick off their Six Nations campaign against Scotland at Murrayfield on February 6, with Jones set to name the first elite player squad of his reign next week.
Slater and Attwood join England's ever-lengthening list of injuries, with props Kieran Brookes and Alex Corbisiero, back-row Dave Ewers, wing Jonny May and centres Henry Slade and Manu Tuilagi set to miss all, or part, of the Six Nations.
Leicster centre Tuilagi will not be involved in next Saturday's east midlands derby against Northampton at Welford Road as he nears the end of his recovery from a long-term groin injury that has prevented him from playing since October 2014.
The absence of any A-league fixtures until March means that the earliest date for Tuilagi's return will be the Champions Cup clash with Benetton Treviso on Saturday week.
"Manu will play when he's ready to play," Leicester rugby director Richard Cockerill said.
"He's very close to playing, we just have to make sure he's right."
Slater sustained medial ligament damage when making a tackle during the first-half of Saturday's Aviva Premiership defeat at Saracens, and Bath head coach Mike Ford confirmed Attwood's lay-off after the player had surgery on Tuesday.
"Dave will be out for a while," Ford told the Bath Chronicle. "He's trapped a nerve and got a bulging disc in his back.
"His Six Nations chances are gone. It will be anywhere between 10 and 12 weeks until he plays again."
While the Tigers are optimistic that Slater will not require surgery, he will miss at least the first half of the Six Nations and, given his position on the fringes of the team, the injury has denied him precious opportunities to impress Jones.
Slater was touted by some pundits as a possible Red Rose captain despite having yet to make his Test debut, but an injury update issued by Cockerill has ended any chance of that unlikely scenario unfolding.
"Ed has medial ligament damage. It's not too bad, but it will probably be six to eight weeks. It's not ideal or what we needed," Cockerill added.
"Hopefully, he won't need surgery, but we will only be able to make a decision on that once the swelling has gone down.
"Thankfully, the injury is not to the same knee that caused his problems last season. It's just bad luck rather than because of ongoing problems."
Attwood, who has won 22 caps but was overlooked for England's World Cup squad by Jones' predecessor Stuart Lancaster earlier this season, and Slater were both expected to be named in Jones' squad.
Although Wasps' Joe Launchbury, in-form Saracens lock George Kruis and Northampton forward Courtney Lawes would almost certainly be Jones' leading second-row options, Attwood and Slater enhanced that strength in depth.