England coach Stuart Lancaster is optimistic both Brad Barritt and Geoff Parling will be fit for the Six Nations opener against Wales on 6 February.
Barritt and Parling are both nursing medial knee ligament strains but Lancaster is "very confident" the pair will be available for the Championship opener.
Tom Wood (ankle) and Kyle Eastmond (shoulder) are also major injury doubts for England, who are already without Joe Launchbury, Ben Foden, Ben Morgan, Owen Farrell and Ed Slater for the entire tournament.
"We lost one or two at the weekend. The current situation is that Geoff Parling and Brad Barritt are in pretty good shape really," said Lancaster. "We don't anticipate the injuries to be any more than another couple of weeks. We'll see how they go over the next 24 hours but we're pretty optimistic.
"Tom Wood and Kyle Eastmond have obviously got further assessments which will take place over the next 24 hours and we'll have a bit more information after those assessments.
"The clock is ticking for the Wales game but I wouldn't rule them out of the Italy game yet. Realistically we'll train Sunday and Monday and you need all the players who are going to be considered for the Wales game to be training then.
"If that comes too soon for rehab we'll try and get them fit to start training the week of the Italy game. That applies to all four really.
"I am very confident Brad and Geoff will be fit sooner rather than later. Tom has made good progress and Kyle we'll have to wait to see what the specialist says."