Nathan Hughes and Elliot Daly will miss at least the first half of England's Six Nations title defence through injury.
The Wasps pair limped off in Sunday's Champions Cup rout of La Rochelle at Coventry's Ricoh Arena and although neither player requires surgery, they face extended spells in the treatment room.
A specialist has confirmed that No.8 Hughes will take eight to 10 weeks to recover from his knee problem while the prognosis for Daly's sprained ankle is 10-12 weeks of rehabilitation - potentially ruling the wing out of the entire Six Nations.
England open their campaign against Italy in Rome on February 4 before hosting Wales a week later and travelling to Scotland on February 24 prior to the tournament pausing for a fortnight.
Six Nations 2018
Saturday February 3
Wales vs Scotland, Millennium Stadium, 2:15pm local, Sunday 1:15am AEDT
France vs Ireland, Stade de France, 4:45pm local, Sunday 2:45am AEDT
Sunday February 4
Italy vs England, Stadio Olimpico, 3pm local, Monday 1am AEDT
Saturday February 10
Ireland vs Italy, Aviva Stadium, 2:15om local, Sunday 1:15am AEDT
England vs Wales, Twickenham, 4:45pm local, Sunday 3:45am AEDT
Sunday February 11
Scotland vs France, Murrayfield Stadium, 3pm local, Monday 2am AEDT
Friday February 23
France vs Italy, Stade de France, 8pm local, Saturday 6am AEDT
Saturday February 24
Ireland vs Wales, Aviva Stadium, 2:15pm local, Sunday 1:15am AEDT
Scotland vs England, Murrayfield Stadium, 4:45pm local, Sunday 3:45am AEDT
Saturday March 10
Ireland vs Scotland, Aviva Stadium, 2:15pm local, Sunday 1:15am AEDT
France vs England, Stade de France, 4:45pm local, Sunday 3:45am AEDT
Sunday March 11
Wales vs Italy, Millennium Stadium, 3pm local, Monday 2am AEDT
Saturday March 17
Italy vs Scotland, Stadio Olimpico, 12:30pm local, 10:30pm AEDT
England vs Ireland, Twickenham, 2:45pm local, Sunday 1:45am AEDT
Wales vs France, Millennium Stadium, 5pm local, Sunday 4am AEDT