Nathan Hughes and Elliot Daly will miss at least the first half of England's NatWest Six Nations title defence through injury.
The Wasps pair limped off in Sunday's Champions Cup rout of La Rochelle at the Ricoh Arena and although neither player requires surgery, they face extended spells in the treatment room.
A specialist has confirmed that number eight 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.
Adding to Wasps' woes is the news that playmaker Jimmy Gopperth will also miss 10 to 12 weeks of the season due to a knee injury.
Director of rugby Dai Young revealed on Tuesday that following scans the trio would be ruled out for at least a month and while none of them needs an operation, they are unavailable until February at the earliest.
Hughes and Gopperth have MCL injuries and Daly has been struck down by a high ankle sprain.
They will sit out Aviva Premiership fixtures against Gloucester, Bath, Saracens, London Irish and Leicester and the climatic rounds of the Champions Cup group phase against Ulster and Harlequins.
Hughes and Daly have become influential figures for England and Eddie Jones must plan for their return at some stage later in the Six Nations.
The appointment with Scotland on February 24 is the earliest possible match for Hughes' comeback, while the penultimate round against France on March 10 is the soonest Daly can be considered even if there are no delays in his recovery.
The absence of Hughes is mitigated by Billy Vunipola's imminent return from knee surgery and while England are well stocked for wings, Jones will mourn the loss of a player such as Daly.