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England will be without the services of Manu Tuilagi against Scotland - and Alex Corbisiero for the entire Six Nations campaign.
Tuilagi has failed to recover from the ankle injury suffered in Leicester's Heineken Cup win over Toulouse earlier this month.
The 21-year-old centre had been given a deadline of Tuesday to prove his fitness, but the Calcutta Cup clash with Scotland has come too soon.
"Manu has run out of time for Scotland and we'll make a call on him for Ireland early next week," said England coach Stuart Lancaster.
Tuilagi was one of England's star performers in November's win over New Zealand, scoring one try and creating two others, and his absence forces Lancaster to form a new centre partnership for the Twickenham clash with the Scots.
Jonathan Joseph and Billy Twelvetrees are the frontrunners to partner Brad Barritt, who can shift from inside to outside centre if required.
Meanwhile, Corbisiero underwent a procedure last week to clear out a "loose body" in his knee, and the initial prognosis from Lancaster was that the London Irish prop would miss the first two games.
However, further surgery has ruled that the 24-year-old out of the entire tournament. He is likely to be sidelined for up to eight weeks.
Sale front-rower Henry Thomas has been called up to replace Corbisiero.