England's Anthony Watson and Luke Cowan-Dickie were both ruled out of next month's entire Test programme at Twickenham on Tuesday in a double blow for Eddie Jones' men.
No sooner had it been confirmed Cowan-Dickie would be replaced in a 34-strong squad for the Tests against Tonga, Australia and South Africa by Jamie George after suffering an ankle injury in Exeter's win at Wasps last weekend, Watson was sidelined as well.
Bath wing Watson, whose England squad place has been taken by Harlequins' Joe Marchant, ruptured the anterior cruciate ligament in his knee during the west country club's humiliating 71-17 loss to Saracens and he could now miss next year's Six Nations as well.
One consolation for England is that lock-cum-flanker Maro Itoje should be available to face Tonga at Twickenham on November 6 despite the Saracens star sustaining a shoulder injury against Bath.
The 28-year-old Cowan-Dickie established himself as England's first-choice hooker during this year's Six Nations and played in all three Tests for the British and Irish Lions in South Africa.
Watson, whose 56 Tests have yielded 22 tries, started in the first and second Lions internationals against the Springboks, and all three Tests on the 2017 tour to New Zealand. His absence will leave Jonny May, Adam Radwan, Tommy Freeman and Marchant vying for the England wing berths next month.
"We are all feeling Anthony's disappointment right now," said Bath director of rugby Stuart Hooper.
"He is a remarkable athlete who will put as much work into his rehabilitation as he does into his on-field performance. We know Anthony will come back stronger from this and we will support him every step of the way."
Cowan-Dickie's unavailability for next month's internationals means Saracens stalwart George finds himself back in the Red Rose squad just a day after he was one of four senior players omitted by England coach Jones including brothers Billy and Mako Vunipola as well as fly-half George Ford.
Jones insisted Monday there was a need to freshen up his squad in the lead-up to the 2023 Rugby World Cup in France.
"We could have the most experienced side at the World Cup but whether they've got that will to go that extra 10 percent and find that discretionary effort... that's something I'm trying to find out at the moment," the veteran Australian coach said.
George, capped 59 times by his country, and Marchant, who mas just one start in six Test appearances, will join an England squad that will travel to Jersey on Monday for a five-day training camp ahead of the Tonga match.
England play Australia on November 13 before facing South Africa, their conquerors in the 2019 World Cup final in Japan, the following Saturday.