England and Bath duo Jonathan Joseph and Anthony Watson have been ruled out of the November international series, delivering another blow to Eddie Jones' under-pressure side.
Winger Watson has failed to recover from a ruptured Achilles tendon suffered in England's Six Nations defeat to Ireland in March while centre Joseph twisted his ankle against Saracens in April.
Bath director of rugby Todd Blackadder said Watson had undergone a second surgery after the first was unsuccessful and is now a doubt for the 2019 Six Nations.
"The initial surgery didn't take basically, [he needed] another tear to have surgery again. He's had to start afresh and it was done about a month ago," Blackadder told reporters.
"JJ [Joseph] is still on track. He'll be somewhere around Christmas time... It's hard to put a timeline on these things."
Blackadder's revelation provides yet more heartache for England head coach Eddie Jones, who is in desperate need of results when his side take on South Africa, New Zealand, Japan and Australia at Twickenham.
The record-equalling winning streak which led England to back-to-back Six Nations crowns in 2016 and 2017 is now a distant memory after a dismal 2018 saw them surrender the title with defeats to Scotland, France and Ireland.
England were then beaten 2-1 in the summer series in South Africa with Joseph and Watson -- who have scored 32 tries between them in 73 appearances -- among a raft of absences due to injury.
Another who missed out was Bath prop Beno Obano who was ruled out for 12 months with ligament and hamstring injuries suffered during an England training camp.
That prompted a public spat between Bath owner Bruce Craig and Jones, who accused Craig of being like "the Donald Trump of rugby". Jones has since apologised.
Blackadder also moved to alleviate some of that tension, saying he hoped to work more closely with the England set-up to ensure players' health.
"There will be lessons learned on both sides on how we get the best out of all our players," he said.
"Hopefully common sense will prevail and we send players [to England] in the best possible nick they can be and we just hope that is reciprocated."