Billy and Mako Vunipola both went off injured in Saracens' 13-3 Champions Cup victory over Glasgow on Sunday, putting their participation in England's autumn internationals in doubt.
The pair were injured in the first half with prop Mako immediately replaced after suffering a calf problem and Billy, who hurt his knee and later his arm, continuing until after the break when he too departed, the latest setback in 18 months marked by several injuries.
Both brothers, who were named in England's training squad for the Autumn series, retreated to the bench, with Mako pictured with his leg in a protective brace and Billy with his arm packed in ice.
The injuries are piling up for England, with lock Joe Launchbury last week ruled out after knee surgery.
Bath full-back Anthony Watson and Exeter forward Sam Simmonds will also miss the games against South Africa, New Zealand, Japan and Australia.
England could ill afford to lose Mako from the front row so soon after Joe Marler announced his international retirement.
Head coach Eddie Jones names his squad for the November games on Thursday Oct. 18.