Manchester United manager Jose Mourinho has confirmed Phil Jones and Chris Smalling sustained "long-term injuries" on England duty.
Saturday's home clash with West Brom is the first of nine matches for United in April as they juggle domestic and European exertions.
Zlatan Ibrahimovic and Ander Herrera miss this weekend's match through suspension and a hamstring issue rules Paul Pogba out, but it is setbacks to Jones and Smalling that could prove most costly in the long run.
Jones withdrew from the England squad last week due to a toe injury that appeared to be sustained in a training ground duel with team-mate Smalling, who days later left the squad with fitness problems of his own.
The defender has been spotted with his right leg in a brace and Mourinho has revealed the pair face a substantial chunk of time on the sidelines.
Asked how long he expects to be without Jones and Smalling, the United boss said: "I don't know, I don't know.
"I know that Zlatan and Herrera have the last match ban, so it's easy to say they will be available after the match.
"I think clearly the two English boys they are long-term injuries and Pogba I have no idea. I don't know."