Wayne Rooney, Anthony Martial, Michael Carrick, Marouane Fellaini and Antonio Valencia were all ruled out of Saturday's clash with Watford with various injuries.
Van Gaal said he was hopeful Rooney and Martial could return against PSV Eindhoven on Wednesday.
But he did admit his surprise at Fellaini still being on the sidelines.
He said: "I think that everybody knows Michael Carrick and Anthony Martial are injured, but also injured is Fellaini.
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Michael Carrick was stretchered off for England last Friday
"That’s a surprise because I thought he was recovered after the international break, but still he is injured.
"And that’s a big blow because Rooney is ill, so we have a big problem, I think."
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