The Manchester City midfielder is now a doubt for his club's trip to West Brom on Saturday, with Santi Cazorla of Arsenal coming on for him after just 13 minutes
The attacking midfielder started alongside Pedro and Cesc Fabregas furthest forward for La Furia Roja, but minutes after teammate Sergio Busquets was clattered by Patrice Evra, Silva looked to be struggling.
After a few moments of attempting to run off the knock, Silva was forced to leave the pitch, clutching his right knee and his hamstring before heading straight for the tunnel at the Vicente Calderon in Madrid, with Arsenal's Santi Cazorla replacing him.
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Following hard on the heels of West Brom is a trip to Amsterdam on Wednesday where they will face Ajax in the Champions League, and after a disappointing draw at home to Borussia Dortmund in matchday 1, City will be desperate to get their first win.