Defender Cole has been sidelined with a hamstring problem picked up in Saturday's Premier League draw at Swansea.
John Terry should return to lead the side after completing his four-match domestic racism ban, Juan Mata and David Luiz are expected to shake off knocks that sidelined them at the weekend, but Frank Lampard (calf) is now a major doubt for England's friendly in Sweden next week.
Shakhtar boss Mircea Lucescu has the luxury of a full-strength squad at his disposal for the trip to London, with no injuries or suspensions affecting the Ukrainian side.
Defender Dmytro Chygrynskiy could be awarded a starting spot after missing the first tie between the two clubs last month.
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