The full-back suffered a hamstring injury during last weekend's Premier League draw with Swansea and Roberto di Matteo, the European champions' manager, said Tuesday that Cole would not be fit in time to face Shakhtar.
As a result the 99-times capped Cole may miss out when England manager Rody Hodgson announces Thursday his squad for next week's friendly away to Sweden.
Injury prevented Cole getting to three figures in an England shirt during the opening World Cup qualifiers against Moldova and Ukraine.
And his Twitter attack on the Football Association's guilty verdict in the racism scandal involving his Chelsea team-mate and friend John Terry may have been a factor in Cole being rested for last month's match with San Marino.
Both Cole and Liverpool midfielder Steven Gerrard won their 99th caps in Poland the following week but the Chelsea man may not now get his 100th until February at the earliest, when England play a friendly against Brazil.
"He has a problem with his hamstring," di Matteo said of Cole. "He shouldn't be too long out, but he won't be able to play tomorrow (Wednesday).
"It's difficult to give exact days. I'm not expecting him to be out for long," the former Chelsea and Italy midfielder added.