Francesc Fabregas will be out for at least six weeks with a cracked bone in his right fibula.
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It means the Arsenal skipper will miss the rest of the Premier League season and is a serious doubt for the World Cup finals. The midfielder will still be injured when Spain have to announce their provisional squad on May 12.
While the loss of Fabregas may not be quite so damaging for Spain, with the 22-year-old starting only three of his country's World Cup qualifiers, Arsenal will surely find it difficult to challenge for honours at home and in Europe without their talismanic captain.
Fabregas, who had been a doubt for Wednesday's Champions League quarter-final first leg against Barcelona after suffering severe bruising to his knee and leg at Birmingham, sustained the small fracture when fouled by Carles Puyol for the crucial late penalty which earned Arsenal a 2-2 draw.
Although he was able to get up and fire home from the spot he was immediately in discomfort during his celebration.
Fabregas left Emirates Stadium on crutches and had admitted he feared the worst.
He is definitely out of the rest of the Premier League season, and would struggle to make the Champions League final at the Bernabeu on May 22.
An Arsenal statement read: "Following a scan this afternoon, the club can confirm that Cesc Fabregas has suffered a small crack in his right fibula as a result of the collision with Barcelona defender Carles Puyol during Wednesday evening's match.
"As a consequence, Cesc will miss the remainder of the domestic campaign as he will be out of action for at six weeks. Everyone at the club wishes Cesc a full and speedy recovery.''
Arsenal trail Premier League leaders Manchester United by four points, and while they may have favourable fixtures the loss of Fabregas could be a fatal blow.
The Gunners have received good news on William Gallas, who will not be out for the rest of the campaign. Both Gallas and Andrei Arshavin will be out for three weeks.
"At the moment, we are like an army who have come back from a big battle,'' he said on the club's website. "We have some bruises but we need to recover and then go to the next battle. Who will be available for the next one? I have to wait 24 hours more.
"William had a recurrence of his calf strain. That is at least three weeks. The next one is Arshavin - calf strain, three weeks.''
They are not the only injuries to have hit the Gunners, with both Gael Clichy and Denilson doubtful to face Wolves on Saturday.
He added: "Gael Clichy is struggling with a back problem. He might need a breather as well. I don't know yet, we will assess that tomorrow. Denilson has a groin problem, we will assess that too.
"The first three (Fabregas, Arshavin and Gallas) are out, Clichy and Denilson are 'possibles' to play at the weekend.''
However, Wenger insisted Arsenal had the strength and depth to overcome the injuries.
"We have (Mikael) Silvestre and (Sol) Campbell available,'' he said. "Then of course there is (Tomas) Rosicky and Eduardo. (Carlos) Vela is coming back too.''