Ander Herrera will be out for "weeks", Manchester United have announced on Tuesday, with the midfielder having suffered fractured ribs in last weekend's 2-1 victory over West Ham.
The news comes as a major blow to Louis van Gaal's much-changed side, with the summer signing having been a real positive in recent weeks. Against the Hammers in particular, his partnership with Rafael on the right of the United lineup had appeared to be beginning to come to fruition.
What is clear is that his absence will leave a real void, despite the Spaniard only having featured four times for the Red Devils. As part of the midfield "rhombus" or diamond, it is his more defensive-minded and energetic presence that has allowed Angel di Maria so much freedom to push forward on the other side. For all United's issues this season, Herrera has been a real positive.
Van Gaal will be reluctant to switch formation again so quickly, with his side having begun to win games and will instead look to find a direct replacement for the right-flank role. With Anderson left-footed and Jesse Lingard injured, his only real options for the berth are Darren Fletcher and Antonio Valencia. One will have to step up and fill in for the absent Spaniard.
Wayne Rooney's absence also adds a further complication given his willingness to drop deep and support the midfield. For all the positives Juan Mata brings to the side, he is less industrious than his colleague and that will add to the pressure on Daley Blind and Herrera's replacement—particularly with games against Everton and Chelsea on the horizon.
For bigger games this season, it would be no surprise to see a back-three redeployed if the club can muster enough fit and available defenders. Yet, given that both sides mentioned as coming opponents operate with a sole centre-forward, it should be considered an unlikely change.
In Rooney's absence, logic would suggest that, as club vice-captain, Fletcher will be called upon to start in Herrera's place. The Scot, like United, had a promising pre-season but endured a tough start to the campaign. He will, though, benefit from the improved quality of those now around him.
He is also well-suited to the demands of the right centre-midfield position. Fletcher has few qualms with hard work and can drift wide if necessary given that he began his career as a right midfielder.
His job, therefore, will be to ensure that a defensive balance is struck that allows the likes of Di Maria, Mata and his team's strikers attacking freedom. With Rafael pushing forward outside him, he also need not be quite as adventurous as Herrera given the quality of opponent United will soon face.
It is a crucially important season for Fletcher's United career given his recent return from long-standing injury concerns. He must prove that he is consistently able to perform at the level the club require or Van Gaal will not hesitate to allow him to move elsewhere next summer. The month ahead will be a major opportunity in that respect.
The club's support will back his inclusion, for Fletcher's desire and commitment is valued by the Red Devils' faithful. United are also currently in real need of leaders on the pitch and the Scot is a well-respected figure in the dressing room, besides his vocal nature on the pitch. If he can perform the role required, his presence could be a real boost as pressure rises in games ahead.
However, that "if" remains.
Likewise, Valencia's future at United is also up in the air and it could be that it is in the vacant role that his future lies, but he will likely need to wait longer for his opportunity. Less willing to take opponents on down the flank than in his earlier years, he undoubtedly still has the stamina and intelligence to play the tucked inside role.
However, for the Ecuadorian, it is a question of whether his ability in retaining the ball can meet his boss' exacting standards. Thus far, despite early faith, he has disappointed under Van Gaal.
October will be a defining month for United's season. Given they are at home to Everton and Chelsea, with an away trip to West Brom sandwiched in between, they cannot afford less than six or seven points. Any lower total would be a major blow to their hopes of a top four finish given that November then holds visits to Manchester City and Arsenal.
If Van Gaal's side want to really make a statement of intent, this is the month to do so. However, they will need to approach that challenge without Rooney and, as of today's announcement, without Herrera also. That is, of course, before considering the side's ongoing defensive injury concerns.
More than Rooney's absence, the loss of Herrera is a blow they could have done without, but it is now up to Valencia or, most likely, Fletcher to step up and prove their worth. The duo's United careers are on the line this season and they will get few such opportunities of a run in the side given the club's relative lack of fixtures this year.
October, then, will be a big month not just for the ambitions of both the club but also many of its individuals. United aspire to return to the top quickly and the coming weeks will provide a major indication of just how long that process will take. Whether Fletcher or Valencia will remain part of that process in the long term will doubtless also come under heavy scrutiny.