Leyton Orient 3 Carlisle United 1: Callum Guy was stretchered off with a serious-looking injury as Carlisle crashed out of the FA Cup in London.
The midfielder went down in agony in the 14th minute at Brisbane Road and received lengthy treatment to his leg before being carried off.
Carlisle were trailing by then to a Joe Pigott penalty, and despite levelling through Joe Garner, went on to lose the first round tie as subs Aaron Drinan and Ruel Sotiriou struck in the second half for Orient.
The Blues were again short of attacking threat in the capital and can have no complaints about their first round exit at the hands of their League One rivals, in front of 463 travelling fans.
The major concern, though, will be Guy who, the initial signs suggested, will be facing a lengthy lay-off.
He was attended to by both physios and a number of medical staff after going down in severe pain when he turned in pursuit of Orient striker Pigott near the right touchline, appearing to twist his knee.
Dylan McGeouch replaced Guy from the bench as Carlisle weighed up the latest in a serious of injury blows.
Manager Simpson brought in Jack Robinson for the suspended left-back Jack Armer in the only change to last weekend's XI.
Fin Back did not make it after injury so Ben Barclay continued in defence. On the bench, McGeouch returned from injury but Carlisle could not call on loan keeper Jokull Andresson, so Gabe Breeze stepped up.
Paul Huntington was not involved amid his injury comeback and Simpson's squad, depleted by injuries and suspensions, meant the manager only named six substitutes out of a permitted nine.
Orient boss Wellens made two changes with Ed Turns and Shaq Forde coming in for Jordan Graham and Sotiriou.
Carlisle, who had new strength and conditioning coach Adam Kwiecien with the backroom staff for the first time, had to battle early on to contain a bright home side.
Idris El Mizouni was an early threat before United came close via Jon Mellish, whose header from a Guy free-kick was well saved by Sol Brynn.
In general, though, Richie Wellens' side were sharper and on 11 minutes they took the lead, after Sam Lavelle was penalised for a high challenge on Dan Happe following a Tom James corner.
Pigott sent Tomas Holy the wrong way with the penalty.
Three minutes later Guy, after giving chase to Pigott, went down in agony and, after more than five minutes of treatment, was stretchered off, McGeouch taking his place as Carlisle looked for a way back into the game, negotiating a dangerous Ethan Galbraith cross and more Theo Archibald inroads before Dan Butterworth, on the break, saw a shot strike team-mate Garner as Orient survived.
This brought about a better Blues spell as Sean Maguire, ghosting onto a Jordan Gibson pass, sent an overhead kick over the bar before Gibson went close from distance.
Orient, though, could easily have doubled their lead at the start of seven added first-half minutes, but Pigott failed to convert El Mizouni's cross from a great position at the back post.
Butterworth had a powerful shot blocked as United reached half-time in arrears.
Simpson made a change at the break, bringing on Corey Whelan for Butterworth, while home boss Wellens introduced Drinan for Shaq Forde.
That saw Mellish pushed up into midfield as Carlisle looked for a way back into the tie.
And United swiftly got back on terms in the 50th minute.
First, Garner was denied by a Brynn save after good work by Mellish, but after the resulting throw, Barclay crossed from the left and Garner was there to head across Brynn and into the bottom corner.
Owen Moxon then went close as Carlisle tried to continue their fightback, while Orient's James was off target from 25 yards at the other end.
United looked to hit Orient again when Whelan and Gibson combined on the right, the hosts forced into more defending.
Wellens' side, though, gradually plugged some of the gaps and then got themselves back in front on 66 minutes.
Drinan, who started on the right of their attack but then moved centrally, read the flight of a James inswinger from the right and got in front of Whelan to slide it home.
Orient could then have killed United off but Holy saved well as Archibald's low cross picked out Drinan again.
And Carlisle survived another near miss when Garner, rising to head clear a free-kick, headed the ball against his own crossbar.
After Archibald went close for Wellens' side, Simpson introduced Terry Ablade for Maguire, with United again sorely in need of more goal threat.
Yet the home side remained much more dangerous, Drinan denied by Holy from close range, Simpson then sending on Luke Plange and Ryan Edmondson to try and salvage the tie.
Moxon shot wide from 25 yards but Carlisle created little else and then Sotiriou, on for Pigott, ran clear of Whelan in the 90th minute to rifle low past Holy.
The sub could have added a fourth in added time, shooting wide of the near post, with United's cup hopes by now having long fizzled out.
It was Carlisle's first defeat at this stage of the cup since 2014.
Leyton Orient: Brynn, James, Turns, Happe, Cooper (Sweeney 64), Brown, El Mizouni (Pratley 90), Galbraith (Moncur 77), Archibald, Forde (Drinan 46), Pigott (Sotiriou 77). Not used: Howes, Beckles, Pegrum.
Goals: Pigott 11pen, Drinan 66, Sotiriou 90.
Booked: Cooper, Forde, El Mizouni, Happe.
Carlisle United: Holy, Barclay, Robinson, Lavelle, Mellish, Guy (McGeouch 20), Moxon, Butterworth (Whelan 46), Gibson (Plange 83), Maguire (Ablade 77), Garner (Edmondson 83). Not used: Breeze.
Goal: Garner 50.
Booked: Robinson.
Ref: Sebastian Stockbridge.
Crowd: 3,808 (463 United fans).
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