Six-time Serie A defending champions Juventus overpowered Sampdoria 3-0 to take a six-point lead over second-placed Napoli, who were held goalless by AC Milan, while Roma and Lazio also played a goalless draw in the capital derby of the Italian football league.
Coast, who came on as a substitute for injured midfielder Miralem Pjanic, set-up the hosts' opening goal for Mandzukic, who crashed home on the volley from Costa's cross from the left.
On the hour-mark, Costa delivered a delightful chipped through ball towards the back post for Howedes to hammer home a header for his first ever goal for the Turin giants, who were coming off a Champions League quarter-final elimination against Real Madrid.
Just 15 minutes later, Khedira fired into the bottom corner after being served the ball on a silver platter from Costa, who completed his hat-trick of assists within half an hour of coming on just before the interval.
"After the substitution, we were able to spread the play more and that was important because the opposition gets up and down the pitch," Juventus chief coach Massimiliano Allegri was quoted as saying by the club's website.
"It was key to win after the Real Madrid game, in which we invested a lot of mental and physical energy. Today we needed to be attentive, technically proficient and intelligent against a team capable of playing good football."
Following the win, Juventus have 84 points, with six rounds of games left. "Six points are not enough. Napoli are still in the race and until it's mathematically certain we have to keep fighting for the title," Allegri said.
In Rome's Olympic Stadium, Roma and Lazio played a 0-0 draw. Roma's Bruno Peres and Eden Dzeko hit the hoodwork as Lazio settled for a point after Stefan Radu was sent off for fouling Cengiz Under.
"We're a bit disappointed about the draw since we went so close towards the end. We've had our fair share of posts and crossbars this season, these are things that sometimes make the difference," Roma coach Eusebio Di Francesco told his club's website.
Lazio and Roma have 61 points each but the former are ahead on a better goal difference.
Earlier in the day, a great save two minutes into the second-half stoppage time by Milan goalkeeper Gianluigi Donnarumma held Napoli to a 0-0 draw, moving the Serie A title a little further from their reach.
Napoli's striker Arkadiusz Milik may regret missing his side's best chance for a win.
Marking his 100th match in Serie A, Donnarumma had one of the best saves of the year in Italy.
Milan are sixth in the table with 53 points -- seven behind cross-town rivals Inter, who also played a 0-0 draw with Atalanta on Saturday.
Meanwhile, Spal put an end to Fiorentina's six-game winning streak with a goalless draw.
Fiorentina are in the seventh position with 51 points, just two points behind Milan, while Spal, after their fifth consecutive draw, remain in the relegation zone with 28 points in 17th place.
Elsewhere in the Serie A, Benevento played to a 2-2 draw against Sassuolo, while Bologna prevailed 2-0 over Hellas Verona.
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