England have been struck by an injury crisis less than a fortnight before the Guinness Six Nations with vice-captain Jamie George heading a significant list of withdrawals from Steve Borthwick’s squad.

Influential scrum-half Alex Mitchell is a doubt for the opener against Ireland on February 1 but his likely replacement Jack Van Poortvliet, second row Alex Coles and number eight Alex Dombrandt have joined George in being definitively ruled out.

George suffered a hamstring problem in Saracens’ defeat by Castres on Sunday, continuing a frustrating seven days for the 34-year-old that began when he was demoted as England captain with his club colleague Maro Itoje chosen as his successor.

He was picked on the bench for the European fixture in north London and watched as the in-form Theo Dan, a rival for hooker duties with England and Saracens, scored two tries in an all-action display.

And then having come on as a replacement in the third quarter, he was forced off by his damaged hamstring. His absence will see Dan and Luke Cowan-Dickie compete for the number two jersey, while George could also be unavailable for England’s clash against France on February 8.

“He is a top-class player, a great leader and a fantastic influence around the other players. So we are desperately disappointed for us as a squad and for him,” Borthwick told reporters at the Six Nations media launch in Rome.

“I spoke to him yesterday (Monday), and I got a sense of determination from him down the phone. He is a fast healer and he is going to get back as soon as possible.”

Northampton scrum-half Mitchell sustained a knee problem against Munster on Saturday but could yet feature against Ireland after being taken to the squad’s pre-Championship training camp in Girona to continue his rehabilitation.

A neck problem ruled him out of the entire autumn series and his return is seen as key to hopes of causing an upset in Dublin as Borthwick plans for a demanding start to the Six Nations.

England are hopeful that Mitchell will recover in time to face Ireland and will give him every opportunity to prove his fitness, given his influence on the team as clear first-choice scrum-half.

“Alex should be fit next week. It’s modified training and personal rehabilitation this week,” Borthwick told BBC Sport.

Van Poortvliet was the likely replacement if Mitchell failed to pull through, but he has also pulled out of the 36-man squad that departed for Spain on Tuesday in a significant test of England’s depth at scrum-half.

A costly weekend of European action has also accounted for Coles and Dombrandt, who are struggling with unspecified injuries.

Ben Spencer and Raffi Quirke have been called up as half-back cover, while Curtis Langdon, Arthur Clark and Henry Pollock fill the vacancies created in the pack.

Itoje will take charge of England for the first time on Saturday week but the Lions second row does have experience of the role, having deputised for George when the hooker was replaced in the second half of games last year.

A consistently-high performer and one of the team’s few world-class players, Itoje wants the leadership duties to elevate his game even higher.

“I hope me having this role doesn’t change how I play. I still want to be as aggressive as I can and I still want to have a high output,” he said at the Six Nations launch in Rome.

“In terms of my performance, if anything I just hope to improve in the areas that I’m strong. My job now is to serve the team and serve the fans and look to do justice to the role.

“It’s a huge honour. It’s a massive, massive privilege. Some great players have had this role in the past for England. I hope to follow in their footsteps.

“England have the potential to do well and win against all the teams. We want to fulfil our potential and take a step in the right direction.”