Wayne Pivac says that Wales will "box on" after seeing a quarter of his original 36-man Guinness Six Nations squad sidelined by injuries or suspension.
Pivac has made five changes for Saturday's Murrayfield appointment with Scotland as George North, Hallam Amos, Johnny Williams, Tomos Williams and Dan Lydiate are all out from the line-up that started against Ireland last weekend.
Scarlets flanker Josh Macleod was selected to make his Test debut as Lydiate's replacement against Scotland, but then ruptured his Achilles tendon in training, while another back-row option – Josh Navidi – is being treated for a neck issue.
Elsewhere, centre Jonathan Davies is continuing his recovery from ankle trouble and wing Josh Adams remains suspended following a breach of Covid-19 protocols.
North had been set for a third-successive start at outside centre on Saturday, winning his 100th Wales cap.
Despite missing the Scotland game, 28-year-old North will still break Australia captain Michael Hooper's record as the youngest player to reach a century of caps for their country if he plays against England on February 27.
Wales head coach Pivac said that North had overcome the problem with his eye suffered during the 21-16 victory over Ireland but was now unavailable because of a foot injury.
With North's fellow centres Johnny Williams and Jonathan Davies also absent, Pivac has turned to Nick Tompkins and Owen Watkin as his midfield partnership at Murrayfield.
Uncapped New Zealand-born Cardiff Blues centre Willis Halaholo, who qualifies for Wales through residency and was only called into Wales' Six Nations squad on Wednesday, is among the replacements.
Centre Williams and Amos are unavailable because of head injuries, while the Ireland fixture also claimed scrum-half Tomos Williams (hamstring) and Lydiate (knee), in addition to North.
Liam Williams returns from a three-match ban to replace Amos, with Gareth Davies taking the number nine shirt and Aaron Wainwright called into the back-row.
On the injuries, Pivac said: "You have just got to box on, you can't dwell on it.
"All coaches will say that one man's misfortune creates an opportunity for somebody else. That is certainly the way we are looking at it.
"It's about getting those boys who are in the team prepared in the best way we can.
"Injuries of any description are not pleasant for the players, and nobody wants them. However, it is part and parcel of the game.
"The most disappointing is probably Josh Macleod, who missed the last camp by getting injured in a club game the day before.
"Then yesterday, to be named in front of his peers and have them celebrate, only to be stretchered off the training field half an hour later is not great for him or any of us.
"We've got about 21 players unavailable from the first Six Nations (last year).
"I haven't gone through the list of injuries to look for patterns, but the medical boys will always do that in due course.
"It is a high number, but I don't know how that compares with other countries."
Pivac summoned Blues trio Halaholo, Lloyd Williams and James Botham – grandson of England cricket great Sir Ian Botham – to his squad as injuries hit, with three times-capped flanker Botham joining Halaholo on the bench.
Experienced scrum-half Rhys Webb and centre Jamie Roberts had been tipped for possible call-ups.
But Pivac added: "I think Rhys has talked about not wanting to be a number three (scrum-half), and Lloyd is a perfect number three for us.
"We had a good long chat around Jamie. He contacted me and I contacted him back, we've had a discussion and he knows exactly where he sits if we need his services."
