Representative stars David Fifita, Latrell Mitchell and Cameron Murray will all sit on the sidelines this weekend, throwing State of Origin selection into disarray.
Queensland are already missing Jai Arrow and Tom Gilbert for Game II through injury, with Fifita now in doubt after suffering delayed concussion symptoms.
The Titans announced he would miss Thursday night's match against Wests Tigers after he presented with symptoms following last round's clash with South Sydney, which are believed to be from an Origin head knock.
The back-rower underwent a HIA during the opening interstate battle but was cleared to play on and was heavily involved in the Maroons' 26-18 win.
Blues coach Brad Fittler is also under pressure with Mitchell (calf) and Murray (groin) to miss Souths' game against St George Illawarra on Saturday night.
Fullback Mitchell was a late withdrawal from Game I while Murray was part of the losing NSW line-up.
Jason Demetriou confirmed to reporters Mitchell was in major doubt to play in the second Origin in Brisbane on June 21, with the Blues set to name their side on Monday.
Tempering the bad news is the return of Rabbitohs forward Siliva Havili, who was expected to miss most of the season with a serious ankle injury.
Parramatta named Dylan Brown for Monday’s game against Canterbury, with the NRL still considering whether the five-eighth is subject to the no-fault stand-down policy after he was charged with sexual touching.
Manly fullback Tom Trbojevic will be given a chance to prove his fitness for Origin II after the Sea Eagles successfully challenged the NRL’s ruling on his concussion in the series opener.
Trbojevic was taken off for a HIA late in the Adelaide Origin with the NRL’s independent doctor, watching the game from Sydney, deeming the NSW centre's head-knock a category one.
Manly overturned the ruling, clearing and naming him at fullback against the Dolphins on Friday.
"Our chief medical officer Paul Bloomfield agreed that Tom had to be removed from the field but at no point was he diagnosed with concussion," Sea Eagles chief executive Tony Mestrov said in a statement on Tuesday.
"Furthermore, Tom does not have a history of concussion issues.
"Throughout this process, Tom has not been diagnosed with concussion from either NSW doctor Nathan Gibbs and Paul Bloomfield, or independent doctor Chris Levi."
In other team changes, Canberra veteran Jarrod Croker will start at centre for his 300th NRL game while fullback Seb Kris (knee) is also back to face the Warriors, while skipper Elliott Whitehead returns from suspension.
Ali Leiataua will make his NRL debut in the Warriors' centres.
Daniel Tupou will replace suspended Roosters centre Joseph Suaalii's for their clash with Penrith on Saturday night while Jack Cogger will wear the No.7 jumper following Nathan Cleary's hamstring injury.
Melbourne have suffered a blow for their Sunday clash with Cronulla, losing blockbusting centre Justin Olam to concussion with Grant Anderson taking his place.
In the game's final round, the Bulldogs named skipper Reed Mahoney to face Parramatta despite suffering a category two concussion with the club hoping to also overturn the ruling.
