Jose Mourinho will not know how damaging this international break has been until his Manchester United players reconvene at for training on Friday.
He has already lost Marouane Fellaini. Phil Jones was sent home from the England camp before he had kicked a ball and Romelu Lukaku missed Belgium's World Cup qualifier against Bosnia on Saturday with an ankle injury.
Elsewhere, Paul Pogba has been in Miami nursing his hamstring injury. Antonio Valencia will be part of the Ecuador team taking on Argentina in Quito on Wednesday and is not expected back until 24 hours before United play Liverpool at Anfield on Saturday.
Mourinho said after the 4-0 win over Crystal Palace nine days ago that he had not thought about Liverpool "even for a minute".
That will not be true anymore. Whether he wants to admit it or not, Liverpool this weekend represents United's biggest game of the season so far. It would be anyway, even if it was not also a test of their title credentials. But if United are going to make a statement at Anfield, they might have to do it without the bulk of their midfield.
Pogba's hamstring problem has put him on the "long-term" absentee list with Zlatan Ibrahimovic and Marcos Rojo. Michael Carrick has missed the last two games through injury while the Belgium Football Association expect Fellaini to miss "a couple of weeks" with the knee ligament strain he suffered against Bosnia.
It leaves Mourinho with just two recognised senior midfielders in Nemanja Matic -- who is set to play for Serbia against Georgia on Monday night -- and Ander Herrera, who was left out of Spain's squad.
It would not usually be a problem. But Mourinho's history in big games away from home suggests he would like to have three central midfielders against Liverpool. In the 0-0 draw at Anfield last season, for example, it was Pogba, Fellaini and Herrera.
If Mourinho is left with just Matic and Herrera against Liverpool, it leaves the United manager with three options. He could throw Daley Blind, Victor Lindelof, Scott McTominay or Axel Tuanzebe into midfield. But of the four, McTominay is the only natural central midfielder and he is 20, with just three senior appearances to his name.
Alternatively, Mourinho could go with just Matic and Herrera. It could even make United a little more adventurous, leaving room for four attacking players rather than three. Henrikh Mkhitaryan, Juan Mata and Marcus Rashford could all start behind Lukaku -- assuming he is fit -- instead of having to leave one out.
There is little chance of seeing Rashford on one side and Anthony Martial on the other. Both are in form but Mourinho has not usually liked to play them together.
Mourinho's third option is, probably, the most likely. Three at the back. Picking three centre-backs and two wing-backs would remove the need for a third midfielder. Mourinho often talks about it as a "defensive" tactic, suggesting Chelsea's title triumph last season with 3-4-3 was built on counterattacking football.
But he trialled it against LA Galaxy during preseason and admitted afterwards his players would keep working on the system "In case during the season we decide to use it."
Without Fellaini, Carrick or Pogba against CSKA Moscow, Mourinho picked a back three with Matic and Herrera in midfield. It worked well enough and United won 4-1. It will have pleased Mourinho that CSKA never got to grips with the system. Martial pushed up high on the left while Mkhitaryan drifted in off the right to leave space for Valencia to get forward.
Liverpool should be better equipped to deal with it, although it will not have escaped Mourinho's attention that playing against Spartak Moscow's back five in the Champions League, Jurgen Klopp's two main weapons, Mohamed Salah and Sadio Mane, found their space more cramped than usual. The game finished 1-1.
Stopping Liverpool will be just as important to Mourinho as hurting them at the other end.
United spent time working on a back three during the summer and Mourinho said: "Maybe we want to do it more times."
Without Pogba and Fellaini at Anfield, it may be that the time has come.